ENDOTHELIN A RECEPTOR BLOCKADE ALLEVIATES HYPERTENSION AND RENAL LESIONS ASSOCIATED WITH CHRONIC NITRIC-OXIDE SYNTHASE INHIBITION

Unopposed actions of vasoconstrictors, such as angiotensin, play an im portant role in the effects of chronic nitric oxide synthase (NOS) inh ibition. In this study, it is hypothesized that endothelin (ET), anoth er important vasoconstrictor, may also play a role in the development of hypertension and renal lesions during chronic NOS inhibition. The E TA receptor was blocked with A-127722 during chronic NOS inhibition wi th N-omega-nitro-L-arginine (L-NNA), a potent NOS inhibitor without an timuscarinic action. Male Sprague Dawley rats were treated for 3 wk wi th L-NNA (40 mg/kg per d), L-NNA (40 mg/kg per d) + A-127722 (30 mg/kg per d), or remained untreated (control). In preliminary experiments, L-NNA (40 mg/kg per d) had been found to cause the maximum increase of systolic BP and a 35% decrease in renal NOS activity. Three weeks of L-NNA treatment resulted in a marked rise in systolic BP (240 +/- 4 ve rsus control 151 +/- 7 mmHg; P < 0.01), proteinuria (209 +/- 46 versus control 27 +/- 3 mg/d; P < 0.01), and a fall in GFR (1.41 +/- 0.16 ve rsus control 2.23 +/- 0.19 ml/min; P < 0.05). Renal morphology showed severe vascular injury, characterized by focal adhesion and infiltrati on of mononuclear cells into the intima and media of preglomerular art eries and arterioles. This was sometimes associated with necrosis of t he media and partial or total obstruction of the lumen with thrombotic material. Ischemic glomeruli were also present. Tubulointerstitial da mage was moderate and accompanied by an influx of monocytes and macrop hages. A-127722 administered simultaneously with L-NNA completely prev ented the increase in proteinuria (39 +/- 8 mg/d) and glomerular ische mia. Vascular injury, tubulointerstitial damage, and the increase in s ystolic BP (191 +/- 6 mmHg) were partially prevented. The protective e ffects of ETA receptor blockade suggest that ET has hemodynamic as wel l as nonhemodynamic effects in the cascade of events following chronic NOS inhibition.