Interaction of the heme oxygenase system with the renin‐angiotensin system in DOCA‐salt hypertensive rats

Abstract

Heme analogues are known to lower blood pressure in a variety of hypertensive models, including angiotensin-II-infused-, phenylephrine-induced- and deoxycorticosterone acetate (DOCA)-salt-induced hypertensive models. In DOCA-salt rats, elevated activity of the renin-angiotensin system (RAS) leads to oxidative stress, inflammation and hypertrophy. Whether the application of a heme oxygenase inducer like hemin will attenuate RAS activity and suppress kidney hypertrophy needs clarification. Moreover, the interaction of the heme oxygenase system with the RAS in DOCA rats is not fully understood. In this study, the administration of hemin (30 mg/kg daily, i.p.) for four weeks to DOCA-salt, significantly lower blood pressure from 189.9±3.6 vs.136.6±1.3 mmHg (p<0.01, n=6) and attenuated kidney hypertrophy from 7.6 ±0.4 vs. 6.0±0.3 g/kg body weight (p< 0.01, n=6). This was accompanied by significant reduction of plasma angiotensin-II (254.8±66.5 vs. 13.6±1.5 pg/ml/protein; p<0.05, n=4) and aldosterone (16.4±0.75 vs. 10.9±2.9 pg/ml/protein; p <0.05, n=4) as well as reduced inflammatory activity, assessed as NF-κβ expression. In DOCA control rats (sham), blood pressure (118.5±0.2 mmHg) was unaffected by hemin. Similarly, hemin had no effect on normotensive Sprague Dawley rats (123.6±1.6 vs. 123±0.7 mmHg, n=5). Our studies unveils that the heme oxygenase system directly modulates angiotensin-II and aldosterone activities in DOCA rats to suppress hypertension and secondarily-induced damages like hypertrophy and inflammation. (This work is supported by Heart & Stroke Foundation of Saskatchewan, Canada)