ETB receptor-deficient rats exhibit reduced contraction to ET-1 despite anincrease in ETA receptors

Several disease states, including hypertension, are associated with elevati ons in plasma endothelin-1 (ET-1) and variable changes in vascular contract ion to ET-1. The spotting lethal (sl) rat carries a deletion of the endothe lin-B (ETB) receptor gene that prevents expression of functional ETB recept ors, resulting in elevated plasma ET-1. On a normal diet, these rats are no rmotensive and thus provide an opportunity to study the vascular effects of chronically elevated ET-1 in the absence of hypertension. Studies were per formed in rats homozygous for the ETB deficiency (sl/sl; n = 8) and in tran sgenic rats heterozygous for the ETB deficiency (sl/+; n = 8). Plasma ET-1 was elevated in sl/sl rats (3.85 +/- 0.55 pg/ml) compared with sl/+ rats (0 .31 +/- 0.11 pg/ml). Mean arterial blood pressure in conscious unrestrained sl/sl and sl/+ rats was 101 +/- 5 and 107 +/- 6 mmHg, respectively. Concen tration-dependent contractions to ET-1 (10(-11)-10(-8) M) were reduced in m esenteric small arteries (150-250 mum) from sl/sl rats, as indicated by an similar to 10-fold increase in EC50. A selective ETA antagonist, A-127722 ( 30 nM), abolished contraction to ET-1 in both groups, whereas a selective E TB antagonist had no effect. Also, ETB agonists (IRL-1620 and sarafatoxin 6 c) produced neither contraction nor relaxation in either group, indicating that contraction to ET-1 in this vascular segment was exclusively ETA depen dent. Despite increased plasma ET-1, protein expression of ETA receptors in membrane protein isolated from mesenteric small arteries was increased in sl/sl compared with sl/+ rats, as shown by Western blotting. These results indicate that, in ETB-deficient rats, ETA-induced contraction is reduced in vessels normally lacking ETB-mediated effects. Reduced contraction may be related to elevated plasma ET-1 and occurs in the presence of increased ETA receptor protein expression, suggesting an uncoupling of ETA receptor expr ession from functional activity.