Role of ETA receptors in the regulation of vascular reactivity in rats with congestive heart failure

Endothelium-derived nitric oxide (NO) and endothelin (ET)-1 interact to reg ulate vascular tone. In congestive heart failure (CHF), the release and/or the activity of both factors is affected. We hypothesized that the increase d ET-1 production associated with CHF may result in a reduced smooth muscle sensitivity to NO. The aim of this study was to evaluate the effects of a chronic treatment with the ETA receptor (ET receptor A) antagonist LU-13525 2 (LU) on cerebrovascular reactivity to sodium nitroprusside (SNP) in the r at infarct model of CHF. Rats were subjected to coronary artery ligation an d were treated for 4 wk with placebo (n = 24) or LU (50 mg . kg(-1) . day(- 1), n = 29). CHF was associated with a decreased (P < 0.05) efficacy of SNP to induce relaxation of isolated middle cerebral arteries. Furthermore, ne ither NO synthase inhibition with N-omega-nitro-L-arginine (L-NNA) nor endo thelial denudation affected the efficacy of SNP. Thus the endothelium no lo nger influences smooth muscle sensitivity to SNP. LU treatment, however, no rmalized (P < 0.05) smooth muscle sensitivity to SNP. Sensitivity of ET-1-i nduced contraction was increased in CHF only in the presence of L-NNA, wher eas contraction induced by ETB receptor (receptor B) stimulation was increa sed (P < 0.05) in endothelium-denuded vessels. LU treatment restored these changes in reactivity and revealed a significant endothelium-dependent ETB- mediated relaxation after NO synthase inhibition. In conclusion, CHF decrea ses and uncouples cerebrovascular smooth muscle sensitivity to SNP from end othelial regulation. The observation that chronic ETA blockade restored mos t of the changes associated with CHF suggests that activation of the ET-1 s ystem importantly contributes to the alteration in vascular reactivity obse rved in experimental CHF.