Eduardo Rivera-Mancilla, Usha M Musterd-Bhaggoe, Dennis Schutter, Antoon van den Bogaerdt, Arnaud J P E Vincent, Carlos M Villalón, Alexander H J Danser, Antoinette MaassenVanDenBrink
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引用次数: 0
Abstract
Background and purpose: Sex-dependent vascular effects of transient receptor potential (TRP) channels and sex dimorphism in migraine are not yet fully characterized. We investigated the differential vasoactive effects of TRP ankyrin 1 (TRPA1), TRP melastatin 3 (TRPM3) and TRP vanilloid 1 (TRPV1) channels, their pharmacological mechanism(s), and localization and expression in human isolated blood vessels.
Experimental approach: Agonist responses to cinnamaldehyde (TRPA1), pregnenolone sulfate (PregS, TRPM3) or capsaicin (TRPV1) were analysed using wire myography in segments of human coronary (HCAs) and middle meningeal (HMMAs) arteries from men and women. The mechanisms involved in these responses were investigated using the antagonists/blockers/inhibitors: HC-030031 (TRPA1), isosakuranetin (TRPM3), capsazepine (TRPV1), olcegepant (calcitonin gene-related peptide [CGRP] receptor), L-NAME (nitric oxide synthase [NOS]), indomethacin (cyclooxygenase [COX]), TRAM-34 + apamin (K+ channels) or MK-801 (N-methyl-d-aspartate [NMDA] receptor). Fluorescence microscopy, quantitative polymerase chain reaction (qPCR), and western blotting were performed to investigate their location and expression, respectively.
Key results: In HCAs and HMMAs, (i) capsaicin-induced relaxation remained unchanged after the above-mentioned antagonists/blockers/inhibitors and (ii) cinnamaldehyde-induced relaxation was blocked by olcegepant. PregS-induced maximal relaxation was significantly enhanced in isolated arteries from females compared with males and was inhibited after isosakuranetin, MK-801 or L-NAME. TRPM3 mRNA and protein expression, along with NMDA protein levels, were higher in arteries from females than males.
Conclusion and implications: Modulation of vascular tone in HCAs and HMMAs by activation of TRPM3 is sex-dependent, likely involving NMDA receptors. This represents a new therapeutic direction, targeting sex dimorphism in migraine and its related cardiovascular events.
期刊介绍：
The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries.
Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues.
In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.
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