Enhanced endothelial nitric oxide activity contributes to the reduced responsiveness of vascular alpha1-adrenoceptors following aortic barodenervation.

We have recently shown that short-term aortic barodenervation diminishes constrictor responses to activation of alpha1-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 alpha1-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 (alpha1-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, 1 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, 3 x 10[-5] M) elevated basal vascular tone and significantly (P < 0.05) increased alpha1-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 (Emax) 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 that cumulative i.v. administration of N(G)-nitro-L-arginine (1, 2, 4 and 8 mg/kg) elicited significantly (P < 0.05) greater pressor 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 alpha1-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.