Endothelin receptor antagonists influence cardiovascular morphology in uremic rats

Background. It is generally held that renal failure results in blood pressu re (BP)-independent structural changes of the myocardium and the vasculatur e. The contribution, if any, of endothelin (ET) to these changes has been u nknown. Methods. We morphometrically studied random samples of the left ventricle m yocardium and small intramyocardial arteries in subtotally (5/6) nephrectom ized (SNx) male Sprague-Dawley rats treated with either the selective ETA r eceptor antagonist BMS182874 (30 mg/kg/day) or the nonselective ETA/ETB rec eptor antagonist Ro46-2005 (30 mg/kg/day) in comparison with either sham-op erated rats, untreated SNx, or SNx rats treated with the angiotensin-conver ting enzyme inhibitor trandolapril (0.1 mg/kg/day). Results. Eight weeks later, systolic BP was lower in trandolapril-treated S Nx compared with untreated SNx animals. No decrease in BP was seen followin g either ET receptor antagonist at the dose used. A significantly increased volume density of the myocardial interstitium was found in untreated SNx r ats as compared with sham-operated controls. Such interstitial expansion wa s prevented by trandolapril and either ET receptor antagonist. SNx caused a substantial increase in the wall thickness of small intramyocardial arteri es. The increase was prevented by trandolapril or BMS182874 treatment. The arteriolar wall:lumen ratio was significantly lower in all treated groups w hen compared with untreated SNx. In contrast, only trandolapril, but not th e ET receptor antagonists, attenuated thickening of the aortic media in SNx animals. Conclusions. The ETA-selective and ETA/ETB-nonselective receptor antagonist s appear to prevent development of myocardial fibrosis and structural chang es of small intramyocardial arteries in experimental chronic renal failure. This effect is independent of systemic BP.