| First Author | Awumey EM | Year | 2013 |
| Journal | J Pharmacol Exp Ther | Volume | 346 |
| Issue | 1 | Pages | 38-47 |
| PubMed ID | 23639802 | Mgi Jnum | J:318978 |
| Mgi Id | MGI:6862177 | Doi | 10.1124/jpet.113.205534 |
| Citation | Awumey EM, et al. (2013) Nitric-oxide synthase knockout modulates Ca(2)(+)-sensing receptor expression and signaling in mouse mesenteric arteries. J Pharmacol Exp Ther 346(1):38-47 |
| abstractText | Extracellular calcium (Ca(2)(+)(e))-induced relaxation of isolated, phenylephrine (PE)-contracted mesenteric arteries is dependent on an intact perivascular sensory nerve network that expresses the Ca(2)(+)-sensing receptor (CaSR). Activation of the receptor stimulates an endocannabinoid vasodilator pathway, which is dependent on cytochrome P450 and phospholipase A(2) 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 Ca(2)(+)(e)-induced relaxation of PE-contracted arteries. Endothelial NOS knockout (eNOS(-/-)) upregulates but neuronal NOS knockout (nNOS(-/-)) downregulates CaSR expression. NOS(-/-) reduced maximum Ca(2)(+)(e)-induced relaxation with no change in EC(5)(0) values, with eNOS(-/-) having the largest effect. The responses of vessels to calindol and Calhex 231 indicate that the CaSR mediates relaxation. L-N(5)-(1-iminoethyl)-ornithine reduced Ca(2)(+)(e)-induced relaxation of PE-contracted arteries from C57BL/6 control mice by approximately 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 N(G)-nitro-L-arginine methylester and N(G)-monomethyl-L-arginine significantly reduced the relaxation maxima in all groups. Interestingly, the nNOS-selective inhibitor S-methyl-L-thiocitrulline significantly increased the EC(5)(0) value by approximately 60% in tissues from C57BL/6 mice but reduced the maximum response by approximately 80% in those from nNOS(-/-) mice. Ca(2)(+)-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 Ca(2)(+)(e)-induced relaxation. |
