Olmesartan Improves Endothelin-Induced Hypertension and Oxidative Stress in Rats
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<B>Recent studies have indicated that both endothelin (ET) and angiotensin (Ang) II stimulate oxidative stress, which contributes to the development of hypertension. Here, we examined the effects of Ang II type 1 (AT<SUB>1</SUB>) receptor blockade on reactive oxygen species (ROS) formation in ET-dependent hypertension. Chronic ET-1 infusion (2.5 pmol/kg/min, i.v., <I>n</I> =7) into rats for 14 days increased systolic blood pressure from 113±1 to 141±2 mmHg. ET-1-infused rats showed greater plasma renin activity (8.1±0.8 Ang I/ml/h), and greater Ang I (122±28 fmol/ml) and Ang II levels (94±13 fmol/ml) than vehicle (0.9% NaCl)-infused rats (3.1±0.6 Ang I/ml/h, 45±8 and 47±7 fmol/ml, respectively, <I>n</I> =6). Angiotensin converting enzyme and AT<SUB>1</SUB> receptor expression in aortic tissues were similar between the vehicle- and ET-1-infused rats. Vascular superoxide anion (O<SUB>2</SUB><SUP>-</SUP>) production and plasma thiobarbituric acid-reactive substance (TBARS) levels were greater in ET-1-infused rats (27±1 counts per minutes [CPM]/mg dry tissue weight and 8.9±0.8μmol/l, respectively) than vehicle-infused rats (16±1 CPM/mg and 5.1±0.1μmol/l, respectively). The ET-1-induced hypertension was prevented by simultaneous treatment with a new AT<SUB>1</SUB> receptor antagonist, olmesartan (0.01% in chow, 117±5 mmHg, <I>n</I> =7), or hydralazine (15 mg/kg/day in drinking water, 118±4 mmHg, <I>n</I> =6). Olmesartan prevented ET-1-induced increases in vascular O<SUB>2</SUB><SUP>-</SUP> production (15±1 CPM/mg) and plasma TBARS (5.0±0.1μmol/l). Vascular O<SUB>2</SUB><SUP>-</SUP> production and plasma TBARS were also decreased by hydralazine (21±1 CPM/mg and 7.0±0.3μmol/l, respectively), but these levels were significantly higher than in vehicle-infused rats. These data suggest that ET-dependent hypertension is associated with augmentation of Ang II levels and ROS formation. The combined effects of the elevations in circulating ET-1 and Ang II, as well as the associated ROS production, may contribute to the development of hypertension induced by chronic ET-1 infusion. (<I>Hypertens Res</I> 2004; 27: 493-500)</B>
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日本高血圧学会 | 論文
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