Abstract 283: Predominance of Angiotensin II Type 1 Receptor Blockade Over Angiotensin-(1-7) Mechanisms in the Regulation of Blood Pressure and Renin Angiotensin System in mRen.Lewis Rats

Abstract

We investigated the angiotensin-(1-7) [Ang-(1-7)] mediated effects of Ang II receptor (AT 1 -R) blocker -olmesartan medoxomil-on blood pressure, plasma, renal, and cardiac Ang II as well as activities of the enzymes involved in peptide formation or metabolism in mRen2.Lewis congenic hypertensive rats, a model of Ang II tissue-dependent hypertension. mRen2.Lewis rats were treated with either vehicle (n=14) or olmesartan (0.5 mg/kg/day; n=14) by osmotic minipumps. After 2 weeks rats from both groups were further randomized to receive either the mas receptor antagonist A-779 (0.5 mg/kg/day; n=7 per group) or its vehicle (n=7 per group) for the next 4 weeks. Antihypertensive effect of olmesartan monitored by telemetry (Figure) was associated with an increase in plasma renin concentration (PRC), plasma Ang II (513 ± 115 vs. 31 ± 5 fmol/mL; p<0.05) and Ang-(1-7) (60 ± 5 vs. 27 ± 4 fmol/mL; p<0.05) while reduced kidney Ang II content and no changes in kidney Ang-(1-7), angiotensin converting enzyme (ACE), ACE2 and neprilysin activities were noted in olmesartan treated group when compared to the controls (Figure). Olmesartan had no effect on cardiac peptide levels . Concomitant administration of A-779 increased PRC but had no effect on blood pressure or other RAS components. Our study highlights the independent regulation of RAS among plasma, heart, and kidney tissue in response to AT 1 -R blockade. Ang-(1-7) through mas-receptor does not mediate long-term effects of olmesartan besides counterbalancing renal renin release in response to AT 1 -R blockade.