title: Evidence in favor of a calcium-sensing receptor in arterial endothelial cells: studies with calindol and Calhex 231.
abstract: Small increases in extracellular Ca2+ dilate isolated blood vessels. In the present study, the possibility that a vascular, extracellular Ca2+-sensing receptor (CaSR) could mediate these vasodilator actions was investigated. Novel ligands that interact with the CaSR were used in microelectrode recordings from rat isolated mesenteric and porcine coronary arteries. The major findings were that (1) raising extracellular Ca2+ or adding calindol, a CaSR agonist, produced concentration-dependent hyperpolarizations of vascular myocytes, actions attenuated by Calhex 231, a negative allosteric modulator of CaSR. (2) Calindol-induced hyperpolarizations were inhibited by the intermediate conductance, Ca2+-sensitive K+ (IKCa) channel inhibitors, TRAM-34, and TRAM-39. (3) The effects of calindol were not observed in the absence of endothelium. (4) CaSR mRNA and protein were present in rat mesenteric arteries and in porcine coronary artery endothelial cells. (5) CaSR and IKCa proteins were restricted to caveolin-poor membrane fractions. We conclude that activation of vascular endothelial CaSRs opens endothelial cell IKCa channels with subsequent myocyte hyperpolarization. The endothelial cell CaSR may have a physiological role in the control of arterial blood pressure.
authors.affiliation: Faculty of Life Sciences, University of Manchester, UK.
authors.forename: Arthur H
authors.initials: AH
authors.lastname: Weston
authors.forename: Mais
authors.initials: M
authors.lastname: Absi
authors.forename: Donald T
authors.initials: DT
authors.lastname: Ward
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Ohanian
authors.forename: Robert H
authors.initials: RH
authors.lastname: Dodd
authors.forename: Philippe
authors.initials: P
authors.lastname: Dauban
authors.forename: Christophe
authors.initials: C
authors.lastname: Petrel
authors.forename: Martial
authors.initials: M
authors.lastname: Ruat
authors.forename: Gillian
authors.initials: G
authors.lastname: Edwards
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology; D001794:Blood Pressure; D002118:Calcium / Q000378:metabolism; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D003514:Cyclohexylamines / Q000494:pharmacology*; D042783:Endothelial Cells / Q000502:physiology*; D008297:Male; D008638:Mesenteric Arteries / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D010455:Peptides / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044169:Receptors, Calcium-Sensing / Q000032:analysis / Q000502:physiology*; D013552:Swine
chemical_list: D001549:Benzamides; D001562:Benzimidazoles; D003514:Cyclohexylamines; C482333:N(1)-(4-chlorobenzoyl)-N(2)-(1-(1-naphthyl)ethyl)-1,2-diaminocyclohexane; D010455:Peptides; D015221:Potassium Channels; D044169:Receptors, Calcium-Sensing; D010656:Phenylephrine; C064719:iberiotoxin; C102635:1-ethyl-2-benzimidazolinone; D002118:Calcium