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

摘要

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) pH i 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 CO 2/HCO 3 - present, steady-state pH i 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 Ca 2+ responses were unaffected. Blood pressure was 25 mmHg lower in NHE1 knockout than wild-type mice. Omission of CO 2/HCO 3 - caused 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 CO 2/HCO 3 - inhibited acetylcholine-induced NO-mediated relaxations in arteries from NHE1 knockout but not wild-type mice. Without CO 2/HCO 3 -, 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 Ca 2+ response to acetylcholine, VSMC Ca 2+ response to noradrenaline and vasorelaxation to S-nitroso-N-acetylpenicillamine were unaffected. In conclusion, NHE1 mediates the Na +/H + exchange in ECs and VSMCs. Under physiological conditions, CO 2/HCO 3 --dependent mechanisms mask the pH i-regulatory function of NHE1. NHE1 knockout causes hypotrophy of VSMCs, reduced artery tension and lower blood pressure. At acidic pH i, NO-mediated vasorelaxation and rho kinase-dependent VSMC Ca 2+ sensitivity are reduced.