Blocking the CGRP Receptor: Differences across Human Vascular Beds

Round 1

Reviewer 1 Report

The study in question aims to evaluate whether an evaluation of measurements obtained with a Schild plot can be used as a pharmacological tool to enhance comprehension of the interaction between a receptor antagonist and the receptor(s) it binds to. The work protocol and methodology are adequate for the purpose of the work, and so are the figures and references. The discussion is well articulated and the possible interpretations of the data obtained are clear and coherent. These data strongly suggest that there is a relevant cross-activation within the CGRP receptor family. The conclusions are balanced and consequent with the discussion elaborated

Author Response

We are very happy to hear that the work performed in the manuscript is considered adequate, well-articulated, clear and coherent. We want to thank the reviewer for their efforts.

Reviewer 2 Report

 This is a study assessing the effect of zavegepant in human coronary arteries. Moreover, the authors put their results in the context of other similar studies performed by this group. The study design and execution are scientifically sound. There are no major limitations to this study. Among minor issues I would recommend:

- increasing the relevance of results to readers by indicating how the concentrations used in experiment relate to plasma levels achieved in vivo;

- comment whether CGRP receptor polymorphisms may have influenced the results, especially since the experiment was performed on arteries obtained from just 7 donors. In this context, I would also like to draw the attention of authors to a recent study that indicated that baseline cerebral blood flow is different in good respondents to CGRP-pathway antagonists (10.3389/fneur.2022.895476). One of the expalnation of this observation might be related to differnece in responce to CGRP, at the receptor level.

- rephrasing part of line 36 where authors seem to refer to seven-transmembrane-domain G protein-coupled receptor;

In conclusion, this is a highly relevant, well performed study. The results are significant, especially in a context of recent worldwide introduction of gepants for migraine therapy. Gepants are considered to pose little cardiovascular risk. However, the conclusions from this study indicate, that these medications are not homogenous in this aspect. Future studies should concentrate especially on cardiovascular safety of zavegepant and ubrogepant.

Author Response

Please see the attachment.

Author Response File: Author Response.docx