Hypotensive and prophylactic effects of angiotensin II subtype 1 receptor antagonist, irbesartan, in stroke-prone spontaneously hypertensive rats.

We determined the acute hypotensive effect of a single administration and the prophylactic effect of chronic treatment with Irbesartan, an angiotensin II receptor antagonist, on the development of end-organ damage in stroke-prone spontaneously hypertensive rats (SHRSP). The acute hypotensive effect was determined by a telemetrical method in SHRSP fed a normal diet. The prophylactic effect was examined by biochemical, histopathological and immunohistochemical methods in SHRSP fed a high-salt and low-protein diet. Irbesartan (3, 10, 30 and 100 mg/kg) reduced blood pressure in a dose-dependent manner without affecting heart rate. Irbesartan (3, 10 and 30 mg/kg) increased the survival rate in SHRSP fed a high-salt and low-protein diet. Furthermore, Irbesartan ameliorated the appearance of stroke symptoms in dose-dependent manner showing association with the prevention of microscopic lesions. Irbesartan ameliorated the increases in urinary protein excretion and N-acetyl-D-glucosamidase activity by preventing nephrosclerosis, as judged by microscopic observations, and ameliorated the increases in the expression of collagen IV and fibronectin in the kidney. These findings demonstrate that Irbesartan is a potent antihypertensive drug offering a protective effect on the development of hypertension-induced end-organ damages in SHRSP. Thus, Irbesartan is useful for the therapy of hypertension with end-organ damage.

Effects of losartan and benazepril on abnormal circadian blood pressure rhythm and target organ damage in SHRSP.

The effects of chronic treatment with losartan, an angiotensin II type 1 (AT1) receptor antagonist, and benazepril, an angiotensin converting enzyme (ACE) inhibitor, on target-organ damage and abnormal circadian blood pressure (BP) rhythm were compared in stroke-prone spontaneously hypertensive rats (SHRSP). Losartan and benazepril were given by intraperitoneal infusion for 3 weeks after 17 weeks of age to minimize any influence of their different pharmacokinetic properties. BP was continuously monitored by telemetrical method before treatment and at the end of the observation period. The left ventricular (LV) weight, 24-hour urinary albumin excretion (UalbV) and morphological changes in the kidney were observed. Losartan and benazepril (1, 3 and 10 mg/day) reduced BP and LV weight in a dose-dependent manner with good correlation between the effects. Losartan significantly improved UalbV in a dose-dependent manner, whereas benazepril was effective at only 10 mg/day. Renal morphological analysis showed that reduction of glomerulosclerosis and collagen fiber thickness was related to the effect on UalbV, but not to the antihypertensive effects. Losartan improved the shifted circadian BP rhythm towards the active phase in a dose-dependent manner, whereas the improvement caused by 1 and 3 mg/day of benazepril was less effective than the same dosage of losartan. These results suggest that both losartan and benazepril can reduce cardiac hypertrophy showing good correlation with their antihypertensive effects, but losartan, especially at a low dose, alleviates renal damage more effectively than benazepril, with its effect correlating well with improvement of the abnormal circadian BP rhythm in SHRSP. Thus, the protective effect against hypertensive target organ damage of the AT1 receptor antagonist seems to be more effective than that of ACE inhibitor.