Effects of chronic treatment with Iosartan on blood pressure, endothelin-like immunoreactivity and nitric oxide in normotensive rats

BACKGROUND: Losartan is a new angiotensin II type 1 (AT1) receptor antagonist and an antihypertensive drug. Nitric oxide is a vasodilating agent and endothelins are powerful vasoconstrictors, both synthesized by and released from endothelial cells. Angiotensin II promotes the release of endothelins in cultured cells and this effect is prevented by losartan. Nitric oxide is also synthesized in the macula densa; therefore this substance may affect the regulation of renin excretion. OBJECTIVE: The aim of the present study was to evaluate the effects of losartan on blood pressure, endothelin-like immunoreactivity and nitric oxide in normotensive rats. MATERIALS AND METHODS: Male Wistar-Kyoto rats were divided into two groups. One group (n = 10) was treated with losartan at 10 mg/kg once a day by gavage for 4 weeks and a placebo group (n = 10) was given the same volume of water once a day by gavage. Blood pressure was measured weekly with a tail cuff and 24-h urine was collected at the beginning and at the end of the study. After 4 weeks all rats were killed and blood samples taken. Endothelin-like immunoreactivity was determined in plasma and urine using a 125I endothelin radioimmunuoassy kit. The stable metabolic products of nitric oxide, NO2- and NO3-, were measured in urine by the brucine method. RESULTS: After 4 weeks blood pressure was significantly lower in the losartan group (131 +/- 4 versus 118 +/- 6 mmHg, P = 0.001). Plasma endothelin-like immunoreactivity was similar in both groups while 24-h urinary endothelin-like immunoreactivity was significantly increased in the losartan group (29 +/- 25, 32 +/- 21, 43 +/- 19, 72 +/- 30 pg/24 h; F = 0.0003). NO2- and NO3- were unchanged in both groups. CONCLUSIONS: Our data show that chronic AT1 receptor blockade does not modify plasma endothelin-like immunoreactivity but increases urinary endothelin-like immunoreactivity. The significance of this finding remains obscure. It may represent a compensatory mechanism against the sustained vasodilation caused by losartan. Nitric oxide does not seem to affect the antihypertensive effect of losartan, since the urinary excretion of nitric oxide metabolites was unchanged.