NHE1 knockout reduces blood pressure and arterial media/lumen ratio with no effect on resting pHi in the vascular wall

Acid-base transport in the vascular wall remains incompletely understood. Here, we investigated (a) implications of Na+/H+ exchanger NHE1 knockout for vascular smooth muscle (VSMC) and endothelial cell (EC) pHi regulation, mesenteric artery morphology, vasomotor function and blood pressure regulation, and (b) consequences of sustained EC and VSMC acidification for vasomotor function. Na+/H+ exchange activity was abolished in VSMCs and ECs from NHE1 knockout mice, but with CO2/HCO3-present, steady-state pHi was unaffected. Active tension was 30% smaller in arteries from NHE1 knockout than wild-type mice, and media thickness equally reduced. Number of VSMCs per unit artery length was unchanged whereas volume and cross-sectional area of individual VSMCs were reduced. Media stress, force production per VSMC cross-sectional area and VSMC Ca2+ responses were unaffected. Blood pressure was 25 mmHg lower in NHE1 knockout than wild-typemice. Omission of CO2/HCO3caused VSMCs and ECs to acidify substantially more in NHE1 knockout (0.3-0.6 pH-units) than wild-type (0.02-0.1 pH units) mice. Removing CO2/HCO3-inhibited acetylcholine-induced NO-mediated relaxations in arteries from NHE1 knockout but not wild-type mice. Without CO2/HCO3-, effects of NO synthase and rho kinase inhibition on noradrenaline-induced contractions were smaller in arteries from NHE1 knockout than wild-type mice whereas the EC Ca2+ response to acetylcholine, VSMC Ca2+ response to noradrenaline and vasorelaxation to S-nitroso-N-acetylpenicillaminewere unaffected. In conclusion, NHE1mediates the Na+/H+ exchange in ECs and VSMCs. Under physiological conditions, CO2/HCO3-- of VSMCdependent mechanisms mask the pHi-regulatory function of NHE1. NHE1 knockout causes hypotrophys, reduced artery tension and lower blood pressure. At acidic pHi, NO-mediated vasorelaxation and rho kinase-dependent VSMC Ca2+ sensitivity are reduced.