title: Stimulation of calcium-sensing receptors induces endothelium-dependent vasorelaxations via nitric oxide production and activation of IKCa channels.
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.
authors.affiliation: Vascular Biology Research Centre, Institute of Cardiovascular & Cell Sciences, St. George's, University of London, Cranmer Terrace, London SW17 0RE, UK. Electronic address: m0600877@sgul.ac.uk.
authors.forename: Harry Z E
authors.initials: HZ
authors.lastname: Greenberg
authors.affiliation: Vascular Biology Research Centre, Institute of Cardiovascular & Cell Sciences, St. George's, University of London, Cranmer Terrace, London SW17 0RE, UK.
authors.forename: Jian
authors.initials: J
authors.lastname: Shi
authors.affiliation: Vascular Biology Research Centre, Institute of Cardiovascular & Cell Sciences, St. George's, University of London, Cranmer Terrace, London SW17 0RE, UK.
authors.forename: Kazi S
authors.initials: KS
authors.lastname: Jahan
authors.affiliation: Vascular Biology Research Centre, Institute of Cardiovascular & Cell Sciences, St. George's, University of London, Cranmer Terrace, London SW17 0RE, UK.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Martinucci
authors.affiliation: Vascular Biology Research Centre, Institute of Cardiovascular & Cell Sciences, St. George's, University of London, Cranmer Terrace, London SW17 0RE, UK.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Gilbert
authors.affiliation: Vascular Biology Research Centre, Institute of Cardiovascular & Cell Sciences, St. George's, University of London, Cranmer Terrace, London SW17 0RE, UK.
authors.forename: W-S
authors.initials: WS
authors.lastname: Vanessa Ho
authors.affiliation: Vascular Biology Research Centre, Institute of Cardiovascular & Cell Sciences, St. George's, University of London, Cranmer Terrace, London SW17 0RE, UK.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Albert
mesh_terms: D000818:Animals; D002122:Calcium Chloride / Q000494:pharmacology; D055724:Electrophysiological Phenomena; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D009213:Myography; D009569:Nitric Oxide / Q000096:biosynthesis*; D018408:Patch-Clamp Techniques; D011817:Rabbits; D044169:Receptors, Calcium-Sensing / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
chemical_list: D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D044169:Receptors, Calcium-Sensing; D009569:Nitric Oxide; D002122:Calcium Chloride
keywords: BKCa; Calcium-sensing receptors; IKCa; Nitric oxide