Abstract
The potential role of calcimimetics as vasculotropic agents has been suggested since the discovery that calcium sensing receptors (CaSRs) are expressed in cardiovascular tissues. However, whether this effect is CaSR-dependent or -independent is still unclear. In the present study the vascular activity of calcimimetic R-568 was investigated in mesenteric vascular beds (MVBs) isolated from Spontaneously Hypertensive rats (SHR) and the relative age-matched Wistar-Kyoto (WKY) control rats. Pre-constricted MBVs were perfused with increasing concentrations of R-568 (10 nM– 30 μM) resulting in a rapid dose-dependent vasodilatation. However, in MVBs from SHR this was preceded by a small but significant vasoconstriction at lowest nanomolar concentrations used (10–300 nM). Pre-treatment with pharmacological inhibitors of nitric oxide (NO) synthase (NOS, L-NAME), KCa channels (CTX), cyclo-oxygenase (INDO) and CaSR (Calhex) or the endothelium removal suggest that NO, CaSR and the endothelium itself contribute to the R-568 vasodilatory/vasoconstrictor effects observed respectively in WKY/SHR MVBs. Conversely, the vasodilatory effects resulted by highest R-568 concentration were independent of these factors. Then, the ability of lower R-568 doses (0.1–1 μM) to activate endothelial-NOS (eNOS) pathway in MVBs homogenates was evaluated. The Akt and eNOS phosphorylation levels resulted increased in WKY homogenates and Calhex significantly blocked this effect. Notably, this did not occur in the SHR. Similarly, vascular smooth muscle cells (vSMCs) stimulation with lower R-568 doses resulted in Akt activation and increased NO production in WKY but not in SHR cells. Interestingly, in these cells this was associated with the absence of the biologically active dimeric form of the CaSR thus potentially contributing to explain the impaired vasorelaxant effect observed in response to R-568 in MVB from SHR compared to WKY. Overall, these findings provide new insight on the mechanisms of action of the calcimimetic R-568 in modulating vascular tone both in physiological and pathological conditions such as hypertension.
Highlights
The extracellular calcium (Ca2+) sensing receptors (CaSRs) are important in maintaining and regulating mineral ion homeostasis in parathyroid, kidney, gut and bone tissues [1, 2]
The discovery that calcium sensing receptors (CaSRs) are widely expressed in the heart as well as in the blood vessels has suggested their physiological involvement in cardiovascular processes such as vessel remodeling and calcification; acute CaSR-mediated activation has been proposed to participate in the maintenance of vascular tone and modulation of blood pressure levels [3,4,5,6,7,8]
Calcimimetics are allosteric CaSR activators proposed as potential anti-hypertensive drugs following the discovery that their systemic administration reduces blood pressure in animal models [3,4,5]
Summary
The extracellular calcium (Ca2+) sensing receptors (CaSRs) are important in maintaining and regulating mineral ion homeostasis in parathyroid, kidney, gut and bone tissues [1, 2]. CaSR seems actively involved in the modulation of myogenic tone in response to changes in Ca2+ concentration, as initially demonstrated in rat subcutaneous small arteries and more recently observed in aorta and mesenteric artery of transgenic mice with specific CaSR knockout (CaSR KO) in vascular smooth muscle cells (vSMCs) [5, 12] These data, together with other recent evidences, suggest that CaSR may mediate a dual direct activity on blood vessels: activation of endothelial CaSR results in a NO-dependent pro-relaxing effect, whereas stimulation of CaSR located on vSMCs may elicit a pro-contractile effect [13, 14]
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