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

Abstract

), and, recently, a receptor that senses changes in Ca 2ϩ , the calcium-sensing receptor (CaR), has been detected in vascular tissue. We investigated whether the CaR is involved in the regulation of myogenic tone in rat subcutaneous small arteries. Immunoblot analysis using a monoclonal antibody against the CaR demonstrated its presence in rat subcutaneous arteries. To determine whether the CaR was functionally active, segments of artery (Ͻ250 m internal diameter) mounted in a pressure myograph with an intraluminal pressure of 70 mmHg were studied after the development of myogenic tone. Increasing Ca o 2ϩ concentration ([Ca 2ϩ ]o) cumulatively from 0.5 to 10 mM induced an initial constriction (0.5-2 mM) followed by dilation (42 Ϯ 5% loss of tone). The dose-dependent dilation was mimicked by other known CaR agonists including magnesium (1-10 mM) and the aminoglycosides neomycin (0.003-10 mM) and kanamycin (0.003-3 mM). PKC activation with the phorbol ester phorbol-12,13-dibutyrate (20nM) inhibited the dilation induced by high [Ca 2ϩ ]o or neomycin, whereas inhibition of PKC with GF109203X (10 M) increased the responses to Ca o 2ϩ or neomycin, consistent with the role of PKC as a negative regulator of the CaR. We conclude that rat subcutaneous arteries express a functionally active CaR that may be involved in the modulation of myogenic tone and hence the regulation of peripheral vascular resistance. vascular smooth muscle; magnesium; aminoglycosides; contractility; peripheral vascular resistance THE EXTRACELLULAR CALCIUM-SENSING RECEPTOR (CaR) is a G protein-coupled receptor capable of sensing changes in extracellular calcium (Ca o 2ϩ ) concentration ([Ca 2ϩ ] o ). Primarily, the CaR regulates calcium homeostasis by suppressing parathyroid hormone secretion and renal Ca 2ϩ reabsorption. In addition, the CaR is also expressed in tissues and cell types outside the calcium homeostatic system including neural and cardiovascular tissues [reviewed by Brown and Macleod (8)]. However, the functional significance of the receptor in these noncalcium homeostatic tissues remains unclear.Calcium is an important regulator of contractility. Elevated intracellular calcium (Ca i 2ϩ ) levels stimulate smooth muscle contraction (17), and Ca o 2ϩ is required for the maintenance of myogenic tone (14), the intrinsic contractile activity of arterial wall smooth muscle that represents an important determinant of vascular resistance. The response to Ca o 2ϩ varies between artery type with some tissues showing contraction and others relaxation (3, 22, 35, 49 -51), but, in either case, these studies demonstrate that arteries can sense changes in [Ca 2ϩ ] o . 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...

Acute Blood Pressure Effects and Chronic Hypotensive Action of Calcimimetics in Uremic Rats

“…This is compatible with a compensatory increase in HR in response to a decrease of BP induced by vasodilation of resistance arteries. The CaR is expressed in a wide variety of rat small arteries, including renal, mesenteric, cerebral, and subcutaneous vessels (11)(12)(13). It has been localized in adventitial perivascular nerves.…”

“…Activation of the CaR by a progressive increase in ambient calcium results in a U-shaped response with constriction at medium calcium concentrations and marked vasodilation at high and low calcium concentrations. The known agonists magnesium and aminoglycosides induce dose-dependent vascular (11); the neuronally released vasodilator substance is a cannabinoid receptor agonist (14). Accordingly, R-568 may result in reduced peripheral vascular resistance in the rat model, either directly via activation of the CaR or indirectly by the decrease of ionized calcium to subnormal levels.…”

Hypertensive effect of calcilytic NPS 2143 administration in rats

“…Several investigators have reported that the CaR is expressed in many cardiovascular tissues, including human aortic endothelial cells (Ziegelstein et al 2006), rat cardiomyocytes (Tfelt-Hansen et al 2006) and is also present in rat s.c. small arteries (Ohanian et al 2005). Therefore, the influence of calcilytic on blood pressure is not excluded.…”

Impact of Treatment with Calcimimetics on Hyperparathyroidism and Vascular Mineralization

“…The most valuable explanation is related to the control of PTH levels without increasing the Ca ϫ P. Lopez et al (49), in addition, pointed to a direct action of calcimimetic at the cellular level on the arterial wall. Vessels express CaR (50), and some investigators have demonstrated the presence of CaR using a polyclonal antibody to the CaR (51), whereas other preliminary studies have failed to detect CaR in bovine and human VSMC using RNase protection assays (52). Calcium modulates the function of vessels, and it is of considerable importance the findings that calcimimetics influence BP profile.…”