Intracellular acidification inhibits NO synthesis and rho‐kinase‐mediated signaling in arteries

Abstract

We studied the background for pHi‐mediated effects on artery function and blood pressure regulation in knockout mice for Na+,HCO3−‐cotransporter NBCn1 and Na+/H+‐exchanger NHE1. When compared to arteries from wild type, intracellular acidification in arteries from both knockout mouse strains inhibited acetylcholine‐induced NO‐mediated vasodilation while vasodilation to NO‐donors was unaffected. NO concentrations and NO‐synthase activity were reduced in arteries from NBCn1 knockout mice while NO‐synthase expression (total and Ser‐1177 phosphorylated) and endothelial Ca2+ i‐responses to acetylcholine were unchanged. Intracellular acidification also reduced rho‐kinase‐dependent smooth muscle Ca2+‐sensitivity and phosphorylation of myosin phosphatase targeting subunit at Thr‐850. NBCn1 knockout mice were mildly hypertensive at rest and displayed reduced blood pressure responses to L‐NAME treatment, rho‐kinase inhibition or angiotensin II infusion. In conclusion, intracellular acidification inhibits NO synthesis and rho‐kinase‐dependent smooth muscle Ca2+‐sensitivity in arteries and perturbs blood pressure regulation. Financial support: Danish Council for Independent Research and Danish Heart Foundation.