receptordeficient rats exhibit reduced contraction to ET-1 despite an increase in ET A receptors. Am J Physiol Heart Circ Physiol 281: H2680-H2686, 2001.-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 ETB receptors, resulting in elevated plasma ET-1. On a

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... 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 ϭ 8) and in transgenic rats heterozygous for the ET B deficiency (sl/ϩ; n ϭ 8). Plasma ET-1 was elevated in sl/sl rats (3.85 Ϯ 0.55 pg/ml) compared with sl/ϩ rats (0.31 Ϯ 0.11 pg/ml). Mean arterial blood pressure in conscious unrestrained sl/sl and sl/ϩ rats was 101 Ϯ 5 and 107 Ϯ 6 mmHg, respectively. Concentration-dependent contractions to ET-1 (10 Ϫ11 -10 Ϫ8 M) were reduced in mesenteric small arteries (150-250 m) from sl/sl rats, as indicated by an ϳ10fold increase in EC50. A selective ETA antagonist, A-127722 (30 nM), abolished contraction to ET-1 in both groups, whereas a selective ETB antagonist had no effect. Also, ETB 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 ETA dependent. 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/ϩ 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 ET A receptor expression from functional activity. endothelin-1; homozygous ETB-deficient rats; heterozygous ETB-deficient rats; resistance arteries; arterial pressure ENDOTHELIN-1 (ET-1) is a potent vasoconstrictor peptide thought to contribute to several cardiovascular dis-