Renal and vascular effects of chronic nitric oxide synthase inhibition: involvement of endothelin 1 and angiotensin II

Endothelin 1 (ET-1) is a potent vasoconstrictor implicated in the control o f blood pressure and renal function. Its effects can be modulated by nitric oxide (NO), which inhibits ET-1 production and action. Recently, we report ed that ET-1 production can also be modulated by angiotensin II (AngII) in vivo. To investigate the interactions between NO, ET-1, and AngII in hypert ension and renal dysfunction, we assessed immunoreactive ET-1 (ir-ET-1) con centration in plasma and urine as well as in vascular and renal tissues of rats with chronic inhibition of NO synthesis, in the presence and the absen ce of the AngII type 1 receptor antagonist losartan. Normal (protocols A an d B) and uninephrectomized rats (protocol C) received the L-arginine analog N-G-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthesis, 0.05% (protocol A) or 0-1% (protocols B and C), with or without losartan (2 0 mg.kg(-1)day(-1)). After 6 weeks, systolic blood pressure was significant ly increased in L-NAME rats compared with the controls (p < 0.01), while se rum creatinine and urea, creatinine clearance, and proteinuria were similar to control values. However, ir-ET-1 concentration in plasma and in the tho racic aorta was augmented in animals receiving 0.1% L-NAME (p < 0.01), whil e it was unchanged in the mesenteric arterial bed, preglomerular arteries, and glomeruli. In contrast, ir-ET-1 concentration was decreased in the rena l papilla (p < 0.05) as well as in the urine of L-NAME rats (p < 0.01). Tre atment with losartan significantly attenuated the rise in systolic blood pr essure induced by L-NAME (p < 0.01). Losartan also normalized the increased ir-ET-1 concentration in plasma and in the thoracic aorta, but had no effe ct on tissues with normal or reduced ir-ET-1 levels. These results indicate that chronic inhibition of NO synthase with L-NAME induces hypertension wi thout renal dysfunction. Increased ET-1 production in some blood vessels an d elevated circulating ET-1 concentration may contribute to the maintenance of high blood pressure. The reduction of systolic blood pressure by losart an supports a role for AngII in the pathogenesis of this form of hypertensi on, which may be due, at least in part, to the modulation of ET-1 productio n.