ET(B) receptor-deficient rats exhibit reduced contraction to ET-1 despite an increase in ET(A) receptors

Several disease states, including hypertension, are associated with elevations in plasma endothelin-1 (ET-1) and variable changes in vascular contraction to ET-1. The spotting lethal (sl) rat carries a deletion of the endothelin-B (ET(B)) receptor gene that prevents expression of functional ET(B) receptors, resulting in elevated plasma ET-1. On a normal diet, these rats are normotensive and thus provide an opportunity to study the vascular effects of chronically elevated ET-1 in the absence of hypertension. Studies were performed in rats homozygous for the ET(B) deficiency (sl/sl; n = 8) and in transgenic rats heterozygous for the ET(B) 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. Concentration-dependent contractions to ET-1 (10(-11)-10(-8) M) were reduced in mesenteric small arteries (150-250 microm) from sl/sl rats, as indicated by an approximately 10-fold increase in EC(50). A selective ET(A) antagonist, A-127722 (30 nM), abolished contraction to ET-1 in both groups, whereas a selective ET(B) antagonist had no effect. Also, ET(B) agonists (IRL-1620 and sarafatoxin 6c) produced neither contraction nor relaxation in either group, indicating that contraction to ET-1 in this vascular segment was exclusively ET(A) dependent. Despite increased plasma ET-1, protein expression of ET(A) 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 ET(B)-deficient rats, ET(A)-induced contraction is reduced in vessels normally lacking ET(B)-mediated effects. Reduced contraction may be related to elevated plasma ET-1 and occurs in the presence of increased ET(A) receptor protein expression, suggesting an uncoupling of ET(A) receptor expression from functional activity.