Hemodynamic, renal, and endocrine responses to acute ETA blockade at different ANG II plasma levels

Angiotensin (ANG) II effects may be partly mediated by endothelin (ET)-1. T his study analyses the hemodynamic, renal, and hormonal responses of acute ETA receptor antagonism (LU-135252) at two ANG II plasma levels in eight co nscious dogs. Protocol 1 involved a 60-min baseline, followed by two doses of ANG II for 60 min each (4 and 20 ng.kg(-1).min(-1)), termed ANG II 4 (sl ightly increased) and ANG II 20 (pathophysiologically increased ANG II plas ma concentration). Protocol 2 was the same as protocol 1 but included 15 mg /kg iv LU-135252 after the baseline period. Protocol 3 was a 3-h time contr ol. ANG II without LU-135252 did not increase plasma big ET-1 and ET-1, whe reas LU-135252 increased ET-1 transiently after injection. This transient E T-1 increase was not reflected in urinary ET-1 excretion. The ANG II induce d decreases in sodium, water, and potassium excretion, glomerular filtratio n rate, and fractional sodium excretion were not different with and without LU-135252. Mean arterial pressure increased during ANG II and was not lowe r with LU-135252 (-6 mmHg, not significant). Most importantly, during ANG I I 20 LU-135252 prevented the decrease in cardiac output. Simultaneously, sy stemic vascular resistance increased 40% less, pulmonary vascular resistanc e was maintained at baseline levels, and central venous and wedge pressure were lower. Because ANG II stimulated endothelin de novo synthesis should j ust have started after 2 h of ANG II infusion, there must be mechanisms oth er than blocking the coupling of de novo synthesized endothelins to the ETA receptors to explain the effects of acute ETA receptor inhibition in our s etting.