Short-term aortic barodenervation diminishes alpha 1-adrenoceptor reactivity in rat aortic smooth muscle.

Our previous studies have shown that aortic baroreceptor denervation elicits acute increases in blood pressure and significant elevations of sympathetic activity and peripheral vascular resistance. This study investigated the short-term (3 and 48 h) effect of aortic barodenervation and associated sympathetic hyperactivity on the functional activity of alpha 1-adrenoceptors in rat aortic smooth muscle. Compared with sham operation, aortic barodenervation caused acute rises in blood pressure and heart rate and reductions in baroreflex sensitivity. Blood pressure and heart rate remained elevated when measured in conscious aortic barodenervated rats 3 h after surgery but subsided to sham-operated levels at 48 h; the baroreflex sensitivity, however, remained attenuated. Hexamethonium (0.5-4 mg/kg, i.v.) elicited significantly (P < 0.05) greater depressor responses in conscious aortic barodenervated rats than in sham-operated rats at both 3 and 48 h, suggesting a higher sympathetic activity in denervated rats. Exposure of aortic rings from aortic barodenervated and sham-operated rats to cumulative addition of phenylephrine (alpha 1-adrenoceptor agonist, 3 x 10(-8)-1 x 10(-4) M) resulted in concentration related contractile responses that were similar in the two groups of rats at 3 h in contrast to significantly (P < 0.05) smaller contractions in rings from denervated rats at 48 h. The maximum contraction developed (Emax) at 48 h showed approximately 50% reduction in rings from aortic barodenervated compared with sham-operated rats (239 +/- 16 vs. 558 +/- 15 mg tension/mg tissue). The pA2 value for prazosin (alpha 1-adrenoceptor antagonist) was not altered by aortic barodenervation at 3 h but showed significant (P < 0.05) increases, compared with sham-operated values, at 48 h. It is concluded that short-term aortic barodenervation results in an elevation of sympathetic activity that coincides with reduced responsiveness of aortic smooth muscle to alpha 1-adrenoceptor activation. The aortic barodenervation-induced alpha 1-adrenoceptor desensitization is not a result of decreased receptor affinity but may involve an alteration of receptor density or in the post-receptor activation events.

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.