Stimulation of the calcium‐sensing receptor induces relaxations of rat mesenteric arteries by endothelium‐dependent and ‐independent pathways via BKCa and KATP channels

Abstract

AbstractStimulation of the calcium‐sensing receptor (CaSR) induces both vasoconstrictions and vasorelaxations but underlying cellular processes remain unclear. This study investigates expression and effect of stimulating the CaSR by increasing external Ca2+ concentration ([Ca2+]o) on contractility of rat mesenteric arteries. Immunofluorescence studies showed expression of the CaSR in perivascular nerves, vascular smooth muscle cells (VSMCs), and vascular endothelium cells. Using wire myography, increasing [Ca2+]o from 1 to 10 mM induced vasorelaxations which were inhibited by the calcilytic Calhex‐231 and partially dependent on a functional endothelium. [Ca2+]o‐induced vasorelaxations were reduced by endothelial NO synthase (eNOS, L‐NAME) and large conductance Ca2+‐activated K+ channels (BKCa, iberiotoxin), with their inhibitory action requiring a functional endothelium. [Ca2+]o‐induced vasorelaxations were also markedly inhibited by an ATP‐dependent K+ channel (KATP) blocker (PNU37883), which did not require a functional endothelium to produce its inhibitory action. Inhibitor studies also suggested contributory roles for inward rectifying K+ channels (Kir), Kv7 channels, and small conductance Ca2+‐activated K+ channels (SKCa) on [Ca2+]o‐induced vasorelaxations. These findings indicate that stimulation of the CaSR mediates vasorelaxations involving multiple pathways, including an endothelium‐dependent pathway involving NO production and activation of BKCa channels and an endothelium‐independent pathway involving stimulation of KATP channels.