Nitric Oxide Synthase Knockout Modulates Ca2+‐Sensing Receptor Expression and Signaling in Mesenteric Arteries

Abstract

Ca2+e‐induced relaxation of mesenteric artery is dependent on the perivascular nerve (PvN) Ca2+‐sensing receptor (CaSR). The CaSR stimulates a cannabinoid vasodilator pathway, with a small (~20%) nitric oxide (NO)‐dependent component. Wire myography of phenylephrine (PE)‐contracted mesenteric arteries was used to determine the source of NO contributing to CaSR‐mediated relaxation in NO synthase (NOS) gene knockout mice in combination with NOS inhibitors. . Endothelial NOS gene knockout (eNOS−/−) up‐regulates, whereas neuronal NOS gene knockout (nNOS−/−) down‐regulates CaSR protein expression. nNOS−/− reduced maximum Ca2+ e‐induced relaxation by ~ 34% with no change in EC50 values, consistent with down‐regulation of the receptor as the non‐selective NOS inhibitor, L‐N5‐(1‐Iminoethyl)‐Ornithine (10 μM) reduced Ca2+ e‐induced relaxation in C57BL/6 control mice by ~ 38% (p < 0.05), but not eNOS−/− mice. The nNOS inhibitor, 7‐Nitroindazole had no effect on arteries from nNOS−/− mice. Both NG‐Nitro‐L‐Arginine Methylester and NG‐Monomethyl‐L‐Arginine reduced Ca2+‐induced relaxation maxima by about 55%, 50% and 30% in C57BL/6, nNOS−/− and eNOS−/− mice, respectively. Thus eNOS down‐regulates the CaSR in mesenteric arteries and contributes to the NO‐mediated Ca2+‐induced relaxation, but nNOS is not a major contributor.Support: HL064761, HL059868, MD000175 & HL099139