L-Type Voltage-Gated Ca2+ Channels Are Targeted by Terpenes from Hyptis crenata Essential Oil in Vascular Electromechanical Coupling

Background: Electromechanical coupling is a fundamental process in the regulation of vascular smooth muscle contraction. It is characterized by changes in electrical potential membrane (depolarization). Voltage-gated calcium channels (VGCCs) play a central role in this process by mediating calcium influx necessary for vascular contraction. As highly conserved macromolecules in mammals, VGCCs represent translationally relevant targets for the development of vasorelaxant agents. Inhibition of these channels reduces calcium influx and attenuates the tonic smooth muscle contraction, making them strategic targets for novel therapeutic approaches. This is particularly important given the high prevalence of cardiovascular diseases, which remain the leading cause of global mortality. Methods: The aim of this study is to investigate the mechanism of action of terpenes in VGCCs. Terpenes are phytochemicals that have been widely studied as drug candidates. To this end, the oil from Hyptis crenata was extracted and characterized, revealing monoterpenes and sesquiterpenes as its main constituents. Results: In vitro assays on isolated aortic rings, with and without endothelium, demonstrated that these compounds reverse and block KCl (80 mM)-induced contractions in an endothelium-independent manner. Conclusions: Analyses of the ionic influx of calcium and barium indicated a progressive blockade of contraction, reinforcing the hypothesis of a direct interaction with the macromolecules of the VGCCs. Computational analyses, for the first time, suggest a potential synergistic interaction among terpenes in their binding to these macromolecules.