RT Journal Article SR Electronic T1 Nitric-Oxide Synthase Knockout Modulates Ca2+-Sensing Receptor Expression and Signaling in Mouse Mesenteric Arteries JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 38 OP 47 DO 10.1124/jpet.113.205534 VO 346 IS 1 A1 Emmanuel M. Awumey A1 Lakeesha E. Bridges A1 Cicely L. Williams A1 Debra I. Diz YR 2013 UL http://jpet.aspetjournals.org/content/346/1/38.abstract AB Extracellular calcium (Ca2+e)-induced relaxation of isolated, phenylephrine (PE)-contracted mesenteric arteries is dependent on an intact perivascular sensory nerve network that expresses the Ca2+-sensing receptor (CaSR). Activation of the receptor stimulates an endocannabinoid vasodilator pathway, which is dependent on cytochrome P450 and phospholipase A2 but largely independent of the endothelium. In the present study, we determined the role of nitric oxide (NO) in perivascular nerve CaSR-mediated relaxation of PE-contracted mesenteric resistance arteries isolated from mice. Using automated wire myography, we studied the effects of NO synthase (NOS) gene knockout (NOS−/−) and pharmacologic inhibition of NOS on Ca2+e-induced relaxation of PE-contracted arteries. Endothelial NOS knockout (eNOS−/−) upregulates but neuronal NOS knockout (nNOS−/−) downregulates CaSR expression. NOS−/− reduced maximum Ca2+e-induced relaxation with no change in EC50 values, with eNOS−/− having the largest effect. The responses of vessels to calindol and Calhex 231 indicate that the CaSR mediates relaxation. l-N5-(1-iminoethyl)-ornithine reduced Ca2+e-induced relaxation of PE-contracted arteries from C57BL/6 control mice by ≈38% but had a smaller effect in vessels from eNOS−/− mice. 7-Nitroindazole had no significant effect on relaxation of arteries from NOS−/− mice, but both NG-nitro-l-arginine methylester and NG-monomethyl-l-arginine significantly reduced the relaxation maxima in all groups. Interestingly, the nNOS-selective inhibitor S-methyl-l-thiocitrulline significantly increased the EC50 value by ≈60% in tissues from C57BL/6 mice but reduced the maximum response by ≈80% in those from nNOS−/− mice. Ca2+-activated big potassium channels play a major role in the process, as demonstrated by the effect of iberiotoxin. We conclude that CaSR signaling in mesenteric arteries stimulates eNOS and NO production that regulates Ca2+e-induced relaxation.