Central and peripheral renin‐angiotensin systems in ouabain‐induced hypertension 1

Abstract

Chronic subcutaneous infusion of ouabain causes hypertension via central pathways involving AT1 receptor stimulation. The present study assessed plasma and tissue Ang I and II levels as well as AT1 receptor and angiotensin converting enzyme (ACE) mRNA levels and binding densities by real–time PCR and in vitro autoradiography in relevant brain nuclei and peripheral tissues (heart and kidney) in rats at 1 and/or 2 weeks after start of ouabain infusion at 50 μg/day. After 2 weeks (but not after 1 week) blood pressures significantly increased (+15 mmHg). At 2 weeks, plasma Ang II levels were markedly suppressed by ouabain from 15 ± 4 to 3 ± 1 pg/ml. In contrast, in the heart and kidneys Ang I levels were not affected and Ang II levels tended to decrease, whereas in the hypothalamus Ang II content clearly increased from 3 ± 2 to 18 ± 6 pg/g. At 1 week, no changes in ACE and AT1 receptor densities were seen. After 2 weeks, there were significant decreases in AT1 receptor mRNA by 30–50% and densities by ~15% in the organum vasculosum of the laminae terminalis (OVLT), subfornical organ (SFO) and paraventricular nucleus (PVN), as well as decreases in ACE densities in the OVLT and SFO by 25–50%. In the kidneys, at 2 weeks both AT1 receptor and ACE densities were decreased but mRNA abundance did not change. The heart showed no significant changes. The increase in hypothalamic Ang II content and associated decreases in central AT1 receptor and ACE densities support the involvement of the brain RAS in the central hypertensive mechanism of action of ouabain.