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

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.

Evidence for a functional calcium-sensing receptor that modulates myogenic tone in rat subcutaneous small arteries

“…However, the recent discovery of the CaR in vascular tissues raises the possibility that such a receptor could play a role also in modulating contractility in response to changes in [Ca 2ϩ ] o . The CaR has been found in a wide range of rat small arteries: mesenteric, basilar, renal, coronary (10,43), and here in subcutaneous vessels, where we detected a 159-kDa CaR-reactive protein consistent with that observed in the rat kidney (47). Immunohistochemistry demonstrated that in mesenteric, basilar, renal, and coronary arteries, the receptor was localized to perivascular nerves (10,43), although the expression in coronary arteries was low compared with the other arteries.…”

“…The CaR has been found in a wide range of rat small arteries: mesenteric, basilar, renal, coronary (10,43), and here in subcutaneous vessels, where we detected a 159-kDa CaR-reactive protein consistent with that observed in the rat kidney (47). Immunohistochemistry demonstrated that in mesenteric, basilar, renal, and coronary arteries, the receptor was localized to perivascular nerves (10,43), although the expression in coronary arteries was low compared with the other arteries. Increasing [Ca 2ϩ ] o from 1.5 to 5 mM caused a concentration-dependent relaxation of these arteries except for the coronaries, which showed very little response (43), suggesting that Ca o 2ϩ was activating a neuronally mediated vasodilatory response possibly through the CaR.…”

“…Increasing [Ca 2ϩ ] o from 1.5 to 5 mM caused a concentration-dependent relaxation of these arteries except for the coronaries, which showed very little response (43), suggesting that Ca o 2ϩ was activating a neuronally mediated vasodilatory response possibly through the CaR. Further studies with rat mesenteric arteries demonstrated that this most probably was the case (10,34,44) and that the neuronally released vasodilator substance was a cannibinoid (21). However, these studies were all performed using arteries preconstricted by agonists and under isometric conditions.…”

“…In this regard, CaR expression has been reported in the perivascular sensory nerves of rat small mesenteric (10), basilar, renal, and coronary arteries (43). Increasing [Ca 2ϩ ] o (1.25-5 mM) induced a concentration-dependent relaxation of rat small mesenteric arteries precontracted with norepinephrine that was dependent on intact perivascular nerves (10,34,44) and associated with the release of a neurally derived relaxing factor, possibly the cannabinoid anandamide (21).…”

Prognostic Significance of Serum Calcium Level in a Sample of Egyptian Patients With Intracerebral Hemorrhage.

“…As calcium in its normal levels was reported to induce vascular relaxation of isolated arteries through activation of calcium receptors in the perivascular nerves 25 . The last proposed mechanism that explain the association between Ca and ICH is that lower serum Ca could reflect a poor liver function as stated by Inuo et ., 13 who observed in their study a higher percentage of ICH patients having poor liver function and hence poor coagulation resulting in the large hematoma volume.…”