Downregulation of propranolol‐sensitive β ‐adrenoceptor signaling after inhibition of nitric oxide synthesis

The β ‐adrenoceptor agonist, isoprenaline, elicits vasodilation and tachycardia in anesthetized rats via activation of propranolol‐sensitive β 1 ‐ and β 2 ‐adrenoceptors and also by propranolol‐insensitive β 1 ‐ and β 3 ‐adrenoceptors. The aim of this study was to determine whether the relative contribution of propranolol‐sensitive and ‐insensitive β ‐adrenoceptors to the changes in heart rate (HR) and vascular resistances elicited by isoprenaline is altered after blockade of nitric oxide (NO) synthase, in pentobarbital‐anesthetized rats. The hemodynamic responses elicited by isoprenaline (0.1 and 0.5  μ g kg −1 , i.v.) were determined before and after injection of saline or the NO synthase inhibitor, N G ‐nitro‐ L ‐arginine methylester ( L ‐NAME, 50  μ mol kg −1 , i.v.), and again after injection of the β 1 ‐ and β 2 ‐adrenoceptor antagonist, propranolol (1 mg kg −1 , i.v.). The responses elicited by the above doses of isoprenaline were also determined before and during infusion of the α 1 ‐adrenoceptor agonist, phenylephrine (3  μ g kg −1  min −1 , i.v.), and again 15–20 min after injection of propranolol (1.0 mg kg −1 , i.v.). Both doses of isoprenaline elicited tachycardia and reductions in vascular resistances. Propranolol eliminated the responses elicited by the lower dose of isoprenaline and substantially diminished the responses elicited by the higher dose of the β 1 ‐, β 2 ‐ and β 3 ‐adrenoceptor agonist. The maximal vasodilator responses elicited by both doses of isoprenaline were not diminished whereas the maximal increases in HR were higher after injection of L ‐NAME. The ability of propranolol to diminish the hemodynamic actions of isoprenaline was substantially diminished in L ‐NAME‐treated rats, whereas propranolol retained its potency in rats that received an equi‐pressor infusion of the α 1 ‐adrenoceptor agonist, phenylephrine. The finding that the maximal vasodilator responses elicited by isoprenaline were not diminished by L ‐NAME suggests that the vasodilation elicited by this drug was due to direct activation of β ‐adrenoceptors on vascular smooth muscle and that the full compliment of isoprenaline‐sensitive receptors was not changed after inhibition of NO synthesis. However, these results suggest that the activities of propranolol‐sensitive β ‐adrenoceptors are downregulated, whereas propranolol‐insensitive β ‐adrenoceptors are upregulated upon the loss of exposure to endothelial nitrosyl factors.British Journal of Pharmacology (2006) 147 , 755–764. doi: 10.1038/sj.bjp.0706675