Intracellular alkalinization induced by bradykinin sustains activation of the constitutive nitric oxide synthase in endothelial cells

Circulation Research
I FlemingR Busse

Abstract

The transient increase in [Ca2+]i in endothelial cells after stimulation with bradykinin can account for the initiation but not the sustained production of nitric oxide (NO). Therefore, we investigated whether this sustained activation of the constitutive NO synthase (cNOS) could be mediated by an increase in pHi, which is induced by an activation of the Na(+)-H+ exchanger rather than an increase in [Ca2+]i. Cultured human endothelial cells grown on coverslips were loaded with either C.SNAFL-2 or fura 2-AM for fluorometric analysis of either pHi or [Ca2+]i. NO release was assayed by the ability of effluent from endothelial cells to stimulate purified soluble guanylyl cyclase. The pH dependence of a microsomal cNOS preparation was determined by assay of L-[3H]citrulline formation from L-[3H]arginine. Bradykinin (10 nmol/L) induced a biphasic change in endothelial pHi consisting of an initial acidification followed by a prolonged alkalinization above resting values. Inhibition of the Na(+)-H+ exchanger using HOE 694 (10 mumol/L) prevented this increase in pHi. The L-citrulline assay revealed a twofold increase in cNOS activity on increasing pH from 6.7 to 7.4, an optimum at pH 7.5, and a complete abolition of activity at pH 8.6. ...Continue Reading

Associated Clinical Trials

Mar 24, 2015·Eduesley Santana Santos

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Citations

Nov 19, 2002·Journal of Physiology and Biochemistry·T CarbonellL Palacios
Sep 12, 2000·Current Hypertension Reports·R Busse, I Fleming
Aug 4, 1997·The American Journal of Cardiology·I Fleming, R Busse
Jul 25, 1997·Atherosclerosis·G R UpchurchJ Loscalzo
Nov 1, 1996·Progress in Cardiovascular Diseases·P M Vanhoutte, J V Mombouli
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Oct 7, 2017·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Ebbe Boedtkjer

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