Stimulation of the calcium-sensing receptor induces relaxations of rat mesenteric arteries by endothelium-dependent and -independent pathways via BK_Ca and K_ATP channels

Stimulation 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 (BK_Ca , iberiotoxin), with their inhibitory action requiring a functional endothelium. [Ca²⁺ ]_o -induced vasorelaxations were also markedly inhibited by an ATP-dependent K⁺ channel (K_ATP ) 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 (K_ir ), Kv7 channels, and small conductance Ca²⁺ -activated K⁺ channels (SK_Ca ) 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 BK_Ca channels and an endothelium-independent pathway involving stimulation of K_ATP channels.