Unopposed actions of
vasoconstrictors, such as
angiotensin, play an important role in the effects of chronic
nitric oxide synthase (NOS) inhibition. In this study, it is hypothesized that
endothelin (ET), another important
vasoconstrictor, may also play a role in the development of
hypertension and renal lesions during chronic NOS inhibition. The ET(A) receptor was blocked with
A-127722 during chronic NOS inhibition with Nomega-nitro-
L-arginine (L-NNA), a potent NOS inhibitor without
antimuscarinic action. Male Sprague Dawley rats were treated for 3 wk with 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 versus 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 versus control 2.23+/-0.19 ml/min; P < 0.05). Renal morphology showed severe
vascular injury, characterized by focal adhesion and infiltration of mononuclear cells into the intima and media of preglomerular arteries and arterioles. This was sometimes associated with
necrosis of the media and partial or total obstruction of the lumen with thrombotic material. Ischemic glomeruli were also present. Tubulointerstitial damage was moderate and accompanied by an influx of monocytes and macrophages.
A-127722 administered simultaneously with L-NNA completely prevented the increase in
proteinuria (39+/-8 mg/d) and glomerular
ischemia.
Vascular injury, tubulointerstitial damage, and the increase in systolic BP (191+/-6 mmHg) were partially prevented. The protective effects of ET(A) receptor blockade suggest that ET has hemodynamic as well as nonhemodynamic effects in the cascade of events following chronic NOS inhibition.