Published online before print July 21, 2005, doi: 10.1161/01.RES.0000178787.59594.a0
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© 2005 American Heart Association, Inc.
Integrative Physiology |
Evidence in Favor of a Calcium-Sensing Receptor in Arterial Endothelial Cells
Studies With Calindol and Calhex 231
From the Faculty of Life Sciences (A.H.W., M.A., D.T.W., G.E.) and Faculty of Medical and Health Sciences (J.O.), University of Manchester, UK; Institut de Chimie des Substances Naturelles (R.H.D., P.D.), UPR 2301, CNRS, Gif-sur-Yvette, France; and Signal Transduction and Developmental Neuropharmacology (M.R., C.P.), UPR 9040 and IFR 2118, CNRS, Gif-sur-Yvette, France.
Correspondence to Gillian Edwards, University of Manchester, School of Biological Sciences, G38 Stopford Bldg, Oxford Rd, Manchester M13 9PT, UK. E-mail Gillian.Edwards{at}manchester.ac.uk
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.
Key Words: endothelium • calcium-sensing receptor • potassium channel • calindol • Calhex 231
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