Enhanced endothelial nitric oxide activity contributes to the reduced responsiveness of vascular alpha(1)-adrenoceptors following aortic barodenervation

We have recently shown that short-term aortic barodenervation diminishes constrictor responses to activation of alpha(1)-adrenoceptors in rat aortic smooth muscle. This study investigated the potential role of vascular endothelium and its derived vasoactive substances, nitric oxide and prostaglandins, in the reduced alpha(1)-adrenoceptor responsiveness after aortic barodenervation. Exposure of isolated aortic rings from aortic barodenervated and sham-operated rats 48 h after surgery to cumulative addition of phenylephrine (alpha(1)-adrenoceptor agonist, 3 x 10(-8)-1 x 10(-4) M) resulted in concentration-related contractions that were significantly (P < 0.05) smaller in rings of denervated rats. Removal of the endothelium increased phenylephrine-mediated contractions in rings obtained from aortic barodenervated rats to near sham-operated levels as demonstrated by the similar contractile responses and slopes of the regression lines of the concentration-response curves. Pretreatment with indomethacin (cyclooxygenase inhibitor, x 10(-5) M) had no effect on contractile responses to phenylephrine in rings from both groups of rats. In contrast, N-G-nitro-L-arginine (nitric oxide synthase inhibitor, 1 x 10(-5) M) elevated basal vascular tone and significantly (P < 0.05) increased alpha(1)-adrenoceptor responsiveness, effects that were more evident in rings from denervated compared with sham-operated rats. N-G-nitro-L-arginine produced significantly (P < 0.05) greater increases in the slopes of the regression lines (136.1 +/- 22% vs. 73.0 +/- 8.6% mg tension/mg tissue/log molar concentration) and maximum contractile response (E-max) to phenylephrine (161.2 +/- 8.2% vs. 76.7 +/- 6.1%) in rings from denervated compared with sham-operated rats suggesting an enhanced nitric oxide activity in aortas of denervated rats. This notion is further supported by the finding :hat cumulative i.v. administration of N-G-nitro-L-arginine (1, 2, 4 and 8 mg/kg) elicited significantly (P < 0.05) greater presser responses in conscious barodenervated compared with sham-operated rats. These results suggest that the endothelium plays a major role in the reduced constrictor responses to alpha(1)-adrenoceptor activation that occurs shortly after aortic barodenervation. This effect of the endothelium appears to involve, at least in part, enhancement of endothelial nitric oxide activity. (C) 1997 Elsevier Science B.V.