MECHANISMS OF HYPERTENSION IN TRANSGENIC RATS EXPRESSING THE MOUSE REN-2 GENE

Transgenic (TG) rats carrying the mouse Ren-2 gene (Ren-2(d))27 are a newly established monogenetic model in hypertension research. To gain an insight into the mechanisms of this form of hypertension we determi ned the effects of a 13-day therapy with losartan (10 mg/kg) or lisino pril (20 mg/kg) on the blood pressure (BP) and plasma levels of angiot ensin (ANG) peptides of mature female TG hypertensive and Sprague-Dawl ey (SD) rats. The contribution of endothelium-derived nitric oxide (NO ) to the maintenance of their hypertension and the response to therapy was evaluated by systemic injection of either N-G-monomethyl-L-argini ne (L-NMMA) or endothelin-1. Hypertension in TG rats was associated wi th decreased plasma ANG I, no differences in plasma ANG II, and plasma ANG-(1-7) near the detectable level. Lisinopril lowered BP more than losartan in both TG hypertensive and normotensive controls. In both st rains, the chronic fall in BP produced by lisinopril was accompanied b y significant increases in plasma ANG I and ANG-(1-7), while losartan augmented plasma ANG I and ANG II in both strains and plasma ANG-(1-7) in TG rats. Inhibition of NO synthase reversed the fall in BP produce d by either lisinopril or losartan in SD controls. In contrast, admini stration of L-NMMA to TG rats given the same therapy did not. The tran sient endothelium-mediated relaxing phase of the depressor response to systemic injections of endothelin-1 was attenuated by losartan and li sinopril in TG rats. These studies indicate that hypertension in femal e TG rats is mediated by the RAS. Moreover, the data suggest that in t his model of hypertension endothelium-derived relaxing factors do not contribute to the long-term antihypertensive effects of angiotensin-co nverting enzyme inhibition or AT(1) receptor blockade.