(Hypertension. 1997;30:1431-1439.)
© 1997 American Heart Association, Inc.
Articles |
Perivascular Sensory Nerve Ca2+ Receptor and Ca2+-Induced Relaxation of Isolated Arteries
From the Section of Hypertension and Vascular Research, Departments of Internal Medicine (R.D.B., K.B., M.M.), Physiology and Molecular Biophysics (R.D.B.), and Pharmacology and Toxicology (R.D.B., Y.W.), University of Texas Medical Branch, Galveston Island, Tex.
Correspondence to Richard Bukoski, PhD, Professor of Medicine and Physiology, 8.104 Medical Research Building, University of Texas Medical Branch, Galveston, TX 77555-1065. E-mail rbukoski{at}impo1.utmb.edu
Abstract The present study tested two hypotheses: (1) that a receptor for extracellular Ca2+ (Ca2+ receptor [CaR]) is located in the perivascular sensory nerve system and (2) that activation of this receptor by physiological concentrations of extracellular Ca2+ results in the release of vasodilator substance that mediates Ca2+-induced relaxation. Reverse transcription-polymerase chain reaction using primers derived from rat kidney CaR cDNA sequence showed that mRNA encoding a CaR is present in dorsal root ganglia but not the mesenteric resistance artery. Western blot analysis using monoclonal anti-CaR showed that a 140-kD protein that comigrates with the parathyroid CaR is present in both the dorsal root ganglia and intact mesenteric resistance artery. Immunocytochemical analysis of whole mount preparations of mesenteric resistance arteries showed that the anti-CaR–stained perivascular nerves restricted to the adventitial layer. Biophysical analysis of mesenteric resistance arteries showed that cumulatively raising Ca2+ from 1 to 1.25 mol/L and above relaxes precontracted arteries with an ED50 value of 2.47±0.17 mmol/L (n=12). The relaxation is endothelium independent and is unaffected by blockade of nitric oxide synthase but is completely antagonized by acute and subacute phenolic destruction of perivascular nerves. A bioassay showed further that superfusion of Ca2+ across the adventitial surface of resistance arteries releases a diffusible vasodilator substance. Pharmacological analysis indicates that the relaxing substance is not a common sensory nerve peptide transmitter but is a phospholipase A2/cytochrome P450–derived hyperpolarizing factor that we have classified as nerve-derived hyperpolarizing factor. These data demonstrate that a CaR is expressed in the perivascular nerve network, show that raising Ca2+ from 1 to 1.25 mol/L and above causes nerve-dependent relaxation of resistance arteries, and suggest that activation of the CaR induces the release of a diffusible hyperpolarizing vasodilator. We propose that this system could serve as a molecular link between whole-animal Ca2+ balance and arterial tone.
Key Words: calcium • receptors, sensory • muscle, smooth, vascular • resistance • hyperpolarizing factor
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