Knockout of Na+/Ca^sup 2+^ exchanger in smooth muscle attenuates vasoconstriction and L-type Ca^sup 2+^ channel current and lowers blood pressure

Mice with smooth muscle (SM)-specific knockout of Na.../Ca... exchanger type-1 (NCX1...) and the NCX inhibitor, SEA0400, were used to study the physiological role of NCX1 in mouse mesenteric arteries. NCX1 protein expression was greatly reduced in arteries from NCX1... mice generated with Cre recombinase. Mean blood pressure (BP) was 6-10 mmHg lower in NCX1... mice than in wild-type (WT) controls. Vasoconstriction was studied in isolated, pressurized mesenteric small arteries from WT and NCX1... mice and in heterozygotes with a global null mutation (NCX1...). Reduced NCX1 activity was manifested by a marked attenuation of responses to low extracellular Na... concentration, nanomolar ouabain, and SEA0400. Myogenic tone (MT, 70 mmHg) was reduced by 15% in NCX1... arteries and, to a similar extent, by SEA0400 in WT arteries. MT was normal in arteries from NCX1... mice, which had normal BP. Vasoconstrictions to phenylephrine and elevated extracellular K... concentration were significantly reduced in NCX1... arteries. Because a high extracellular K... concentration-induced vasoconstriction involves the activation of L-type voltage-gated Ca... channels (LVGCs), we measured LVGC-mediated currents and Ca... sparklets in isolated mesenteric artery myocytes. Both the currents and the sparklets were significantly reduced in NCX1... (vs. WT or NCX1...) myocytes, but the voltage-dependent inactivation of LVGCs was not augmented. An acute application of SEA0400 in WT myocytes had no effect on LVGC current. The LVGC agonist, Bay K 8644, eliminated the differences in LVGC currents and Ca... sparklets between NCX1... and control myocytes, suggesting that LVGC expression was normal in NCX1... myocytes. Bay K 8644 did not, however, eliminate the difference in myogenic constriction between WT and NCX1...arteries. We conclude that, under physiological conditions, NCX1-mediated Ca... entry contributes significantly to the maintenance of MT. In NCX1... mouse artery myocytes, the reduced Ca... entry via NCX1 may lower cytosolic Ca... concentration and thereby reduce MT and BP. The reduced LVGC activity may be the consequence of a low cytosolic Ca... concentration. (ProQuest: ... denotes formulae/symbols omitted.)