Renin-angiotensin inhibition reverses advanced cardiac remodeling in aging spontaneously hypertensive rats.

BACKGROUND: Many experiments using young hypertensive animal models support the evidence that angiotensin-converting enzyme inhibitor or angiotensin receptor type 1 blocker attenuates the progression of cardiac hypertrophy. However, it is still unclear whether inhibiting the renin-angiotensin system can reverse age-related cardiac hypertrophy. To clarify the role of renin-angiotensin system inhibition in naturally advanced myocardial hypertrophy we treated spontaneously hypertensive, aging rats with an angiotensin-converting enzyme inhibitor or an angiotensin receptor type 1 blocker. METHODS: We used osmotic pumps to deliver the blood-pressure reducers temocaprilat, olmesartan, hydralazine, or saline for 4 weeks. RESULTS: Heart and body weights were significantly reduced in animals treated with temocaprilat or olmesartan compared with animals treated with hydralazine or saline. Histologic myocyte size and cardiac fibrosis were significantly attenuated by temocaprilat or olmesartan. Real-time polymerase chain reaction (PCR) revealed that temocaprilat or olmesartan suppressed expression of cardiac transforming growth factor-beta1 and fibroblast growth factor-2 mRNA, a marker of cardiac fibrosis. Cardiac and systemic oxidative stress assessed by 8-isoprostane levels was significantly reduced in animals treated with temocaprilat or olmesartan compared with hydralazine-treated or saline-treated rats. Renin-angiotensin system inhibition reduced cardiac expression of NAD(P)H oxidative components p22phox, p47phox, and gp91phox. CONCLUSIONS: Renin-angiotensin system inhibition can reverse age-related, advanced cardiac hypertrophy. The mechanism of reversal is partly due to suppression of cardiac oxidative stress.

Low-dose doxazosin improved aortic stiffness and endothelial dysfunction as measured by noninvasive evaluation.

Evaluation of atherosclerosis is important in the treatment of hypertension. To evaluate the preventive effects of a small amount of alpha-blockade, arterial and endothelial dysfunction were measured by noninvasive tests, i.e., pulse wave velocity, acceleration plethysmography and strain-gauge plethysmography, in patients with essential hypertension. Fifteen patients (65+/-3 years old) with essential hypertension (WHO stage I or II) were analyzed in this study. We performed noninvasive evaluations to measure aortic stiffness and endothelial dysfunction, in addition to measuring blood pressure, cholesterol profile, and levels of cells adhesion molecules and nitric oxide before and 6 and 12 months after the start of doxazosin treatment (1.0 mg/day). Blood pressure and heart rate did not significantly change during treatment. The pulse wave velocity index was significantly reduced both at 6 (7.72+/-0.23 m/s; p<0.05) and 12 (7.34+/-0.26 m/s; p<0.05) months after the start of treatment compared to the pretreatment level that at baseline. There was also a significant improvement in b/a after 12 months (-0.46+/-0.04; p<0.05) and in d/a after 6 months (-0.38+/-0.03; p<0.05) and 12 months (-0.39+/-0.03; p=0.05) compared to the pretreatment values. Moreover, reactive hyperemia evaluated by strain-gauge plethysmography after 6 months (1.34+/-0.11; p<0.05) and 12 months (1.49+/-0.16; p<0.05) was significantly improved compared to that before treatment, and NOx was significantly increased after 12 months (89.7+/-15.7 micromol/l; p<0.005). These data suggest that a low dose of doxazosin may play an important role in improving arterial stiffness and endothelial dysfunction without changing cardiac hemodynamics.