EtB receptor-deficient rats exhibit reduced contraction to ET-1 despite an increase in ETA receptors

Academic Article


  • 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 (ETB) receptor gene that prevents expression of functional ETB 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 ETB deficiency (sl/sl; n = 8) and in transgenic 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. Concentration-dependent contractions to ET-1 (10-11-10-8 M) were reduced in mesenteric small arteries (150-250 μm) from sl/sl rats, as indicated by an ∼10-fold 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/+ 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 expression from functional activity.
  • Digital Object Identifier (doi)

    Pubmed Id

  • 25145364
  • Author List

  • Perry MG; Molero MM; Giulumian AD; Katakam PVG; Pollock JS; Pollock DM; Fuchs LC
  • Volume

  • 281
  • Issue

  • 6 50-6