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α1-Adrenergic Receptors: Insights into Potential Therapeutic Opportunities for COVID-19, Heart Failure, and Alzheimer’s Disease

The Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195, USA
Int. J. Mol. Sci. 2023, 24(4), 4188;
Original submission received: 31 January 2023 / Revised: 6 February 2023 / Accepted: 8 February 2023 / Published: 20 February 2023
(This article belongs to the Special Issue G Protein-Coupled Receptors: Signaling and Regulation)


α1-Adrenergic receptors (ARs) are members of the G-Protein Coupled Receptor superfamily and with other related receptors (β and α2), they are involved in regulating the sympathetic nervous system through binding and activation by norepinephrine and epinephrine. Traditionally, α1-AR antagonists were first used as anti-hypertensives, as α1-AR activation increases vasoconstriction, but they are not a first-line use at present. The current usage of α1-AR antagonists increases urinary flow in benign prostatic hyperplasia. α1-AR agonists are used in septic shock, but the increased blood pressure response limits use for other conditions. However, with the advent of genetic-based animal models of the subtypes, drug design of highly selective ligands, scientists have discovered potentially newer uses for both agonists and antagonists of the α1-AR. In this review, we highlight newer treatment potential for α1A-AR agonists (heart failure, ischemia, and Alzheimer’s disease) and non-selective α1-AR antagonists (COVID-19/SARS, Parkinson’s disease, and posttraumatic stress disorder). While the studies reviewed here are still preclinical in cell lines and rodent disease models or have undergone initial clinical trials, potential therapeutics discussed here should not be used for non-approved conditions.

1. Introduction

Receptors that are activated by the adrenaline-type catecholamines, epinephrine (Epi) and norepinephrine (NE), are called adrenergic receptors (ARs). They belong to the G-Protein Coupled Receptor (GPCR) superfamily, which are receptors that transduce their intracellular signals through G-proteins. According to their physiological effects on the body, they were initially assigned as classifications α and β [1]. α-ARs were later further subdivided into α1- and α2-ARs, after noting that some functions were distinctively different between the two families. Upon further tissue characterization and molecular cloning, α1-ARs were further subdivided into the α1A-, α1B-AR, and α1D-AR subtypes based upon the subsequent cloning of the receptors [2,3,4]. The α1C-AR is missing from the current α1-AR nomenclature due to misclassification and incomplete pharmacological characterization of the α1A-AR subtype [4,5].

2. Pharmacology

α1A-ARs can be pharmacologically distinguished in tissues and cell lines from the α1B-AR subtype based upon a 10–100-fold higher binding affinity for several ligands that are commercially available [6,7] (Table 1). The α1D-ARs share more pharmacological similar and genetic homology with the α1A- than the α1B-AR but buspirone analogs (i.e., BMY7378) have been developed that have at least a 10-fold higher binding affinity for the α1D-AR over the α1A-AR subtype [8,9] and 100-fold selectivity compared with the α1B-AR subtype. α1B-AR does not have sufficiently selective ligands developed yet, but with the recent crystal structure of the α1B-AR bound with the antagonist cyclazosin [10], chiral analogs are being developed [11].

3. Signal Transduction

While the nine subtypes (α1A, α1B, α1D, α2A, α2B, α2C, α1, α2, and α3) bind Epi and NE with comparative affinities, the three different families couple to different G-proteins and effector pathways that allow specificity in function. While all GPCRs can couple to multiple G-proteins, they strongly couple to only a few. α-ARs couple more efficiently to Gαs, which stimulates adenylate cyclase and increases cAMP levels. α2-ARs are transduced by Gαi, which inhibits the production of cAMP. α1-ARs couple to Gαq to activate phospholipase C that causes the hydrolysis of membrane-bound phosphatidylinositol 4,5-bisphosphate to release inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 binds to IP3 receptors located on the endoplasmic reticulum which causes the release of calcium. DAG activates protein kinase C (PKC), an enzymatic effector that can phosphorylate many proteins to amplify signals downstream in the signaling cascade. α1-ARs, as in all GPCRs, can signal directly or through cross-talk to couple to many other signaling pathways, both G-protein-dependent and independent, and through spatio-temporal as well as biased-agonistic mechanisms [13,14,15,16,17,18]

4. General Physiology

Blood Pressure

The best described function of the α1-AR activation is to increase blood pressure via the contraction of the vasculature which highly expresses α1-ARs in the smooth muscle layer [19]. α1-ARs regulate blood pressure through IP-mediated increased calcium release, causing the contraction of the vascular smooth muscle by activating myosin light chain kinase and actin/myosin cross-bridge formation [20], and may involve several different signaling pathways involving PKC, PI3K, Rho Kinase, and MAPK [21,22]. Transgenic and KO mice have been developed for all three α1-AR subtypes, using receptors that are WT or contain constitutively-active mutations, some have cardiac-specific promoters and others that are systemically or conditionally expressed [23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38]. These mouse models provided various insights into the physiological differences between the subtypes. Using these mouse models, all of the α1-AR subtypes have been reported to affect phenylephrine-induced blood pressure [24,33,39] but only the α1D-AR KO decreased resting blood pressure [39,40].

5. α1A-AR Agonists

5.1. Currently Approved Uses

α1-AR agonists are not commonly prescribed because of the potential to raise blood pressure but are approved for the treatment of vasodilatory shock, hypotension, hypoperfusion, septic and refractory shock, and cardiopulmonary arrest. Approximately 7% of critically ill patients develop refractory shock causing a 50% short-term mortality rate [41]. Vasopressor agents used to maintain blood pressure and preserve tissue perfusion during shock are methoxamine (discontinued in the US) or norepinephrine/epinephrine [42,43]. α1-AR agonists such as phenylephrine have been used in procedures to dilate the iris [44]. Phenylephrine, naphazoline, and oxymetazoline are also used in nasal decongestion and edema [45,46] and the facial erythema associated with rosacea [47,48].

5.2. Heart Failure and Cardioprotection

The human heart contains both the α1A and α1B-AR subtypes with a total density of approximately 11–60 fmoles [49,50,51]. The α1D-AR may be present in the myocyte but at very low levels [52,53]. The current hypothesis is that selective α1A-AR agonists may be a potential treatment in heart failure [54,55], since chronic α1B-AR stimulation, as evidenced through transgenic mouse models, appears to be maladaptive by inducing dilated cardiomyopathy [29] or heart failure [37]. While α-AR blockers are a current treatment option for heart failure, using α1A-AR selective agonists may provide potentially greater benefits such as preventing dementia [56], improving metabolic function and glucose tolerance [56,57,58], increasing lifespan with reduce cancer risk [59,60] and reducing inflammation and cataracts [58,61].
The preclinical evidence that the α1A-AR subtype is cardioprotective and could be therapeutic for heart failure is abundant. Transgenic mice with heart-targeted α1A-AR overexpression were protected from dysfunction due to myocardial infarction [26], pressure-overload [25], or imparted ischemic preconditioning [34,62]. Correspondingly, α1A-AR KO mice had induced greater heart injury after myocardial infarction [55]. The α1A-AR selective agonists, A61603 or dabuzalgron, prevented damage from the cardiotoxic agent, doxorubicin [63,64,65] and increased contraction during heart failure [66]. Removing load by mechanical assist devices in failing human hearts improved function and re-distributed α1A-ARs from the peri- to intra-myocyte location [67]. However, there are currently no clinical trials underway, most likely due to the potential to increase blood pressure and the risk of stroke. The use of positive allosteric modulators (PAMs) for the α1A-AR developed to treat Alzheimer’s disease [12] are currently in preclinical studies in mice and to assess potential benefits in heart failure.
The ability of the α1A- and not the α1B-AR to cardioprotect may be due to several mechanisms. One is the ability of the α1A-AR to increase inotropy [30,68,69]. Another mechanism may be due to increased glucose uptake and oxidation in the heart [70] as glucose oxidation has been shown to repair heart damage after ischemia or heart failure [71,72,73,74,75,76]. Transgenic α1A- but not α1B-AR mice increased glucose uptake into the heart and only the α1A-AR KO mice displayed decreased glucose uptake into the heart [57]. Heart failure has been described as a metabolic disease of energy starvation [77] and so any therapeutic that can increase ATP production may improve heart function.

5.3. Cognition and Memory

α1-ARs have long been associated with learning and memory functions [7]. α1-AR agonists promoted while α1-AR antagonists blocked long-term potentiation (LTP, a mechanism of memory formation) in the rat CA1 hippocampus [78], neocortex [79], and may coordinate with β-AR signaling [80,81,82,83]. α1A-AR systemically overexpressing transgenic mice increased synaptic plasticity, LTP, and performance in a battery of cognitive tests of spatial memory, while α1A-AR KO mice performed poorly [60]. α1B-AR KO mice had impaired spatial learning to novelty and exploration [84], and a decrease in memory consolidation and fear-motivated exploration [85]. While α1D-AR KO mice did not show deficits in spatial learning [86], they did show deficits in working memory and attention [87]. While all three α1-AR subtypes are localized in the brain and expressed in overlapping domains, the α1A-AR subtype appears to have greater expression in cognitive areas such as the hippocampus and amygdala, as well as particular areas of the cortex and neurogenic regions involved in learning and memory [88,89]. The α1A-AR selective agonist cirazoline increased cognition and BrdU incorporation in normal adult mice, while the α1A-AR overexpressing transgenic mice had increased BrdU incorporation in both the subventricular and subgranular neurogenic regions [88].
In order to develop suitable therapeutic α1A-AR agonists to treat heart failure, cardiac ischemia, or Alzheimer’s disease, PAMs with sufficient signal bias would need to be developed that could regulate heart or brain function without effects on the vascular system to increase blood pressure. PAMs will increase a receptor activation and function but in such a way that it does not bind to the same site as the endogenous agonist (i.e., orthosteric), such as NE [90]. Allosteric modulators result in decreased side effects and have greater selectivity by binding to non-conserved regions of the receptor resulting in conformational bias that can alter the receptor’s signaling pathways. There are now many GPCR allosteric modulators in clinical trials [91]. Another issue is the poor brain penetration of most of the current α1-AR agonists which limit their use in neurological conditions. The first PAM at the α1-ARs with high selectivity for the α1A-AR subtype has been developed [12] that can cross the blood–brain barrier sufficiently enough to improve cognitive functions and modify disease in Alzheimer’s disease mouse models without increased blood pressure. This drug (i.e., Cmpd-3, Table 1) only activates the NE-bound receptor and can potentiate cAMP signaling without effects on IP-signaling. IP-signaling and the resulting calcium release causes the increase in blood pressure. However, NE-mediated cAMP signaling in the brain regulates learning and memory [92,93,94,95,96,97]. This drug is currently in preclinical studies to treat heart failure.

6. α1-AR Antagonists

6.1. Currently Approved Uses

As in the vascular system, α1-AR antagonists affect the contraction of smooth muscle in several organ systems. α1-AR blockage results in the relaxation of smooth muscle in the prostate and ureter to increase urinary flow [98,99,100]. Since the 1980s and 1990s, α1-AR antagonists are frequently used medications in the management of benign prostatic hyperplasia (BPH), kidney stones, and in therapy-resistant arterial hypertension, two conditions frequently found in older adults. As a powerful anti-hypertensive, α1-AR antagonists are not recommended as a first-line treatment [101,102] as they are counter indicative for those with heart disease. While α1-AR antagonists are effective in the relief of urinary symptoms and improve the quality of life in BPH, they appear less effective in preventing disease progression [103,104]. α1-AR blockers are also used to treat pheochromocytoma, a rare condition where a tumor forms on the adrenal gland or other paraganglia to cause excessive catecholamine release and severe hypertension. The tumor is excised immediately under the use of an α1-AR blocker to reduce hemodynamic instability, morbidity and mortality [105]. General counterindications for α1-AR antagonists will be discussed at the end of this article.

6.2. COVID-19/SARS

Coronavirus disease 2019 (COVID-19) and the causative agent, severe acute respiratory syndrome coronavirus 2 (SARS), can elicit a vigorous systemic immune response (i.e., hyperinflammation) in the lungs as well as multiple organs, resulting in heart and kidney failure, liver damage, precipitating severe illness, and increased mortality [106]. Recent evidence suggests that some patients with COVID-19 develop a cytokine storm syndrome that is associated with increased release of pro-inflammatory cytokines, disease severity, and poor clinical outcomes [107].
Beyond their role in neurotransmission, cardiovascular, and the stress response, α1-ARs have been shown to modulate the immune system [108,109], innate immunity [110], and inflammatory damage by increasing cytokine production in immune cells [111,112]. α1-ARs have been identified on a wide variety of immune cells. Identification of immune cells using flow cytometry depends upon highly avid antibodies whose specificity are questioned for the current commercially available antibodies for the α1-ARs and many other GPCRs [113]. However, many studies have utilized mRNA expression and ligand binding analysis. Human neutrophils contain the mRNA for all three α1-AR subtypes [114]. Monocytes contain the mRNA for the α1B- and α1D-ARs [112,115,116]. NK killer cells, leukocytes [117,118,119], and lymphocytes, including human peripheral blood lymphocytes [120,121], also contain α1-ARs but the subtypes are not clearly defined.

6.2.1. α1-AR Antagonists May Protect against Severe COVID-19

Several studies indicate that α1-AR antagonists may reduce morbidity and mortality in patients at risk for hyperinflammation and cytokine storm that is often associated with COVID-19 and other conditions that result in severe respiratory tract conditions. Blockade of α1-AR function with prazosin prevents cytokine storm following pro-inflammatory conditions and increases survival in preclinical studies [122]. A retrospective analysis in two large cohorts of patients with acute respiratory distress (n = 18,547) and three cohorts with pneumonia (n = 400,907) found that patients exposed to α1-AR antagonists had a significantly lower risk (34%) for mechanical ventilation and death [123]. Similar results were obtained in a subsequent retrospective analysis on US veterans [124] and another large cohort study of influenza or pneumonia patients in Denmark [125]. These studies led to a clinical trial to test whether prazosin can prevent the cytokine storm syndrome [126] caused by COVID-19 (, accessed on 7 February 2023) but this trial is currently halted due to lack of recruitment. These results extend circumstantial findings that prazosin may be an early preemptive therapy in COVID-19 and may prevent the cytokine storm and severe complications due to hyperinflammation.

6.2.2. α1-AR Antagonists May Not Prevent COVID-19 Infection

The protective effects of α1-AR blockers against COVID-19 were recently challenged in a study using meta-analysis of millions of patients prescribed α1-AR blockers (alfuzosin, doxazosin, prazosin, silodosin, tamsulosin, and terazosin), compared to alternative medications (dutasteride, finasteride, and 5-α-reductase inhibitors) or tadalafil (PDE5 inhibitor) to treat BPH. This study found no reduction in the risk of COVID-19 infection due to the sustained use of α1-AR blockers [127]. The negative results are unlikely due to the comparison to non-α1-AR blocker treatments for BPH as the study of Thomsen et al. [125] also included non-users (normal controls). However, this study did find significant but not large differences on the ability of α1-AR blockers to confer protective benefits against death and ICU admission due to COVID-19.
The study of Nishimura et al. [127] suggested that previous positive results from clinical trials had systematic biases from residual confounding [128,129]. For example, patients with severe asthma are more likely to be prescribed α-agonists and to die from their asthma than patients with less severe disease but not receiving treatment. Therefore, such confounding would make α-agonists appear they were associated with asthma mortality. However, all epidemiology studies that utilize user vs. non-user comparisons from databases are prone to systematic biases from residual confounding. The study of Nishimura et al. [127] used a database of older male patients that are at higher-risk for COVID-19 and for developing severe COVID-19 compared to the general population, and then analyzed the risks of developing COVID-19, being hospitalized, or hospitalizations that also require intensive services requiring ventilation or oxygenation. The study of Thomsen et al. [125] and others, while also analyzing older men, used a database of high-risk patients already hospitalized with hyperinflammation or cytokine storm (pneumonia, severe COVID, and influenza) and measured α1-AR blocker effects on more severe outcomes (ICU, mortality). Therefore, one interpretation is that α1-AR blockers do confer protection, but the amount of pre-emptive protection is not that significant for use in the general population but only for a subset of severely ill patients once the cytokine storm has developed, and then used to reduce mortality. All of these studies have limitations in that they measured outcomes on men who are more likely to be prescribed α1-AR blockers due to BPH and may not reflect possible outcomes for women. Nevertheless, these results suggest the need for further clinical trials to include women and whether α1-AR blockers first ameliorates the severe symptoms of lower respiratory tract infection-associated hyperinflammation and the risk of death.

6.2.3. The Case for Anti-Hyperinflammation as a Direct α1-AR Mediated Effect

There is precedent in preclinical studies for the ability of α1-AR blockers to reduce hyperinflammation. Prazosin prevents cerebral infarction by inhibition of the inflammatory cascade [130]. One mechanism that α1-ARs may use to combat hyperinflammation is through their association with chemokine receptors. Chemokines are a group within the cytokine family whose general function is to induce cell migration and are potential therapeutic targets in numerous inflammatory diseases, such as COVID-19. Several chemokine genes have been associated with disease severity and susceptibility to infection with COVID-19 [131]. At least 20 members of the human chemokine receptor family heterodimerize with the α1B or α1D-AR subtypes and inhibited their function and were detectable in human monocytes [118]. The CXCR2 has been reported to heterodimerize with the α1A-AR in prostatic smooth muscle [132]. Many GPCRs can form homo- and hetero-oligomers, which is thought to alter their pharmacological behavior and function and may play a role in pathophysiology [133,134,135]. Another mechanism that is described is through catecholamine excess [136]. In animal studies, the blockade of catecholamine synthesis (and indirect blockage of α1-ARs) reduced cytokine release and protected mice against COVID-19 lethal complications [122]. Furthermore, autoantibodies against GPCRs, including the α1-AR, were observed in patients after SARS infection and suggested to cause impaired blood flow, the formation of microclots, and autoimmune dysfunction contributing to long-COVID symptoms [137,138]. These results suggest a direct effect of α1-AR antagonists in blocking α1-AR mediated adverse effects in hyperinflammation.

6.2.4. The Case for Non-α1-AR Mediated Effects of Quinazoline Antagonists: PGK1

It is possible that the protective anti-inflammatory effects of prazosin, doxazosin and terazosin may be non-α1-AR mediated through activation of phosphoglycerate kinase (PGK1)-mediated ATP production. Terazosin and its related “osins” are postulated to mediate protective mechanisms by binding adjacent to the ADP-ATP site of PKG1 and facilitating its activation. PGK1 is the first enzyme in glycolysis where ADP enters the cleft of the active site and is converted into ATP and shown to inhibit apoptosis [139,140]. Terazosin increases the release of ATP by competing for the same binding site, re-exposing the binding pocket, thereby exerting an agonistic effect [140]. PKG1 binding and activation has also been demonstrated in related α1-AR antagonists that contain quinazoline motifs, such as alfuzosin, prazosin, and doxazosin [140]. PGK1 activation may improve cellular functions in disorders with an established energy deficit, common with critically ill patients [141] and COVID-19 patients [142,143]. Terazosin was shown to increase PGK1 activity and glycolysis in motor neuron models of amyotrophic lateral sclerosis (ALS), which correlated with protection and survival [144]. The effects of prazosin-like compounds appear directed at the quinazoline structural motif, as tamulosin, also an α1-AR blocker but with some selectivity for the α1A-AR [145], does not appear to mediate anti-inflammatory effects, does not contain the quinazoline motif, and does not interact with PGK1 [139,146]. Furthermore, an analysis of the Truven database and Danish nationwide health registries demonstrated that individuals treated with terazosin, alfuzosin, or doxazosin showed lower rates of Parkinson’s disease (PD) and PD-related diagnoses when compared with patients treated with tamsulosin [147]. Therefore, quinazoline-based antagonists of the α1-ARs may confer therapeutic levels of protection against inflammation and morbidity through non-α1-AR -mediated effects of increasing glucose metabolism by binding to the active site of PGK1.
While the above protective effects of PGK1 appear to be metabolic, α1-AR quinazolines (i.e., not tamsulosin) have also been shown in several studies to induce apoptosis in different cell lines and in vivo through non-α1-AR mechanisms [148,149,150]. Pyroptosis, a proinflammatory form of apoptosis, acts as a host defense mechanism against infections. Pyroptosis decreases the replicative ability of viruses by inducing the apoptosis of infected cells and exposing the virus to extracellular immune defenses. Several therapeutics that target inflammasomes, caspases, or cytokines are in clinical trials to evaluate efficacy in mitigating the severe outcomes of COVID-19 [151]. Therefore, the ability to reduce severity of COVID-19 outcomes by prazosin and other quinazolines may be due to their ability to increase apoptosis, improve energy deficit, or both.
These two different but protective mechanisms (metabolic verses apoptotic) may be cell-type, α1-AR subtype, or disease-dependent. All of the pro-apoptotic effects of quinazolines are non-α1-AR mediated and mostly found in cancer cell lines, while metabolic effects are more systematic and may be α1-AR subtype dependent. The non-quinazoline tamsulosin does not exhibit cytotoxic or apoptotic activity in cancer cell lines [148]. Prazosin treatment protects the brain by decreasing oxidative stress and apoptotic pathways [152]. A non-quinazoline α1-AR antagonist reduced inflammation and immune cell infiltration and improved insulin signaling in the adipose of fructose-fed rats [153], as well as cardiac, vascular, and renal dysfunction in hypertensive rats [154].

6.3. α1A-AR Activation but α1B-AR Blockage Is Protective

Concerning α1-AR subtype-dependent effects of antagonists, there is evidence that α1A-AR activation is protective, while chronic α1B-AR activation is damaging and neurodegenerative. Therefore, α1A-AR agonists would be protective and in systems where chronic α1B-AR activation is damaging, non-selective blockers may exert protective effects. Systemic overexpression of the α1A-AR in mice has anti-tumor effects [59], preconditions the heart against ischemia [34], reverses heart failure and cardiac apoptosis [62,65,66], and increases longevity [59]. In contrast, systemic overexpression of the α1B-AR subtype in mice was neurogenerative, induced autonomic dysfunction, heart failure, apoptosis [37,38,155,156], and decreased lifespan [59]. Tamsulosin has a 10-fold higher binding affinity and slower dissociation kinetics compared to the other two subtypes, rendering it an α1A-AR selective antagonist [145,157]. The epidemiology study of [158], while finding that usage of terazosin/alfuzosin/doxazosin failed to see any changes in the risk in Parkinson’s disease (PD) development, did find that tamulosin increased PD risk and may associate with disease progression. Protective effects of prazosin may be due to α1B-AR blockage since tamsulosin (α1A-AR blockage) does not induce apoptosis nor binds with PGK1. The study of Koenecke (2021) [123] found that doxazosin was two-fold more efficacious than tamsulosin in preventing COVID mortality, suggesting blockage of α1B or α1D-mediated pro-inflammatory effects. There is an increased expression and cellular proliferation of the α1B-AR subtype in prostatic cancer cell lines that exhibit apoptosis with prazosin [159]. α1B-AR activation mediates unchecked cell cycle progression and induced foci formation [160], supporting a cancer-inducing paradigm. Therefore, protective effects of α1-AR blockage might indicate that the α1B- or α1D-AR subtype is being blocked in the particular tissue or disease.

6.4. Other Neurological Benefits of α1-AR Quinazoline Antagonists: Parkinson’s, ALS, PTSD

Neuroprotection, just like cardioprotection, may be mediated through increased metabolism [161]. As the heart is energy-starved during failure, so too are several neurodegenerative diseases. Glucose metabolism is essential for proper brain function, accounting for 20% of whole-body energy consumption, but compiles only 2% of body mass. Therefore, brain energy demand is mostly met by the metabolism of glucose [162]. Bioenergetic and mitochondrial dysfunction are common hallmarks of PD and ALS, and regulate disease onset and progression [161,163,164]. In ALS pathogenesis, the early dysregulation of the AMPK signaling pathway was found in motor neurons and in a large proportion of patients [165]. Preclinical and epidemiologic data suggest that terazosin, a quinazoline antagonist, may be neuroprotective in PD and ALS [144,166] and impart a decreased risk for developing PD [139]. However, another study that analyzed a large database of terazosin/alfuzosin/doxazosin users failed to see any changes in the risk of PD development [158]. A clinical study evaluating the safety and tolerability of terazosin, 5 mg once daily for 12 weeks, in patients with PD has been initiated (NCT03905811). Doxazosin can also reduce oxidative stress, pro-inflammatory cytokines, and cell death in rat photoreceptor cells in vivo [167]. Terazosin protected against organ damage, sepsis, and death in rodent models [140]. Therefore, nonselective α1-AR quinazoline antagonists may also be useful in other neurodegenerative diseases.
Posttraumatic stress disorder (PTSD) is associated with elevated noradrenergic activity [168,169,170]. In clinical trials and meta-analysis, prazosin has been effective and well-tolerated to reduce combat trauma nightmares, sleep disorders, and general clinical status in veterans [171,172,173] and for general trauma-related nightmares [174]. Compared with image rehearsal therapy which is the recommended treatment for trauma-induced nightmares, prazosin was more efficacious at relieving the frequency and stress-related symptoms but image rehearsal therapy combined with cognitive behavioral therapy was better at improving sleep quality [175]. A more recent study by Raskind et al. (2018) [176] also showed that prazosin did not improve sleep-related problems in PTSD. However, it is unclear whether or not prazosin will reduce the risk of nightmares in people without trauma or whether other α1-AR blockers (non-quinazolines) are effective. α1A-AR stimulation has been suggested to mediate stress-induced memory formation and consolidation [7] and, therefore, blockage with prazosin may be psychotherapeutic, resulting from a direct α1A-AR antagonistic effect.

7. Counterindications

7.1. α1A-AR Blockers but Not Non-Selective Antagonists May Increase Dementia and Depression

While non-selective α1-AR quinazoline antagonists appear to improve symptoms in neurodegenerative diseases and PTSD, regardless of whether they are α1-AR or non-α1-AR mediated, antagonists that are selective for the α1A-AR subtype may potentiate neurodegeneration and dementia. This would be consistent with α1A-AR activation demonstrating increased cognitive performance and reversing Alzheimer’s disease as discussed in this review. Just as tamsulosin does not follow the protective properties of quinazoline antagonists as discussed in the above sections, tamsulosin, which is α1A-AR selective, increases the risk of dementia modestly and other adverse cognitive effects, in particular among patients over age 61 [177]. This study utilized cohorts taking various medications (including 5a-reductase and quinazoline α1-AR blockers) for BPH as well as those taking no medications and followed them for 20 months after the first prescription was filled. However, two subsequent clinical studies contradict these results [178,179]. While tamsulosin did increase the risk of dementia, there was no evidence of a dose–response, and after adjustments for confounding variables, the results were not significant [179]. Differences between the three studies could be due to the mean age that was assessed. The two negative studies used a mean age of 78.7 [178], and 76.1 years [179], while the positive study of Duan et al. (2018) [177] used younger patients for a mean age of 73.2. As the risk of cognitive decline increases dramatically with age [180,181] or genetic variant status (APOE e4) [182], the amount of baseline neurodegeneration may have been substantially different in the two studies to mask any benefit. The study of Tae et al. (2019) [179] acknowledged that age was the strongest variable in the risk of dementia in all their comparisons. Another variable is the length of follow up. The positive study followed patients for 20 months [177], while the other two negative studies followed patients for 56 months [179] and 36 months [178]. Again, the two negative studies would have increased dementia at study end given the advanced age of the patients.
The amygdala can regulate psychological stressors and anxiety, besides regulating fear-conditioned memory and memory consolidation [7,183], and is regulated by the α1A-AR subtype [89,184]. Transgenic mice overexpressing the α1A-AR but not the α1B-AR showed antidepressant behavior [185]. α1A-AR blockage with WB4101 induces learned despair in mice [186] and tamsulosin facilitated depressive-like behavior in mice [187]. While a small clinical study found that tamsulosin decreased patient-reported depressive symptoms in BPH patients, contrary to the hypothesized effect in mice [188], BPH itself is associated with increased depressive and anxiety symptoms [189,190] and suicide [191]. Further large-scale clinical studies are needed to determine if tamsulosin and other α1A-AR blockers may increase depressive and anxiety-based disorders as hypothesized.

7.2. α1-AR Blockers May Increase Risk of Heart Failure

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is a large, randomized double-blind study comparing four different classes of antihypertensive agents in patients older than 55 years [101]. The use of doxazosin (i.e., Cardura) increased the risk of stroke and the development of heart failure twice as much as those receiving a thiazide diuretic and caused this arm of the study to terminate early. In addition, doxazosin is not recommended as a first-line antihypertensive, particularly in the elderly [101,103]. However, this effect is not just isolated to doxazosin. A recent study of 175,200 men with BPH treated with either 5-alpha reductase inhibitors, various α1-AR antagonists, or a combination, found a 22% increased risk of cardiac failure among the users of α1-AR blockers [192]. Non-selective α1-AR blockers (terazosin, doxazosin, and alfuzosin) were significantly associated with an 8% higher risk for heart failure compared with selective α1A-AR blockers (silodosin and tamsulosin). Silodosin is 500-fold more selective for the α1A-AR than α1B-AR [193], while tamsulosin is 10-fold selective [145]. The α1A-AR is theorized to be cardioprotective and agonists protect against heart failure [56], but why are α1A-AR blockers then not associated with a higher risk of heart failure compared to non-selective blockers? There may be other non-α1-AR mediated effects associated with the increased risk of heart failure, such as increased apoptosis [148,149,150], particularly with α1-AR quinazoline blockers. While α1-AR blockers are still a popular treatment for BPH, and particularly in younger men who may not display heart failure, it is advised that physicians assess the cardiovascular health of the patient before long-term use.

7.3. α1A-AR Blockers May Have Adverse Ocular Effects

Another adverse effect of the long-term use of α1-AR antagonists is intraoperative floppy iris syndrome (IFIS), that increases serious complications and is characterized by a poor pupillary response, iris billowing, and prolapse during cataract surgery [194]. α1-ARs, and particularly the α1A-AR subtype, regulates the dilator smooth muscle of the iris [195,196], intraocular pressure [197,198], and the extracellular matrix and metabolic functions in human retinal pigment epithelium cells [199]. Tamsulosin has been identified to causing IFIS among BPH patients, with risks increased up to forty times more compared to other α1-AR antagonists and causing severe IFIS [200,201,202,203,204], but other non-selective α1-AR antagonists can also cause it. A large meta-analysis of over 6000 cases using various α1-AR antagonists indicate that most α1-AR blockers associate with a higher risk of IFIS [205]. With the increasing prevalence of both BPH and cataracts in the aging population, it is recommended that tamsulosin use is stopped 2 weeks before cataract surgery or is replaced by another α1-AR blocker.

8. Summary

The use of α1-AR agonists to potentially treat heart failure, cardiac ischemia, Alzheimer’s disease, and other dementias are targeted to the α1A-AR subtype. However, all of these studies are preclinical in cell lines and mouse models or in initial clinical trials and it is not currently recommended to use these agents for non-approved use. Current development of positive allosteric modulators would be the choice as first-in-class therapeutics to avoid issues with increasing blood pressure to reduce other adverse side effects. The use of non-selective α1-AR antagonists of the quinazoline class to treat severe COVID-19/SARS, PTSD, and neurodegenerative disorders, such as Parkinson’s disease and ALS, have extensive evidence of efficacy in many clinical trials. However, the mechanism of action may be non-α1-AR mediated. Counterindications for α1-AR blockers are focused on those with established heart disease. Future clinical studies and larger, randomized, cross-over trials are required before drawing firmer conclusions about the counterindications of tamsulosin or other α1A-AR selective blockers.


This work was supported by a grant from The Edward N. and Della L. Thome Memorial Foundation Award Programs in Alzheimer’s Disease Drug Discovery Research and an RO1 from the National Institute of Aging (AG066627).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Ahlquist, R.P. A study of the adrenotropic receptors. Am. J. Physiol. Content 1948, 153, 586–600. [Google Scholar] [CrossRef] [PubMed]
  2. Cotecchia, S.; Schwinn, D.A.; Randall, R.R.; Lefkowitz, R.J.; Caron, M.G.; Kobilka, B.K. Molecular cloning and expression of the cDNA for the hamster alpha 1-adrenergic receptor. Proc. Natl. Acad. Sci. USA 1988, 85, 7159–7163. [Google Scholar] [CrossRef] [PubMed][Green Version]
  3. Perez, D.M.; Piascik, M.T.; Graham, R.M. Solution-phase library screening for the identification of rare clones: Isolation of an alpha 1D-adrenergic receptor cDNA. Mol. Pharmacol. 1991, 40, 876–883. [Google Scholar] [PubMed]
  4. Perez, D.M.; Piascik, M.T.; Malik, N.; Gaivin, R.; Graham, R.M. Cloning, expression, and tissue distribution of the rat homo-log of the bovine alpha 1C-adrenergic receptor provide evidence for its classification as the alpha 1A subtype. Mol. Pharm. 1994, 46, 823–831. [Google Scholar]
  5. Laz, T.M.; Forray, C.; Smith, K.E.; Bard, J.A.; Vaysse, P.J.; Branchek, T.A.; Weinshank, R.L. The rat homologue of the bovine al-pha1c-adrenergic receptor shows the pharmacological properties of the classical alpha1A subtype. Mol. Pharm. 1994, 46, 414–422. [Google Scholar]
  6. Morrow, A.L.; Creese, I. Characterization of alpha 1-adrenergic receptor subtypes in rat brain: A reevaluation of [3H]WB4104 and [3H]prazosin binding. Mol. Pharmacol. 1986, 29, 321–330. [Google Scholar]
  7. Perez, D.M. α1-Adrenergic Receptors in Neurotransmission, Synaptic Plasticity, and Cognition. Front. Pharmacol. 2020, 11, 581098. [Google Scholar] [CrossRef]
  8. Goetz, A.S.; King, H.K.; Ward, S.D.; True, T.A.; Rimele, T.J.; Saussy, D.L. BMY 7378 is a selective antagonist of the D subtype of α1-adrenoceptors. Eur. J. Pharmacol. 1995, 272, R5–R6. [Google Scholar] [CrossRef]
  9. Saussy, D.L., Jr.; Goetz, A.S.; Queen, K.L.; King, H.K.; Lutz, M.W.; Rimele, T.J. Structure activity relationships of a series of buspirone analogs at alpha-1 adrenoceptors: Further evidence that rat aorta alpha-1 adrenoceptors are of the al-pha-1D-subtype. J. Pharm. Exp. 1996, 278, 136–144. [Google Scholar]
  10. Deluigi, M.; Morstein, L.; Schuster, M.; Klenk, C.; Merklinger, L.; Cridge, R.R.; de Zhang, L.A.; Klipp, A.; Vacca, S.; Vaid, T.M.; et al. Crystal structure of the α1B-adrenergic receptor reveals molecular determinants of selective ligand recognition. Nat. Commun. 2022, 13, 382. [Google Scholar] [CrossRef]
  11. Sagratini, G.; Buccioni, M.; Marucci, G.; Poggesi, E.; Skorski, M.; Costanzi, S.; Giardinà, D. Chiral analogues of (+)-cyclazosin as potent α1B-adrenoceptor selective antagonist. Bioorg. Med. Chem. 2018, 26, 3502–3513. [Google Scholar] [CrossRef]
  12. Papay, R.S.; Macdonald, J.D.; Stauffer, S.R.; Perez, D.M. Characterization of a novel positive allosteric modulator of the α1A-Adrenergic receptor. Curr. Res. Pharmacol. Drug Discov. 2023, 4, 100142. [Google Scholar] [CrossRef]
  13. Akinaga, J.; Lima, V.; Kiguti, L.R.; Hebeler-Barbosa, F.; Alcántara-Hernández, R.; García-Sáinz, J.A.; Pupo, A.S. Differential phos-phorylation, desensitization, and internalization of a1A-adrenoceptors activated by norepinephrine and oxymetazoline. Mol. Pharm. 2013, 83, 870–881. [Google Scholar] [CrossRef]
  14. Junior, E.D.D.S.; Sato, M.; Merlin, J.; Broxton, N.; Hutchinson, D.S.; Ventura, S.; Evans, B.A.; Summers, R.J. Factors influencing biased agonism in recombinant cells expressing the human α1A-adrenoceptor. Br. J. Pharmacol. 2017, 174, 2318–2333. [Google Scholar] [CrossRef][Green Version]
  15. Hague, C.; Bernstein, L.S.; Ramineni, S.; Chen, Z.; Minneman, K.P.; Hepler, J.R. Selective Inhibition of α1A-Adrenergic Receptor Signaling by RGS2 Association with the Receptor Third Intracellular Loop. J. Biol. Chem. 2005, 280, 27289–27295. [Google Scholar] [CrossRef][Green Version]
  16. Perez, D.M.; Deyoung, M.B.; Graham, R.M. Coupling of expressed alpha 1B- and alpha 1D-adrenergic receptor to multiple signaling pathways is both G protein and cell type specific. Mol. Pharmacol. 1993, 44, 784–795. [Google Scholar]
  17. Perez-Aso, M.; Segura, V.; Monto, F.; Barettino, D.; Noguera, M.A.; Milligan, G.; D’Ocon, P. The three α1-adrenoceptor subtypes show different spatio-temporal mechanisms of internalization and ERK1/2 phosphorylation. Biochim. Biophys. Acta 2013, 1833, 2322–2333. [Google Scholar] [CrossRef][Green Version]
  18. Segura, V.; Pérez-Aso, M.; Montó, F.; Carceller, E.; Noguera, M.A.; Pediani, J.; Milligan, G.; McGrath, I.C.; D’Ocon, P. Differences in the Signaling Pathways of α1A- and α1B-Adrenoceptors Are Related to Different Endosomal Targeting. PLoS ONE 2013, 8, e64996. [Google Scholar] [CrossRef][Green Version]
  19. Hussain, M.B.; Marshall, I. Characterization of α 1 -adrenoceptor subtypes mediating contractions to phenylephrine in rat thoracic aorta, mesenteric artery and pulmonary artery. Br. J. Pharmacol. 1997, 122, 849–858. [Google Scholar] [CrossRef][Green Version]
  20. Somlyo, A.P.; Somlyo, A.V. Ca2+ Sensitivity of Smooth Muscle and Nonmuscle Myosin II: Modulated by G Proteins, Kinases, and Myosin Phosphatase. Physiol. Rev. 2003, 83, 1325–1358. [Google Scholar] [CrossRef][Green Version]
  21. Villalba, N.; Stankevicius, E.; Garcia-Sacristán, A.; Simonsen, U.; Prieto, D. Contribution of both Ca2+ entry and Ca2+ sensiti-zation to the alpha1-adrenergic vasoconstriction of rat penile small arteries. Am. J. Physiol. Heart Circ. Physiol. 2007, 292, H1157–H1169. [Google Scholar] [CrossRef] [PubMed]
  22. Wier, W.G.; Morgan, K.G. α1-Adrenergic signaling mechanisms in contraction of resistance arteries. Rev. Physiol. Biochem. Pharmacol. 2003, 150, 91–139. [Google Scholar] [CrossRef] [PubMed]
  23. Akhter, S.A.; Milano, C.A.; Shotwell, K.F.; Cho, M.C.; Rockman, H.A.; Lefkowitz, R.J.; Koch, W.J. Transgenic mice with cardiac overexpression of a1B-adrenergic receptors. In vivo a1-adrenergic receptor-mediated regulation of b-adrenergic signaling. J. Biol. Chem. 1997, 272, 21253–21259. [Google Scholar] [CrossRef] [PubMed][Green Version]
  24. Cavalli, A.; Lattion, A.L.; Hummler, E.; Nenniger, M.; Pedrazzini, T.; Aubert, J.F.; Michel, M.C.; Yang, M.; Lembo, G.; Vecchione, C.; et al. Decreased blood pressure response in mice deficient of the a1B-adrenergic receptor. Proc. Natl. Acad. Sci. USA 1997, 94, 11589–11594. [Google Scholar] [CrossRef] [PubMed][Green Version]
  25. Du, X.-J.; Fang, L.; Gao, X.-M.; Kiriazis, H.; Feng, X.; Hotchkin, E.; Finch, A.M.; Chaulet, H.; Graham, R.M. Genetic Enhancement of Ventricular Contractility Protects against Pressure-Overload-Induced Cardiac Dysfunction. J. Mol. Cell. Cardiol. 2004, 37, 979–987. [Google Scholar] [CrossRef]
  26. Du, X.-J.; Gao, X.-M.; Kiriazis, H.; Moore, X.-L.; Ming, Z.; Su, Y.; Finch, A.; Hannan, R.A.; Dart, A.; Graham, R.M. Transgenic α1A-adrenergic activation limits post-infarct ventricular remodeling and dysfunction and improves survival. Cardiovasc. Res. 2006, 71, 735–743. [Google Scholar] [CrossRef][Green Version]
  27. Eckhart, A.D.; Duncan, S.J.; Penn, R.B.; Benovic, J.L.; Lefkowitz, R.J.; Koch, W.J. Hybrid Transgenic Mice Reveal In Vivo Specificity of G Protein–Coupled Receptor Kinases in the Heart. Circ. Res. 2000, 86, 43–50. [Google Scholar] [CrossRef][Green Version]
  28. Grupp, I.L.; Lorenz, J.N.; Walsh, R.A.; Boivin, G.P.; Rindt, H. Overexpression of α1B-adrenergic receptor induces left ventricular dysfunction in the absence of hypertrophy. Am. J. Physiol. Circ. Physiol. 1998, 275, H1338–H1350. [Google Scholar] [CrossRef]
  29. Lemire, I.; Ducharme, A.; Tardif, J.-C.; Poulin, F.; Jones, L.R.; Allen, B.G.; Hébert, T.E.; Rindt, H. Cardiac-directed overexpression of wild-type α1B-adrenergic receptor induces dilated cardiomyopathy. Am. J. Physiol. Circ. Physiol. 2001, 281, H931–H938. [Google Scholar] [CrossRef][Green Version]
  30. Lin, F.; Owens, W.A.; Chen, S.; Stevens, M.E.; Kesteven, S.; Arthur, J.F.; Woodcock, E.A.; Feneley, M.P.; Graham, R.M. Targeted α 1A -Adrenergic Receptor Overexpression Induces Enhanced Cardiac Contractility but not Hypertrophy. Circ. Res. 2001, 89, 343–350. [Google Scholar] [CrossRef][Green Version]
  31. Methven, L.; Simpson, P.C.; McGrath, J.C. a1A/B-knockout mice explain the native a1D-adrenoceptor’s role in vasoconstriction and show that its location is independent of the other a1-subtypes. Br. J. Pharm. 2009, 158, 1663–1675. [Google Scholar] [CrossRef][Green Version]
  32. O’Connell, T.D.; Ishizaka, S.; Nakamura, A.; Swigart, P.M.; Rodrigo, M.; Simpson, G.L.; Cotecchia, S.; Rokosh, G.; Grossman, W.; Foster, E.; et al. The α1A/C- and α1B-adrenergic receptors are required for physiological cardiac hypertrophy in the double-knockout mouse. J. Clin. Investig. 2003, 111, 1783–1791. [Google Scholar] [CrossRef]
  33. Rokosh, D.G.; Simpson, P.C. Knockout of the α1A/C-adrenergic receptor subtype: The α1A/C is expressed in resistance arteries and is required to maintain arterial blood pressure. Proc. Natl. Acad. Sci. USA 2002, 99, 9474–9479. [Google Scholar] [CrossRef][Green Version]
  34. Rorabaugh, B.R.; Ross, S.A.; Gaivin, R.J.; Papay, R.S.; McCune, D.F.; Simpson, P.C.; Perez, D.M. α1A- but not α1B-adrenergic receptors precondition the ischemic heart by a staurosporine-sensitive, chelerythrine-insensitive mechanism. Cardiovasc. Res. 2005, 65, 436–445. [Google Scholar] [CrossRef][Green Version]
  35. Sanbe, A.; Tanaka, Y.; Fujiwara, Y.; Tsumura, H.; Yamauchi, J.; Cotecchia, S.; Koike, K.; Tsujimoto, G.; Tanoue, A. α 1 -Adrenoceptors are required for normal male sexual function. Br. J. Pharmacol. 2007, 152, 332–340. [Google Scholar] [CrossRef][Green Version]
  36. Tanoue, A.; Nasa, Y.; Koshimizu, T.-A.; Shinoura, H.; Oshikawa, S.; Kawai, T.; Sunada, S.; Takeo, S.; Tsujimoto, G. The α1D-adrenergic receptor directly regulates arterial blood pressure via vasoconstriction. J. Clin. Investig. 2002, 109, 765–775. [Google Scholar] [CrossRef]
  37. Wang, B.H.; Du, X.J.; Autelitano, D.J.; Milano, C.A.; Woodcock, E.A. Adverse effects of constitutively active al-pha(1B)-adrenergic receptors after pressure overload in mouse hearts. Am. J. Physiol. Heart Circ. Physiol. 2000, 279, H1079–H1086. [Google Scholar] [CrossRef]
  38. Zuscik, M.; Sands, S.; Ross, S.A.; Waugh, D.; Gaivin, R.J.; Morilak, D.; Perez, D.M. Overexpression of the α1B-adrenergic receptor causes apoptotic neurodegeneration: Multiple system atrophy. Nat. Med. 2000, 6, 1388–1394. [Google Scholar] [CrossRef]
  39. Vecchione, C.; Fratta, L.; Rizzoni, D.; Notte, A.; Poulet, R.; Porteri, E.; Frati, G.; Guelfi, D.; Trimarco, V.; Mulvany, M.J.; et al. Cardiovascular Influences of α 1b -Adrenergic Receptor Defect in Mice. Circulation 2002, 105, 1700–1707. [Google Scholar] [CrossRef][Green Version]
  40. Hosoda, C.; Koshimizu, T.-A.; Tanoue, A.; Nasa, Y.; Oikawa, R.; Tomabechi, T.; Fukuda, S.; Shinoura, H.; Oshikawa, S.; Takeo, S.; et al. Two α1-Adrenergic Receptor Subtypes Regulating the Vasopressor Response Have Differential Roles in Blood Pressure Regulation. Mol. Pharmacol. 2004, 67, 912–922. [Google Scholar] [CrossRef][Green Version]
  41. Jentzer, J.C.; Vallabhajosyula, S.; Khanna, A.K.; Chawla, L.S.; Busse, L.W.; Kashani, K.B. Management of Refractory Vasodilatory Shock. Chest 2018, 154, 416–426. [Google Scholar] [CrossRef] [PubMed]
  42. Colling, K.; Banton, K.L.; Beilman, G.J. Vasopressors in Sepsis. Surg. Infect. 2018, 19, 202–207. [Google Scholar] [CrossRef] [PubMed]
  43. Sacha, G.L.; Bauer, S.R.; Lat, I. Vasoactive Agent Use in Septic Shock: Beyond First-Line Recommendations. Pharmacother. J. Hum. Pharmacol. Drug Ther. 2018, 39, 369–381. [Google Scholar] [CrossRef] [PubMed]
  44. Balal, S.; Jbari, A.S.; Nitiahpapand, R.; Cook, E.; Akhtar, W.; Din, N.; Sharma, A. Management and outcomes of the small pupil in cataract surgery: Iris hooks, Malyugin ring or phenylephrine? Eye 2020, 35, 2714–2718. [Google Scholar] [CrossRef]
  45. Ralston, S.; Roohi, M. A Randomized, Controlled Trial of Nasal Phenylephrine in Infants Hospitalized for Bronchiolitis. J. Pediatr. 2008, 153, 795–798.e1. [Google Scholar] [CrossRef]
  46. Soleimani, G.; Akbarpour, M.; Mohammadi, M. Safety and Efficacy of Phenylephrine Nasal Drops in Bronchiolitis. Iran. J. Pediatr. 2014, 24, 593–597. [Google Scholar]
  47. Del Rosso, J.Q.; Tanghetti, E. Topical Oxymetazoline Hydrochloride Cream 1% for the Treatment of Persistent Facial Erythema of Rosacea in Adults: A Comprehensive Review of Current Evidence. J. Clin. Aesthetic Dermatol. 2021, 14, 32–37. [Google Scholar]
  48. Patel, N.U.; Shukla, S.; Zaki, J.; Feldman, S.R. Oxymetazoline hydrochloride cream for facial erythema associated with rosacea. Expert Rev. Clin. Pharmacol. 2017, 10, 1049–1054. [Google Scholar] [CrossRef]
  49. Jensen, B.C.; Swigart, P.M.; De Marco, T.; Hoopes, C.; Simpson, P.C. α1-Adrenergic Receptor Subtypes in Nonfailing and Failing Human Myocardium. Circ. Hear. Fail. 2009, 2, 654–663. [Google Scholar] [CrossRef][Green Version]
  50. Shi, T.; Moravec, C.S.; Perez, D.M. Novel proteins associated with human dilated cardiomyopathy: Selective reduction in α1A-adrenergic receptors and increased desensitization proteins. J. Recept. Signal Transduct. 2013, 33, 96–106. [Google Scholar] [CrossRef][Green Version]
  51. Steinfath, M.; Chen, Y.-Y.; Lavický, J.; Magnussen, O.; Nose, M.; Rosswag, S.; Schmitz, W.; Scholz, H. Cardiac α1-adrenoceptor densities in different mammalian species. Br. J. Pharmacol. 1992, 107, 185–188. [Google Scholar] [CrossRef]
  52. Price, D.T.; Lefkowitz, R.J.; Caron, M.G.; Berkowitz, D.; Schwinn, D.A. Localization of mRNA for three distinct alpha 1-adrenergic receptor subtypes in human tissues: Implications for human alpha-adrenergic physiology. Mol. Pharmacol. 1994, 45, 171–175. [Google Scholar]
  53. Scofield, M.A.; Liu, F.; Abel, P.W.; Jeffries, W.B. Quantification of steady state expression of mRNA for α1-adrenergic receptor subtypes using reverse transcription and a competitive polymerase chain reaction. J. Pharm. Exp. 1995, 275, 1035–1042. [Google Scholar]
  54. Perez, D.M.; Doze, V.A. Cardiac and neuroprotection regulated by α1-adrenergic receptor subtypes. J. Recept. Signal Transduct. 2011, 31, 98–110. [Google Scholar] [CrossRef][Green Version]
  55. Zhang, J.; Ash, T.; Huang, W.; Smith, A.; Huang, H.; Jensen, B. An essential protective role for cardiomyocyte al-pha1A-adrenergic receptors in a mouse model of myocardial infarction. Circ. Res. 2020, 127, A408. [Google Scholar] [CrossRef]
  56. Perez, D.M. Current Developments on the Role of α1-Adrenergic Receptors in Cognition, Cardioprotection, and Metabolism. Front. Cell Dev. Biol. 2021, 9, 652152. [Google Scholar] [CrossRef]
  57. Shi, T.; Papay, R.S.; Perez, D.M. The role of α1-adrenergic receptors in regulating metabolism: Increased glucose tolerance, leptin secretion and lipid oxidation. J. Recept. Signal Transduct. 2016, 37, 124–132. [Google Scholar] [CrossRef]
  58. Willis, M.S.; Ilaiwy, A.; Montgomery, M.D.; Simpson, P.C.; Jensen, B.C. The alpha-1A adrenergic receptor agonist A61603 reduces cardiac polyunsaturated fatty acid and endocannabinoid metabolites associated with inflammation in vivo. Metabolomics 2016, 12, 1–13. [Google Scholar] [CrossRef][Green Version]
  59. Collette, K.M.; Zhou, X.D.; Amoth, H.M.; Lyons, M.J.; Papay, R.S.; Sens, D.A.; Perez, D.M.; Doze, V.A. Long-term α1B-adrenergic receptor activation shortens lifespan, while α1A-adrenergic receptor stimulation prolongs lifespan in association with decreased cancer incidence. Age 2014, 36, 1–10. [Google Scholar] [CrossRef]
  60. Doze, V.A.; Papay, R.S.; Goldenstein, B.L.; Gupta, M.K.; Collette, K.M.; Nelson, B.W.; Lyons, M.J.; Davis, B.A.; Luger, E.J.; Wood, S.G.; et al. Long-Term α1A-Adrenergic Receptor Stimulation Improves Synaptic Plasticity, Cognitive Function, Mood, and Longevity. Mol. Pharmacol. 2011, 80, 747–758. [Google Scholar] [CrossRef][Green Version]
  61. Lee, Y.-J.; Jang, Y.-N.; Kim, H.-M.; Han, Y.-M.; Seo, H.S.; Eom, Y.; Song, J.-S.; Jeong, J.H.; Jung, T.W. Stimulation of Alpha-1-Adrenergic Receptor Ameliorates Obesity-Induced Cataracts by Activating Glycolysis and Inhibiting Cataract-Inducing Factors. Endocrinol. Metab. 2022, 37, 221–232. [Google Scholar] [CrossRef] [PubMed]
  62. Zhao, X.; Balaji, P.; Pachon, R.; Beniamen, D.M.; Vatner, D.E.; Graham, R.M.; Vatner, S.F. Overexpression of Cardiomyocyte α 1A -Adrenergic Receptors Attenuates Postinfarct Remodeling by Inducing Angiogenesis Through Heterocellular Signaling. Arter. Thromb. Vasc. Biol. 2015, 35, 2451–2459. [Google Scholar] [CrossRef] [PubMed][Green Version]
  63. Beak, J.Y.; Huang, W.; Parker, J.S.; Hicks, S.T.; Patterson, C.; Simpson, P.C.; Ma, A.; Jin, J.; Jensen, B.C. An Oral Selective Alpha-1A Adrenergic Receptor Agonist Prevents Doxorubicin Cardiotoxicity. JACC Basic Transl. Sci. 2017, 2, 39–53. [Google Scholar] [CrossRef] [PubMed]
  64. Cowley, P.M.; Wang, G.; Swigart, P.M.; Raghunathan, A.; Reddy, N.; Dulam, P.; Lovett, D.H.; Simpson, P.C.; Baker, A.J. Reversal of right ventricular failure by chronic α1A-subtype adrenergic agonist therapy. Am. J. Physiol. Circ. Physiol. 2019, 316, H224–H232. [Google Scholar] [CrossRef]
  65. Montgomery, M.D.; Chan, T.; Swigart, P.M.; Myagmar, B.-E.; Dash, R.; Simpson, P.C. An Alpha-1A Adrenergic Receptor Agonist Prevents Acute Doxorubicin Cardiomyopathy in Male Mice. PLoS ONE 2017, 12, e0168409. [Google Scholar] [CrossRef][Green Version]
  66. Cowley, P.M.; Wang, G.; Chang, A.N.; Makwana, O.; Swigart, P.M.; Lovett, D.H.; Stull, J.T.; Simpson, P.C.; Baker, A.J. The α1A-adrenergic receptor subtype mediates increased contraction of failing right ventricular myocardium. Am. J. Physiol. Circ. Physiol. 2015, 309, H888–H896. [Google Scholar] [CrossRef][Green Version]
  67. Schnee, P.M.; Shah, N.; Bergheim, M.; Poindexter, B.J.; Buja, L.M.; Gemmato, C.; Radovancevic, B.; Letsou, G.V.; Frazier, O.H.; Bick, R.J. Location and Density of α- and β-Adrenoreceptor Sub-types in Myocardium After Mechanical Left Ventricular Unloading. J. Hear. Lung Transplant. 2008, 27, 710–717. [Google Scholar] [CrossRef]
  68. Ross, S.A.; Rorabaugh, B.R.; Chalothorn, D.; Yun, J.; Gonzalez-Cabrera, P.J.; McCune, D.F.; Piascik, M.T.; Perez, D.M. The alpha(1B)-adrenergic receptor decreases the inotropic response in the mouse Langendorff heart model. Cardiovasc. Res. 2003, 60, 598–607. [Google Scholar] [CrossRef][Green Version]
  69. Janssen, P.M.L.; Canan, B.D.; Kilic, A.; Whitson, B.A.; Baker, A.J. Human Myocardium Has a Robust α1A-Subtype Adrenergic Receptor Inotropic Response. J. Cardiovasc. Pharmacol. 2018, 72, 136–142. [Google Scholar] [CrossRef]
  70. Papay, R.S.; Perez, D.M. α1-Adrenergic receptors increase glucose oxidation under normal and ischemic conditions in adult mouse cardiomyocytes. J. Recept. Signal Transduct. Res. 2021, 41, 138–144. [Google Scholar] [CrossRef]
  71. Dyck, J.R.; Hopkins, T.A.; Bonnet, S.; Michelakis, E.D.; Young, M.E.; Watanabe, M.; Kawase, Y.; Jishage, K.-I.; Lopaschuk, G.D. Absence of Malonyl Coenzyme A Decarboxylase in Mice Increases Cardiac Glucose Oxidation and Protects the Heart from Ischemic Injury. Circulation 2006, 114, 1721–1728. [Google Scholar] [CrossRef][Green Version]
  72. Li, T.; Xu, J.; Qin, X.; Hou, Z.; Guo, Y.; Liu, Z.; Wu, J.; Zheng, H.; Zhang, X.; Gao, F. Glucose oxidation positively regulates glucose uptake and improves cardiac function recovery after myocardial reperfusion. Am. J. Physiol. Metab. 2017, 313, E577–E585. [Google Scholar] [CrossRef][Green Version]
  73. Masoud, W.G.; Ussher, J.R.; Wang, W.; Jaswal, J.S.; Wagg, C.S.; Dyck, J.R.; Lygate, C.A.; Neubauer, S.; Clanachan, A.S.; Lopaschuk, G.D. Failing mouse hearts utilize energy inefficiently and benefit from improved coupling of glycolysis and glucose oxidation. Cardiovasc. Res. 2013, 101, 30–38. [Google Scholar] [CrossRef][Green Version]
  74. Shi, T.; Papay, R.S.; Perez, D.M. α1A-Adrenergic receptor prevents cardiac ischemic damage through PKCδ/GLUT1/4-mediated glucose uptake. J. Recept. Signal Transduct. 2015, 36, 261–270. [Google Scholar] [CrossRef][Green Version]
  75. Ussher, J.R.; Wang, W.; Gandhi, M.; Keung, W.; Samokhvalov, V.; Oka, T.; Wagg, C.S.; Jaswal, J.S.; Harris, R.A.; Clanachan, A.S.; et al. Stimulation of glucose oxidation protects against acute myocardial infarction and reperfusion injury. Cardiovasc. Res. 2012, 94, 359–369. [Google Scholar] [CrossRef][Green Version]
  76. Yurista, S.R.; Chen, S.; Welsh, A.; Tang, W.H.W.; Nguyen, C.T. Targeting Myocardial Substrate Metabolism in the Failing Heart: Ready for Prime Time? Curr. Hear. Fail. Rep. 2022, 19, 180–190. [Google Scholar] [CrossRef]
  77. Ingwall, J.S.; Weiss, R.G. Is the Failing Heart Energy Starved? Circ. Res. 2004, 95, 135–145. [Google Scholar] [CrossRef]
  78. Izumi, Y.; Zorumski, C.F. Norepinephrine promotes long-term potentiation in the adult rat hippocampus in vitro. Synapse 1999, 31, 196–202. [Google Scholar] [CrossRef]
  79. Pankratov, Y.; Lalo, U. Role for astroglial α1-adrenoreceptors in gliotransmission and control of synaptic plasticity in the neocortex. Front. Cell. Neurosci. 2015, 9, 230. [Google Scholar] [CrossRef][Green Version]
  80. Hopkins, W.F.; Johnston, D. Frequency-Dependent Noradrenergic Modulation of Long-Term Potentiation in the Hippocampus. Science 1984, 226, 350–352. [Google Scholar] [CrossRef]
  81. Huang, Y.Y.; Nguyen, P.V.; Abel, T.; Kandel, E.R. Long-lasting forms of synaptic potentiation in the mammalian hippocampus. Learn. Mem. 1996, 3, 74–85. [Google Scholar] [CrossRef] [PubMed][Green Version]
  82. Lv, J.; Zhan, S.-Y.; Li, G.-X.; Wang, D.; Li, Y.-S.; Jin, Q.-H. α1-Adrenoceptors in the hippocampal dentate gyrus involved in learning-dependent long-term potentiation during active-avoidance learning in rats. Neuroreport 2016, 27, 1211–1216. [Google Scholar] [CrossRef] [PubMed]
  83. Pedarzani, P.; Storm, J.F. Interaction between alpha- and beta-adrenergic receptor agonists modulating the slow Ca(2+)-activated K+ current IAHP in hippocampal neurons. Eur. J. Neurosci. 1996, 8, 2098–2110. [Google Scholar] [CrossRef] [PubMed]
  84. Spreng, M.; Cotecchia, S.; Schenk, F. A Behavioral Study of Alpha-1b Adrenergic Receptor Knockout Mice: Increased Reaction to Novelty and Selectively Reduced Learning Capacities. Neurobiol. Learn. Mem. 2001, 75, 214–229. [Google Scholar] [CrossRef][Green Version]
  85. Knauber, J.; Müller, W.E. Decreased exploratory activity and impaired passive avoidance behaviour in mice deficient for the α1b-adrenoceptor. Eur. Neuropsychopharmacol. 2000, 10, 423–427. [Google Scholar] [CrossRef]
  86. Sadalge, A.; Coughlin, L.; Fu, H.; Wang, B.; Valladares, O.; Valentino, R.; A Blendy, J. α1d Adrenoceptor signaling is required for stimulus induced locomotor activity. Mol. Psychiatry 2003, 8, 664–672. [Google Scholar] [CrossRef][Green Version]
  87. Mishima, K.; Tanoue, A.; Tsuda, M.; Hasebe, N.; Fukue, Y.; Egashira, N.; Takano, Y.; Kamiya, H.-O.; Tsujimoto, G.; Iwasaki, K.; et al. Characteristics of behavioral abnormalities in α1d-adrenoceptors deficient mice. Behav. Brain Res. 2004, 152, 365–373. [Google Scholar] [CrossRef]
  88. Gupta, M.K.; Papay, R.S.; Jurgens, C.W.D.; Gaivin, R.J.; Shi, T.; Doze, V.A.; Perez, D.M. α1-Adrenergic Receptors Regulate Neurogenesis and Gliogenesis. Mol. Pharmacol. 2009, 76, 314–326. [Google Scholar] [CrossRef][Green Version]
  89. Papay, R.; Gaivin, R.; Jha, A.; Mccune, D.F.; McGrath, J.; Rodrigo, M.C.; Simpson, P.C.; Doze, V.A.; Perez, D.M. Localization of the mouse α1A-adrenergic receptor (AR) in the brain: α1AAR is expressed in neurons, GABAergic interneurons, and NG2 oligodendrocyte progenitors. J. Comp. Neurol. 2006, 497, 209–222. [Google Scholar] [CrossRef]
  90. Christopoulos, A. Allosteric binding sites on cell-surface receptors: Novel targets for drug discovery. Nat. Rev. Drug Discov. 2002, 1, 198–210. [Google Scholar] [CrossRef]
  91. Wold, E.A.; Chen, J.; Cunningham, K.A.; Zhou, J. Allosteric Modulation of Class A GPCRs: Targets, Agents, and Emerging Concepts. J. Med. Chem. 2018, 62, 88–127. [Google Scholar] [CrossRef]
  92. Bevilaqua, L.; Ardenghi, P.; Schröder, N.; Bromberg, E.; Quevedo, J.; Schmitz, P.; Bianchin, M.; Walz, R.; Schaeffer, E.; Medina, J.; et al. Agents that affect cAMP levels or protein kinase A activity modulate memory consolidation when injected into rat hippocampus but not amygdala. Braz. J. Med. Biol. Res. 1997, 30, 967–970. [Google Scholar] [CrossRef][Green Version]
  93. Ferry, B.; Roozendaal, B.; McGaugh, J.L. Involvement of α1-adrenoceptors in the basolateral amygdala in modulation of memory storage. Eur. J. Pharmacol. 1999, 372, 9–16. [Google Scholar] [CrossRef]
  94. Ferry, B.; Roozendaal, B.; McGaugh, J.L. Basolateral amygdala noradrenergic influences on memory storage are mediated by an interaction between b- and a1- adrenoceptors. J. Neurosci. 1999, 19, 5119–5123. [Google Scholar] [CrossRef][Green Version]
  95. Hatfield, T.; McGaugh, J.L. Norepinephrine infused into the basolateral amygdala enhances spatial water maze memory. Neurobiol. Learn Mem. 1999, 71, 232–239. [Google Scholar] [CrossRef][Green Version]
  96. Kandel, E.R. The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB. Mol. Brain 2012, 5, 14. [Google Scholar] [CrossRef][Green Version]
  97. Kida, S.; Serita, T. Functional roles of CREB as a positive regulator in the formation and enhancement of memory. Brain Res. Bull. 2014, 105, 17–24. [Google Scholar] [CrossRef]
  98. Michel, M.; Mehlburger, L.; Bressel, H.-U.; Goepel, M. Comparison of tamsulosin efficacy in subgroups of patients with lower urinary tract symptoms. Prostate Cancer Prostatic Dis. 1998, 1, 332–335. [Google Scholar] [CrossRef][Green Version]
  99. Oestreich, M.C.; Vernooij, R.W.; Sathianathen, N.J.; Hwang, E.C.; Kuntz, G.M.; Koziarz, A.; Scales, C.D.; Dahm, P. Alpha-blockers after shock wave lithotripsy for renal or ureteral stones in adults. Cochrane Database Syst. Rev. 2020, 2020, CD013393. [Google Scholar] [CrossRef]
  100. Sigala, S.; Dellabella, M.; Milanese, G.; Fornari, S.; Faccoli, S.; Palazzolo, F.; Peroni, A.; Mirabella, G.; Cunico, S.C.; Spano, P.; et al. Evidence for the presence of ?1 adrenoceptor subtypes in the human ureter. Neurourol. Urodynamics 2005, 24, 142–148. [Google Scholar] [CrossRef]
  101. ALLHAT. Diuretic versus alpha-blocker as first-step antihypertensive therapy: Final results from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Hypertension 2003, 42, 239–246. [Google Scholar] [CrossRef] [PubMed][Green Version]
  102. James, P.A.; Oparil, S.; Carter, B.L.; Cushman, W.C.; Dennison-Himmelfarb, C.; Handler, J.; Lackland, D.T.; LeFevre, M.L.; MacKenzie, T.D.; Ogedegbe, O.; et al. 2014 evidence-based guideline for the management of high blood pressure in adults: Report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014, 311, 507–520. [Google Scholar] [CrossRef] [PubMed][Green Version]
  103. Mansbart, F.; Kienberger, G.; Sönnichsen, A.; Mann, E. Efficacy and safety of adrenergic alpha-1 receptor antagonists in older adults: A systematic review and meta-analysis supporting the development of recommendations to reduce potentially in-appropriate prescribing. BMC Geriatr. 2022, 22, 771. [Google Scholar] [CrossRef] [PubMed]
  104. Roehrborn, C.G.; Siami, P.; Barkin, J.; Damião, R.; Major-Walker, K.; Nandy, I.; Morrill, B.B.; Gagnier, R.P.; Montorsi, F. The Effects of Combination Therapy with Dutasteride and Tamsulosin on Clinical Outcomes in Men with Symptomatic Benign Prostatic Hyperplasia: 4-Year Results from the CombAT Study. Eur. Urol. 2010, 57, 123–131. [Google Scholar] [CrossRef] [PubMed]
  105. Garg, M.; Kharb, S.; Brar, K.; Gundgurthi, A.; Mittal, R. Medical management of pheochromocytoma: Role of the endocrinologist. Indian J. Endocrinol. Metab. 2011, 15, S329–S336. [Google Scholar] [CrossRef]
  106. Zaim, S.; Chong, J.H.; Sankaranarayanan, V.; Harky, A. COVID-19 and Multiorgan Response. Curr. Probl. Cardiol. 2020, 45, 100618. [Google Scholar] [CrossRef]
  107. Wang, M.; Fan, Y.; Chai, Y.; Cheng, W.; Wang, K.; Cao, J.; Hu, X. Association of Clinical and Immunological Characteristics with Disease Severity and Outcomes in 211 Patients With COVID-19 in Wuhan, China. Front. Cell. Infect. Microbiol. 2021, 11, 667487. [Google Scholar] [CrossRef]
  108. Stavely, R.; Rahman, A.A.; Sahakian, L.; Prakash, M.D.; Robinson, A.M.; Hassanzadeganroudsari, M.; Filippone, R.T.; Fraser, S.; Eri, R.; Bornstein, J.C.; et al. Divergent Adaptations in Autonomic Nerve Activity and Neuroimmune Signaling Associated with the Severity of Inflammation in Chronic Colitis. Inflamm. Bowel Dis. 2022, 28, 1229–1243. [Google Scholar] [CrossRef]
  109. Priyanka, H.P.; ThyagaRajan, S. Selective modulation of lymphoproliferation and cytokine production via intracellular signaling targets by α1- and α2-adrenoceptors and estrogen in splenocytes. Int. Immunopharmacol. 2013, 17, 774–784. [Google Scholar] [CrossRef]
  110. Scanzano, A.; Cosentino, M. Adrenergic regulation of innate immunity: A review. Front. Pharmacol. 2015, 6, 171. [Google Scholar] [CrossRef][Green Version]
  111. Barnes, M.A.; Carson, M.J.; Nair, M.G. Non-traditional cytokines: How catecholamines and adipokines influence macrophages in immunity, metabolism and the central nervous system. Cytokine 2015, 72, 210–219. [Google Scholar] [CrossRef][Green Version]
  112. Grisanti, L.A.; Perez, D.M.; Porter, J.E. Modulation of Immune Cell Function by α1-Adrenergic Receptor Activation. Curr. Top. Membr. 2011, 67, 113–138. [Google Scholar] [CrossRef][Green Version]
  113. Jensen, B.C.; Swigart, P.M.; Simpson, P.C. Ten commercial antibodies for alpha-1-adrenergic receptor subtypes are nonspecific. Naunyn-Schmiedeberg’s Arch. Pharmacol. 2008, 379, 409–412. [Google Scholar] [CrossRef][Green Version]
  114. Scanzano, A.; Schembri, L.; Rasini, E.; Luini, A.; Dallatorre, J.; Legnaro, M.; Bombelli, R.; Congiu, T.; Cosentino, M.; Marino, F. Adrenergic modulation of migration, CD11b and CD18 expression, ROS and interleukin-8 production by human polymorphonuclear leukocytes. Inflamm. Res. 2015, 64, 127–135. [Google Scholar] [CrossRef]
  115. Heijnen, C.J.; Rouppe van der Voort, C.; van de Pol, M.; Kavelaars, A. Cytokines regulate alpha(1)-adrenergic receptor mRNA expression in human monocytic cells and endothelial cells. J. Neuroimmunol. 2002, 125, 66–72. [Google Scholar] [CrossRef]
  116. Rouppe van der Voort, C.; Kavelaars, A.; van de Pol, M.; Heijnen, C.J. Neuroendocrine mediators up-regulate alpha1b- and alpha1d-adrenergic receptor subtypes in human monocytes. J. Neuroimmunol. 1999, 95, 165–173. [Google Scholar] [CrossRef]
  117. Bao, J.-Y.; Huang, Y.; Wang, F.; Peng, Y.-P.; Qiu, Y.-H. Expression of α-AR Subtypes in T Lymphocytes and Role of the α-ARs in Mediating Modulation of T Cell Function. Neuroimmunomodulation 2007, 14, 344–353. [Google Scholar] [CrossRef]
  118. Enten, G.A.; Gao, X.; Strzelinski, H.R.; Weche, M.; Liggett, S.B.; Majetschak, M. a1B/D-adrenoceptors regulate chemokine re-ceptor-mediated leukocyte migration via formation of heteromeric receptor complexes. Proc. Natl. Acad. Sci. USA 2022, 119, e2123511119. [Google Scholar] [CrossRef] [PubMed]
  119. Jetschmann, J.U.; Benschop, R.J.; Jacobs, R.; Kemper, A.; Oberbeck, R.; Schmidt, R.E.; Schedlowski, M. Expression and in-vivo modulation of alpha- and beta-adrenoceptors on human natural killer (CD16+) cells. J. Neuroimmunol. 1997, 74, 159–164. [Google Scholar] [CrossRef]
  120. Ricci, A.; Bronzetti, E.; Conterno, A.; Greco, S.; Mulatero, P.; Schena, M.; Schiavone, D.; Tayebati, S.K.; Veglio, F.; Amenta, F. α 1 -Adrenergic Receptor Subtypes in Human Peripheral Blood Lymphocytes. Hypertension 1999, 33, 708–712. [Google Scholar] [CrossRef][Green Version]
  121. Tayebati, S.K.; Bronzetti, E.; Di Cella, S.M.; Mulatero, P.; Ricci, A.; Rossodivita, I.; Schena, M.; Schiavone, D.; Veglio, F.; Amenta, F. In situ hybridization and immunocytochemistry of alpha1-adrenoceptors in human peripheral blood lymphocytes. J. Auton. Pharmacol. 2000, 20, 305–312. [Google Scholar] [CrossRef] [PubMed]
  122. Staedtke, V.; Bai, R.-Y.; Kim, K.; Darvas, M.; Davila, M.L.; Riggins, G.J.; Rothman, P.B.; Papadopoulos, N.; Kinzler, K.W.; Vogelstein, B.; et al. Disruption of a self-amplifying catecholamine loop reduces cytokine release syndrome. Nature 2018, 564, 273–277. [Google Scholar] [CrossRef] [PubMed]
  123. Koenecke, A.; Powell, M.; Xiong, R.; Shen, Z.; Fischer, N.; Huq, S.; Khalafallah, A.M.; Trevisan, M.; Sparen, P.; Carrero, J.J.; et al. Alpha-1 adrenergic receptor antagonists to prevent hyperinflammation and death from lower respiratory tract infection. Elife 2021, 10, e61700. [Google Scholar] [CrossRef] [PubMed]
  124. Rose, L.; Graham, L.; Koenecke, A.; Powell, M.; Xiong, R.; Shen, Z.; Mench, B.; Kinzler, K.W.; Bettegowda, C.; Vogelstein, B.; et al. The Association Between Alpha-1 Adrenergic Receptor Antagonists and In-Hospital Mortality From COVID-19. Front. Med. 2021, 8, 637647. [Google Scholar] [CrossRef] [PubMed]
  125. Thomsen, R.W.; Christiansen, C.F.; Heide-Jørgensen, U.; Vogelstein, J.T.; Vogelstein, B.; Bettegowda, C.; Tamang, S.; Athey, S.; Sørensen, H.T. Association of α1-Blocker Receipt With 30-Day Mortality and Risk of Intensive Care Unit Admission Among Adults Hospitalized with Influenza or Pneumonia in Denmark. JAMA Netw. Open 2021, 4, e2037053. [Google Scholar] [CrossRef]
  126. Konig, M.F.; Powell, M.A.; Staedtke, V.; Bai, R.-Y.; Thomas, D.L.; Fischer, N.M.; Huq, S.; Khalafallah, A.M.; Koenecke, A.; Xiong, R.; et al. Preventing cytokine storm syndrome in COVID-19 using α-1 adrenergic receptor antagonists. J. Clin. Investig. 2020, 130, 3345–3347. [Google Scholar] [CrossRef]
  127. Nishimura, A.; Xie, J.; Kostka, K.; Duarte-Salles, T.; Fernández Bertolín, S.; Aragón, M.; Blacketer, C.; Shoaibi, A.; DuVall, S.L.; Lynch, K.; et al. International cohort study in-dicates no association between alpha-1 blockers and susceptibility to COVID-19 in benign prostatic hyperplasia patients. Front. Pharm. 2022, 13, 945592. [Google Scholar] [CrossRef]
  128. Lund, J.L.; Richardson, D.B.; Stürmer, T. The Active Comparator, New User Study Design in Pharmacoepidemiology: Historical Foundations and Contemporary Application. Curr. Epidemiol. Rep. 2015, 2, 221–228. [Google Scholar] [CrossRef][Green Version]
  129. Schuemie, M.J.; Ryan, P.B.; Man, K.K.; Wong, I.C.; Suchard, M.A.; Hripcsak, G. A plea to stop using the case-control design in retrospective database studies. Stat. Med. 2019, 38, 4199–4208. [Google Scholar] [CrossRef][Green Version]
  130. Liu, S.; Li, W. Prazosin blocks apoptosis of endothelial progenitor cells through downregulating the Akt/NF κB signaling pathway in a rat cerebral infarction model. Exp. Ther. Med. 2020, 20, 2577–2584. [Google Scholar] [CrossRef]
  131. Ferreira, L.C.; Gomes, C.E.; Rodrigues-Neto, J.F.; Jeronimo, S.M. Genome-wide association studies of COVID-19: Connecting the dots. Infect. Genet. Evol. 2022, 106, 105379. [Google Scholar] [CrossRef]
  132. Mustafa, S.; See, H.B.; Seeber, R.M.; Armstrong, S.P.; White, C.W.; Ventura, S.; Ayoub, M.A.; Pfleger, K.D.G. Identification and Profiling of Novel α1A-Adrenoceptor-CXC Chemokine Receptor 2 Heteromer. J. Biol. Chem. 2012, 287, 12952–12965. [Google Scholar] [CrossRef][Green Version]
  133. Albee, L.J.; Eby, J.M.; Tripathi, A.; LaPorte, H.M.; Gao, X.; Volkman, B.F.; Gaponenko, V.; Majetschak, M. a1-Adrenergic Receptors Function Within Hetero-Oligomeric Complexes with Atypical Chemokine Receptor 3 and Chemokine (C-X-C motif) Receptor 4 in Vascular Smooth Muscle Cells. J. Am. Heart Assoc. 2017, 6, e006575. [Google Scholar] [CrossRef]
  134. Gomes, I.; Ayoub, M.A.; Fujita, W.; Jaeger, W.C.; Pfleger, K.D.; Devi, L.A. G Protein–Coupled Receptor Heteromers. Annu. Rev. Pharmacol. Toxicol. 2016, 56, 403–425. [Google Scholar] [CrossRef][Green Version]
  135. Quitterer, U.; AbdAlla, S. Discovery of Pathologic GPCR Aggregation. Front. Med. 2019, 6, 9. [Google Scholar] [CrossRef][Green Version]
  136. Gubbi, S.; Nazari, M.A.; Taieb, D.; Klubo-Gwiezdzinska, J.; Pacak, K. Catecholamine physiology and its implications in pa-tients with COVID-19. Lancet Diabetes Endocrinol. 2020, 8, 978–986. [Google Scholar] [CrossRef]
  137. Szewczykowski, C.; Mardin, C.; Lucio, M.; Wallukat, G.; Hoffmanns, J.; Schröder, T.; Raith, F.; Rogge, L.; Heltmann, F.; Moritz, M.; et al. Long COVID: Association of Functional Autoantibodies against G-Protein-Coupled Receptors with an Impaired Retinal Microcirculation. Int. J. Mol. Sci. 2022, 23, 7209. [Google Scholar] [CrossRef]
  138. Wallukat, G.; Hohberger, B.; Wenzel, K.; Fürst, J.; Schulze-Rothe, S.; Wallukat, A.; Hönicke, A.-S.; Müller, J. Functional autoantibodies against G-protein coupled receptors in patients with persistent Long-COVID-19 symptoms. J. Transl. Autoimmun. 2021, 4, 100100. [Google Scholar] [CrossRef]
  139. Cai, R.; Zhang, Y.; Simmering, J.E.; Schultz, J.L.; Li, Y.; Carasa, I.F.; Consiglio, A.; Raya, A.; Polgreen, P.M.; Narayanan, N.S.; et al. Enhancing glycolysis attenuates Parkinson’s disease progression in models and clinical databases. J. Clin. Investig. 2019, 129, 4539–4549. [Google Scholar] [CrossRef][Green Version]
  140. Chen, X.; Zhao, C.; Li, X.; Wang, T.; Li, Y.; Cao, C.; Ding, Y.; Dong, M.; Finci, L.; Wang, J.-H.; et al. Terazosin activates Pgk1 and Hsp90 to promote stress resistance. Nat. Chem. Biol. 2014, 11, 19–25. [Google Scholar] [CrossRef][Green Version]
  141. Viana, M.V.; Pantet, O.; Bagnoud, G.; Martinez, A.; Favre, E.; Charrière, M.; Favre, D.; Eckert, P.; Berger, M.M. Metabolic and Nutritional Characteristics of Long-Stay Critically Ill Patients. J. Clin. Med. 2019, 8, 985. [Google Scholar] [CrossRef][Green Version]
  142. Lorente, J.A.; Nin, N.; Villa, P.; Vasco, D.; Miguel-Coello, A.B.; Rodriguez, I.; Herrero, R.; Peñuelas, O.; Ruiz-Cabello, J.; Izquierdo-Garcia, J.L. Metabolomic diferences between COVID-19 and H1N1 influenza induced ARDS. Crit. Care 2021, 25, 1–11. [Google Scholar] [CrossRef]
  143. Viana, M.V.; Pantet, O.; Rd, M.C.; Favre, D.; Piquilloud, L.; Schneider, A.G.; Hurni, C.; Berger, M.M. Specific nutrition and metabolic characteristics of critically ill patients with persistent COVID-19. J. Parenter. Enter. Nutr. 2022, 46, 1149–1159. [Google Scholar] [CrossRef] [PubMed]
  144. Chaytow, H.; Carroll, E.; Gordon, D.; Huang, Y.-T.; van der Hoorn, D.; Smith, H.L.; Becker, T.; Becker, C.G.; Faller, K.M.E.; Talbot, K.; et al. Targeting phosphoglycerate kinase 1 with terazosin improves motor neuron phenotypes in multiple models of amyotrophic lateral sclerosis. eBiomedicine 2022, 83. [Google Scholar] [CrossRef] [PubMed]
  145. Richardson, C.D.; Donatucci, C.F.; Page, S.O.; Wilson, K.H.; Schwinn, D.A. Pharmacology of tamsulosin: Saturation-binding isotherms and competition analysis using cloned alpha 1-adrenergic receptor subtypes. Prostate 1997, 33, 55–59. [Google Scholar] [CrossRef]
  146. Wang, Y.; Qian, S.; Zhao, F.; Wang, Y.; Li, J. Terazosin Analogs Targeting Pgk1 as Neuroprotective Agents: Design, Synthesis, and Evaluation. Front. Chem. 2022, 10, 906974. [Google Scholar] [CrossRef]
  147. Simmering, J.E.; Welsh, M.J.; Liu, L.; Narayanan, N.S.; Pottegård, A. Association of Glycolysis-Enhancing α-1 Blockers with Risk of Developing Parkinson Disease. JAMA Neurol. 2021, 78, 407. [Google Scholar] [CrossRef]
  148. Batty, M.; Pugh, R.; Rathinam, I.; Simmonds, J.; Walker, E.; Forbes, A.; Anoopkumar-Dukie, S.; McDermott, C.M.; Spencer, B.; Christie, D.; et al. The Role of α1-Adrenoceptor Antagonists in the Treatment of Prostate and Other Cancers. Int. J. Mol. Sci. 2016, 17, 1339. [Google Scholar] [CrossRef][Green Version]
  149. Fuchs, R.; Schraml, E.; Leitinger, G.; Stelzer, I.; Allard, N.; Haas, H.S.; Schauenstein, K.; Sadjak, A. α1-adrenergic drugs modulate differentiation and cell death of human erythroleukemia cells through non adrenergic mechanism. Exp. Cell Res. 2011, 317, 2239–2251. [Google Scholar] [CrossRef]
  150. Fuchs, R.; Schwach, G.; Stracke, A.; Meier-Allard, N.; Absenger, M.; Ingolic, E.; Haas, H.S.; Pfragner, R.; Sadjak, A. The anti-hypertensive drug prazosin induces apoptosis in the medullary thyroid carcinoma cell line TT. Anticancer Res. 2015, 35, 31–38. [Google Scholar]
  151. Wang, M.; Chang, W.; Zhang, L.; Zhang, Y. Pyroptotic cell death in SARS-CoV-2 infection: Revealing its roles during the immunopathogenesis of COVID-19. Int. J. Biol. Sci. 2022, 18, 5827–5848. [Google Scholar] [CrossRef]
  152. Malekinejad, Z.; Aghajani, S.; Jeddi, M.; Qahremani, R.; Shahbazi, S.; Bagheri, Y.; Ahmadian, E. Prazosin Treatment Protects Brain and Heart by Diminishing Oxidative Stress and Apoptotic Pathways After Renal Ischemia Reperfusion. Drug Res. 2022, 72, 336–342. [Google Scholar] [CrossRef]
  153. Kubacka, M.; Mogilski, S.; Zadrożna, M.; Nowak, B.; Szafarz, M.; Pomierny, B.; Marona, H.; Waszkielewicz, A.; Jawień, W.; Sapa, J.; et al. MH-76, a Novel Non-Quinazoline α1-Adrenoceptor Antagonist, but Not Prazosin Reduces Inflammation and Improves Insulin Signaling in Adipose Tissue of Fructose-Fed Rats. Pharmaceuticals 2021, 14, 477. [Google Scholar] [CrossRef]
  154. Kubacka, M.; Zadrożna, M.; Nowak, B.; Kotańska, M.; Filipek, B.; Waszkielewicz, A.M.; Marona, H.; Mogilski, S. Reversal of cardiac, vascular, and renal dysfunction by non-quinazoline α1-adrenolytics in DOCA-salt hypertensive rats: A comparison with prazosin, a quinazoline-based α1-adrenoceptor antagonist. Hypertens. Res. 2019, 42, 1125–1141. [Google Scholar] [CrossRef]
  155. Yun, J.; Gaivin, R.J.; McCune, D.F.; Boongird, A.; Papay, R.S.; Ying, Z.; Gonzalez-Cabrera, P.J.; Najm, I.; Perez, D.M. Gene expression profile of neurodegeneration induced by 1B-adrenergic receptor overactivity: NMDA/GABAA dysregulation and apoptosis. Brain 2003, 126, 2667–2681. [Google Scholar] [CrossRef]
  156. Zuscik, M.J.; Chalothorn, D.; Hellard, D.; Deighan, C.; McGee, A.; Daly, C.J.; Waugh, D.J.J.; Ross, S.A.; Gaivin, R.J.; Morehead, A.J.; et al. Hypotension, Autonomic Failure, and Cardiac Hypertrophy in Transgenic Mice Overexpressing the α1B-Adrenergic Receptor. J. Biol. Chem. 2001, 276, 13738–13743. [Google Scholar] [CrossRef][Green Version]
  157. Sato, S.; Hatanaka, T.; Yuyama, H.; Ukai, M.; Noguchi, Y.; Ohtake, A.; Taguchi, K.; Sasamata, M.; Miyata, K. Tamsulosin Potently and Selectively Antagonizes Human Recombinant .ALPHA.1A/1D-Adrenoceptors: Slow Dissociation from the .ALPHA.1A-Adrenoceptor May Account for Selectivity for .ALPHA.1A-Adrenoceptor over .ALPHA.1B-Adrenoceptor Subtype. Biol. Pharm. Bull. 2012, 35, 72–77. [Google Scholar] [CrossRef][Green Version]
  158. Sasane, R.; Bartels, A.; Field, M.; Sierra, M.I.; Duvvuri, S.; Gray, D.L.; Pin, S.S.; Renger, J.J.; Stone, D.J. Parkinson disease among patients treated for benign prostatic hyperplasia with α1 adrenergic receptor antagonists. J. Clin. Investig. 2021, 131, e145112. [Google Scholar] [CrossRef]
  159. Shi, T.; Gaivin, R.J.; McCune, D.F.; Gupta, M.; Perez, D.M. Dominance of the α1B-Adrenergic Receptor and its Subcellular Localization in Human and TRAMP Prostate Cancer Cell Lines. J. Recept. Signal Transduct. 2007, 27, 27–45. [Google Scholar] [CrossRef]
  160. Gonzalez-Cabrera, P.J.; Shi, T.; Yun, J.; McCune, D.F.; Rorabaugh, B.R.; Perez, D.M. Differential regulation of the cell cycle by alpha1-adrenergic receptor subtypes. Endocrinology 2004, 145, 5157–5167. [Google Scholar] [CrossRef][Green Version]
  161. Manzo, E.; Lorenzini, I.; Barrameda, D.; O’Conner, A.G.; Barrows, J.M.; Starr, A.; Kovalik, T.; Rabichow, B.E.; Lehmkuhl, E.M.; Shreiner, D.D.; et al. Glycolysis upregulation is neuroprotective as a compensatory mechanism in ALS. eLife 2019, 8, e45114. [Google Scholar] [CrossRef] [PubMed]
  162. Herculano-Houzel, S. Scaling of brain metabolism with a fixed energy budget per neuron: Implications for neuronal activity, plasticity and evolution. PLoS ONE 2011, 6, e17514. [Google Scholar] [CrossRef] [PubMed][Green Version]
  163. Naeem, U.; Arshad, A.R.; Jawed, A.; Eqbal, F.; Imran, L.; Khan, Z.; Ijaz, F. Glycolysis: The Next Big Breakthrough in Parkinson’s Disease. Neurotox. Res. 2022, 40, 1707–1717. [Google Scholar] [CrossRef] [PubMed]
  164. Strope, T.A.; Birky, C.J.; Wilkins, H.M. The Role of Bioenergetics in Neurodegeneration. Int. J. Mol. Sci. 2022, 23, 9212. [Google Scholar] [CrossRef]
  165. Perera, N.D.; Turner, B.J. AMPK Signalling and Defective Energy Metabolism in Amyotrophic Lateral Sclerosis. Neurochem. Res. 2015, 41, 544–553. [Google Scholar] [CrossRef]
  166. Schultz, J.L.; Brinker, A.N.; Xu, J.; Ernst, S.E.; Tayyari, F.; Rauckhorst, A.J.; Liu, L.; Uc, E.Y.; Taylor, E.B.; Simmering, J.E.; et al. A pilot to assess target engagement of terazosin in Parkinson’s disease. Park. Relat. Disord. 2021, 94, 79–83. [Google Scholar] [CrossRef]
  167. Li, T.; Yang, S.; She, X.; Yan, Q.; Zhang, P.; Zhu, H.; Wang, F.; Luo, X.; Sun, X. Modulation of α-adrenoceptor signalling protects photoreceptors after retinal detachment by inhibiting oxidative stress and inflammation. Br. J. Pharmacol. 2018, 176, 801–813. [Google Scholar] [CrossRef][Green Version]
  168. Geracioti, T.D.; Baker, D.G.; Ekhator, N.N.; West, S.A.; Hill, K.K.; Bruce, A.B.; Schmidt, D.; Rounds-Kugler, B.; Yehuda, R.; Keck, P.E.; et al. CSF Norepinephrine Concentrations in Posttraumatic Stress Disorder. Am. J. Psychiatry 2001, 158, 1227–1230. [Google Scholar] [CrossRef]
  169. Mellman, T.A.; Kumar, A.; Kulick-Bell, R.; Kumar, M.; Nolan, B. Nocturnal/daytime urine noradrenergic measures and sleep in combat-related PTSD. Biol. Psychiatry 1995, 38, 174–179. [Google Scholar] [CrossRef]
  170. Southwick, S.M.; Krystal, J.H.; Morgan, C.A.; Johnson, D.; Nagy, L.M.; Nicolaou, A.; Heninger, G.R.; Charney, D.S. Abnormal Noradrenergic Function in Posttraumatic Stress Disorder. Arch. Gen. Psychiatry 1993, 50, 266–274. [Google Scholar] [CrossRef]
  171. Raskind, M.A.; Peskind, E.R.; Kanter, E.D.; Petrie, E.C.; Radant, A.; Thompson, C.E.; Dobie, D.J.; Hoff, D.; Rein, R.J.; Straits-Tröster, K.; et al. Reduction of Nightmares and Other PTSD Symptoms in Combat Veterans by Prazosin: A Placebo-Controlled Study. Am. J. Psychiatry 2003, 160, 371–373. [Google Scholar] [CrossRef]
  172. Raskind, M.A.; Peskind, E.R.; Hoff, D.J.; Hart, K.L.; Holmes, H.A.; Warren, D.; Shofer, J.; O’Connell, J.; Taylor, F.; Gross, C.; et al. A Parallel Group Placebo Controlled Study of Prazosin for Trauma Nightmares and Sleep Disturbance in Combat Veterans with Post-Traumatic Stress Disorder. Biol. Psychiatry 2007, 61, 928–934. [Google Scholar] [CrossRef]
  173. Raskind, M.A.; Peterson, K.; Williams, T.; Hoff, D.J.; Hart, K.; Holmes, H.; Homas, D.; Hill, J.; Daniels, C.; Calohan, J.; et al. A Trial of Prazosin for Combat Trauma PTSD With Nightmares in Active-Duty Soldiers Returned from Iraq and Afghanistan. Am. J. Psychiatry 2013, 170, 1003–1010. [Google Scholar] [CrossRef]
  174. Zhang, Y.; Ren, R.; Vitiello, M.V.; Yang, L.; Zhang, H.; Shi, Y.; Sanford, L.D.; Tang, X. Efficacy and acceptability of psychotherapeutic and pharmacological interventions for trauma-related nightmares: A systematic review and network meta-analysis. Neurosci. Biobehav. Rev. 2022, 139, 104717. [Google Scholar] [CrossRef]
  175. Yücel, D.E.; van Emmerik, A.A.; Souama, C.; Lancee, J. Comparative efficacy of imagery rehearsal therapy and prazosin in the treatment of trauma-related nightmares in adults: A meta-analysis of randomized controlled trials. Sleep Med. Rev. 2019, 50, 101248. [Google Scholar] [CrossRef]
  176. Raskind, M.A.; Peskind, E.R.; Chow, B.; Harris, C.; Davis-Karim, A.; Holmes, H.A.; Hart, K.L.; McFall, M.; Mellman, T.A.; Reist, C.; et al. Trial of Prazosin for Post-Traumatic Stress Disorder in Military Veterans. N. Engl. J. Med. 2018, 378, 507–517. [Google Scholar] [CrossRef]
  177. Duan, Y.; Grady, J.J.; Albertsen, P.C.; Wu, Z.H. Tamsulosin and the risk of dementia in older men with benign prostatic hyperplasia. Pharmacoepidemiol. Drug Saf. 2018, 27, 340–348. [Google Scholar] [CrossRef]
  178. Latvala, L.; Tiihonen, M.; Murtola, T.J.; Hartikainen, S.; Tolppanen, A. Use of α1-adrenoceptor antagonists tamsulosin and alfuzosin and the risk of Alzheimer’s disease. Pharmacoepidemiol. Drug Saf. 2022. [Google Scholar] [CrossRef]
  179. Tae, B.S.; Jeon, B.J.; Choi, H.; Cheon, J.; Park, J.Y.; Bae, J.H. α-Blocker and Risk of Dementia in Patients with Benign Prostatic Hyperplasia: A Nationwide Population Based Study Using the National Health Insurance Service Database. J. Urol. 2019, 202, 362–368. [Google Scholar] [CrossRef]
  180. Dintica, C.S.; Yaffe, K. Epidemiology and Risk Factors for Dementia. Psychiatr. Clin. N. Am. 2022, 45, 677–689. [Google Scholar] [CrossRef]
  181. Leritz, E.C.; McGlinchey, R.E.; Kellison, I.; Rudolph, J.L.; Milberg, W.P. Cardiovascular Disease Risk Factors and Cognition in the Elderly. Curr. Cardiovasc. Risk Rep. 2011, 5, 407–412. [Google Scholar] [CrossRef] [PubMed][Green Version]
  182. Corley, J.; Conte, F.; Harris, S.E.; Taylor, A.M.; Redmond, P.; Russ, T.C.; Deary, I.J.; Cox, S.R. Predictors of longitudinal cognitive ageing from age 70 to 82 including APOE e4 status, early-life and lifestyle factors: The Lothian Birth Cohort 1936. Mol. Psychiatry 2022, 1–16. [Google Scholar] [CrossRef] [PubMed]
  183. Tanaka, M.; Yoshida, M.; Emoto, H.; Ishii, H. Noradrenaline systems in the hypothalamus, amygdala and locus coeruleus are involved in the provocation of anxiety: Basic studies. Eur. J. Pharmacol. 2000, 405, 397–406. [Google Scholar] [CrossRef] [PubMed]
  184. Braga, M.F.M.; Aroniadou-Anderjaska, V.; Manion, S.T.; Hough, C.J.; Li, H. Stress Impairs α1A Adrenoceptor-Mediated Noradrenergic Facilitation of GABAergic Transmission in the Basolateral Amygdala. Neuropsychopharmacology 2003, 29, 45–58. [Google Scholar] [CrossRef]
  185. Doze, V.A.; Handel, E.M.; Jensen, K.A.; Darsie, B.; Luger, E.J.; Haselton, J.R.; Talbot, J.N.; Rorabaugh, B.R. α1A- and α1B-adrenergic receptors differentially modulate antidepressant-like behavior in the mouse. Brain Res. 2009, 1285, 148–157. [Google Scholar] [CrossRef][Green Version]
  186. Fujita, S.; Yoshida, S.; Matsuki, T.; Jaiswal, M.K.; Seki, K. The α1-adrenergic receptors in the amygdala regulate the induction of learned despair through protein kinase C-beta signaling. Behav. Pharmacol. 2020, 32, 73–85. [Google Scholar] [CrossRef]
  187. Holanda, V.A.; Oliveira, M.C.; Junior, E.D.D.S.; Gavioli, E.C. Tamsulosin facilitates depressive-like behaviors in mice: Involvement of endogenous glucocorticoids. Brain Res. Bull. 2021, 178, 29–36. [Google Scholar] [CrossRef]
  188. Kim, Y.J.; Tae, B.S.; Bae, J.H. Cognitive Function and Urologic Medications for Lower Urinary Tract Symptoms. Int. Neurourol. J. 2020, 24, 231–240. [Google Scholar] [CrossRef]
  189. Wong, S.Y.; Hong, A.; Leung, J.; Kwok, T.; Leung, P.C.; Woo, J. Lower urinary tract symptoms and depressive symptoms in elderly men. J. Affect. Disord. 2006, 96, 83–88. [Google Scholar] [CrossRef]
  190. Yang, Y.J.; Koh, J.S.; Ko, H.J.; Cho, K.J.; Kim, J.C.; Lee, S.-J.; Pae, C.-U. The Influence of Depression, Anxiety and Somatization on the Clinical Symptoms and Treatment Response in Patients with Symptoms of Lower Urinary Tract Symptoms Suggestive of Benign Prostatic Hyperplasia. J. Korean Med. Sci. 2014, 29, 1145–1151. [Google Scholar] [CrossRef][Green Version]
  191. Lee, S.-U.; So, A.-H.; Park, J.-I.; Lee, S.; Oh, I.-H.; Oh, C.-M. Association between benign prostatic hyperplasia and suicide in South Korea: A nationwide retrospective cohort study. PLoS ONE 2022, 17, e0265060. [Google Scholar] [CrossRef]
  192. Lusty, A.; Siemens, D.R.; Tohidi, M.; Whitehead, M.; Tranmer, J.; Nickel, J.C. Cardiac Failure Associated with Medical Therapy of Benign Prostatic Hyperplasia: A Population Based Study. J. Urol. 2021, 205, 1430–1437. [Google Scholar] [CrossRef]
  193. Schilit, S.; Benzeroual, K.E. Silodosin: A selective α1A-adrenergic receptor antagonist for the treatment of benign prostatic hyperplasia. Clin. Ther. 2009, 31, 2489–2502. [Google Scholar] [CrossRef]
  194. Chang, D.F.; Campbell, J.R. Intraoperative floppy iris syndrome associated with tamsulosin. J. Cataract. Refract. Surg. 2005, 31, 664–673. [Google Scholar] [CrossRef]
  195. Nakamura, S.; Taniguchi, T.; Suzuki, F.; Akagi, Y.; Muramatsu, I. Evaluation of α1-adrenoceptors in the rabbit iris: Pharmacological characterization and expression of mRNA. Br. J. Pharmacol. 1999, 127, 1367–1374. [Google Scholar] [CrossRef][Green Version]
  196. Suzuki, F.; Taniguchi, T.; Nakamura, S.; Akagi, Y.; Kubota, C.; Satoh, M.; Muramatsu, I. Distribution of alpha-1 adrenoceptor subtypes in RNA and protein in rabbit eyes. Br. J. Pharmacol. 2002, 135, 600–608. [Google Scholar] [CrossRef]
  197. Wang, R.-F.; Lee, P.-Y.; Mittag, T.W.; Podos, S.M.; Serle, J.B. Effect of 5-methylurapidil, an a1a-adrenergic antagonist and 5-hydroxytryptamine1a agonist, on aqueous humor dynamics in monkeys and rabbits. Curr. Eye Res. 1997, 16, 769–775. [Google Scholar] [CrossRef]
  198. Zhan, G.-L.; Toris, C.B.; Camras, C.B.; Wang, Y.-L.; Yablonski, M.E. Bunazosin Reduces Intraocular Pressure in Rabbits by Increasing Uveoscleral Outflow. J. Ocul. Pharmacol. Ther. 1998, 14, 217–228. [Google Scholar] [CrossRef]
  199. Ida, Y.; Sato, T.; Watanabe, M.; Umetsu, A.; Tsugeno, Y.; Furuhashi, M.; Hikage, F.; Ohguro, H. The Selective α1 Antagonist Tamsulosin Alters ECM Distributions and Cellular Metabolic Functions of ARPE 19 Cells in a Concentration-Dependent Manner. Bioengineering 2022, 9, 556. [Google Scholar] [CrossRef]
  200. Bell, C.M.; Hatch, W.V.; Fischer, H.D.; Cernat, G.; Paterson, J.M.; Gruneir, A.; Gill, S.S.; Bronskill, S.E.; Anderson, G.M.; Rochon, P.A. Association Between Tamsulosin and Serious Ophthalmic Adverse Events in Older Men Following Cataract Surgery. JAMA 2009, 301, 1991–1996. [Google Scholar] [CrossRef][Green Version]
  201. Chang, D.F.; Campbell, J.R.; Colin, J.; Schweitzer, C. Prospective Masked Comparison of Intraoperative Floppy Iris Syndrome Severity with Tamsulosin versus Alfuzosin. Ophthalmology 2014, 121, 829–834. [Google Scholar] [CrossRef] [PubMed]
  202. Chatziralli, I.P.; Sergentanis, T.N. Risk Factors for Intraoperative Floppy Iris Syndrome: A Meta-Analysis. Ophthalmology 2011, 118, 730–735. [Google Scholar] [CrossRef] [PubMed]
  203. Haridas, A.; Syrimi, M.; Al-Ahmar, B.; Hingorani, M. Intraoperative floppy iris syndrome (IFIS) in patients receiving tamsulosin or doxazosin—A UK-based comparison of incidence and complication rates. Graefe’s Arch. Clin. Exp. Ophthalmol. 2013, 251, 1541–1545. [Google Scholar] [CrossRef] [PubMed]
  204. Herd, M.K. Intraoperative floppy-iris syndrome with doxazosin. J. Cataract. Refract. Surg. 2007, 33, 562. [Google Scholar] [CrossRef]
  205. Wang, Y.-H.; Huang, L.-C.; Tsai, S.H.L.; Chen, Y.-J.; Wu, C.-L.; Kang, Y.-N. Risk of intraoperative floppy iris syndrome among selective alpha-1 blockers—A consistency model of 6,488 cases. Front. Med. 2022, 9, 941130. [Google Scholar] [CrossRef]
Table 1. α1-Adrenergic Receptor Agonists and Antagonists.
Table 1. α1-Adrenergic Receptor Agonists and Antagonists.
DrugReceptor SelectivityCurrent IndicationsPotential Indications
Norepinephrineα1 = α2 = βSeptic and refractory
Epinephrineα1 = α2 = βshock, Cardiopulmonary arrest
Phenylephrineα1 > α2 >> βPupil dilation, Rosacea
Oxymetazolineα1A > α1D = α1BNasal decongestion, Rosacea
Methoxamineα1A > α1D > α1BSeptic and refractory shock
Cirazolineα1A > α1D > α1B HF, Ischemia, cataracts
A-61603α1A > α1D = α1B HF, Ischemia, cataracts
Dabuzalgronα1A >> α1D = α1B HF, Ischemia, cataracts
Cmpd-3 1α1A >> α1D > α1B AD, HF, Ischemia, cataracts
Prazosinα1A = α1D = α1BBPH, Therapy-resistantCOVID-19/SARS, PD,
Doxazosinα1A = α1D = α1BHypertension,ALS, PTSD,
Terazosinα1A = α1D = α1BPheochromocytomaHyperinflammation
Alfuzosinα1A = α1D = α1B
BMY7378α1D > α1A >> α1B
Tamsulosinα1A = α1D > α1BBPH, Pheochromocytoma
Silodosinα1A > α1D >> α1BBPH
5-Methylurapidilα1A > α1D > α1B
WB4101α1A = α1D > α1B
1 [12]. AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis; BPH, benign prostatic hyperplasia; HF, heart failure; PD, Parkinson’s disease; PTSD, posttraumatic stress disorder; SARS, severe acute syndrome coronavirus 2.
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Perez, D.M. α1-Adrenergic Receptors: Insights into Potential Therapeutic Opportunities for COVID-19, Heart Failure, and Alzheimer’s Disease. Int. J. Mol. Sci. 2023, 24, 4188.

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Perez DM. α1-Adrenergic Receptors: Insights into Potential Therapeutic Opportunities for COVID-19, Heart Failure, and Alzheimer’s Disease. International Journal of Molecular Sciences. 2023; 24(4):4188.

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Perez, Dianne M. 2023. "α1-Adrenergic Receptors: Insights into Potential Therapeutic Opportunities for COVID-19, Heart Failure, and Alzheimer’s Disease" International Journal of Molecular Sciences 24, no. 4: 4188.

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