Perivascular Sensory Nerve Ca 2+ Receptor and Ca 2+ -Induced Relaxation of Isolated Arteries

Author:

Bukoski Richard D.1,Bian Ka1,Wang Yanlin1,Mupanomunda Maria1

Affiliation:

1. 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.

Abstract

Abstract The present study tested two hypotheses: (1) that a receptor for extracellular Ca 2+ (Ca 2+ receptor [CaR]) is located in the perivascular sensory nerve system and (2) that activation of this receptor by physiological concentrations of extracellular Ca 2+ results in the release of vasodilator substance that mediates Ca 2+ -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 Ca 2+ from 1 to 1.25 mol/L and above relaxes precontracted arteries with an ED 50 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 Ca 2+ 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 A 2 /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 Ca 2+ 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 Ca 2+ balance and arterial tone.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Internal Medicine

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