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Greenberg, Harry Z. E., Shi, Jian, Jahan, Kazi S., Martinucci, Matthew C., Gilbert, Steven J., Ho, W. S. Vanessa and Albert, Anthony P. 
ORCID: https://orcid.org/0000-0002-3596-9634
(2016)
Stimulation of calcium-sensing receptors induces endothelium-dependent vasorelaxations via nitric oxide production and activation of IKCa channels.
Vascular Pharmacology, 80.
pp. 75-84.
ISSN 1537-1891
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 [Ca2+]o from 1 mM to 6 mM induced concentration-dependent relaxations of methoxamine pre-contracted rabbit mesenteric arteries. [Ca2+]o-induced relaxations were dependent on a functional endothelium, and were inhibited by the negative allosteric CaSR modulator Calhex-231. [Ca2+]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) Ca2+-activated K+ channels (iberiotoxin and charybdotoxin), and Kv7 channels (linopirdine) also reduced [Ca2+]o-induced vasorelaxations. Increasing [Ca2+]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.
| Item Type: | Article |
|---|---|
| Additional Information: | Funding Information: This work was supported by a British Heart Foundation PhD Studentship for H. Z. E. Greenberg ( FS/13/10/30021 to A.P.A ); and by the Biotechnology and Biological Sciences Research Council ( BB/J007226/1 to A.P.A ). Publisher Copyright: © 2016 The Authors. |
| Uncontrolled Keywords: | bkca,calcium-sensing receptors,ikca,nitric oxide,physiology,molecular medicine,pharmacology ,/dk/atira/pure/subjectarea/asjc/1300/1314 |
| Faculty \ School: | Faculty of Medicine and Health Sciences > Norwich Medical School |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 29 Oct 2024 09:30 |
| Last Modified: | 03 Nov 2024 07:30 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/97250 |
| DOI: | 10.1016/j.vph.2016.01.001 |
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