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Vascul Pharmacol ; 80: 75-84, 2016 May.
Article in English | MEDLINE | ID: mdl-26772767

ABSTRACT

Stimulation of vascular calcium-sensing receptors (CaSRs) is reported to induce both constrictions and relaxations. However, cellular mechanisms involved in these responses remain unclear. The present study investigates the effect of stimulating CaSRs on vascular contractility and focuses on the role of the endothelium, nitric oxide (NO) and K(+) channels in these responses. In wire myography studies, increasing [Ca(2+)]o from 1mM to 6mM induced concentration-dependent relaxations of methoxamine pre-contracted rabbit mesenteric arteries. [Ca(2+)]o-induced relaxations were dependent on a functional endothelium, and were inhibited by the negative allosteric CaSR modulator Calhex-231. [Ca(2+)]o-induced relaxations were reduced by inhibitors of endothelial NO synthase, guanylate cyclase, and protein kinase G. CaSR activation also induced NO production in freshly isolated endothelial cells (ECs) in experiments using the fluorescent NO indicator DAF-FM. Pre-treatment with inhibitors of large (BKCa) and intermediate (IKCa) Ca(2+)-activated K(+) channels (iberiotoxin and charybdotoxin), and Kv7 channels (linopirdine) also reduced [Ca(2+)]o-induced vasorelaxations. Increasing [Ca(2+)]o also activated IKCa currents in perforated-patch recordings of isolated mesenteric artery ECs. These findings indicate that stimulation of CaSRs induces endothelium-dependent vasorelaxations which are mediated by two separate pathways involving production of NO and activation of IKCa channels. NO stimulates PKG leading to BKCa activation in vascular smooth muscle cells, whereas IKCa activity contributes to endothelium-derived hyperpolarisations.


Subject(s)
Endothelium, Vascular/metabolism , Intermediate-Conductance Calcium-Activated Potassium Channels/metabolism , Mesenteric Arteries/metabolism , Nitric Oxide/biosynthesis , Receptors, Calcium-Sensing/metabolism , Vasodilation/physiology , Animals , Calcium Chloride/pharmacology , Electrophysiological Phenomena , Endothelium, Vascular/drug effects , Endothelium, Vascular/physiopathology , Immunohistochemistry , In Vitro Techniques , Isometric Contraction/drug effects , Male , Mesenteric Arteries/drug effects , Mesenteric Arteries/physiopathology , Myography , Patch-Clamp Techniques , Rabbits , Vasodilation/drug effects
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