Downregulation of propranolol-sensitive beta-adrenoceptor signaling after inhibition of nitric oxide synthesis.
The beta-adrenoceptor agonist, isoprenaline, elicits vasodilation and tachycardia in anesthetized rats via activation of propranolol-sensitive beta1- and beta2-adrenoceptors and also by propranolol-insensitive beta1- and beta3-adrenoceptors. The aim of this study was to determine whether the relative contribution of propranolol-sensitive and -insensitive beta-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 microg 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 micromol kg(-1), i.v.), and again after injection of the beta1- and beta2-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 alpha1-adrenoceptor agonist, phenylephrine (3 microg 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 beta1-, beta2- and beta3-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 alpha1-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 beta-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 beta-adrenoceptors are downregulated, whereas propranolol-insensitive beta-adrenoceptors are upregulated upon the loss of exposure to endothelial nitrosyl factors.
Whalen
Erin J
EJ
Department of Pharmacology, University of Iowa, Iowa City, IA, USA.
Bates
James N
JN
Johnson
Alan Kim
AK
Lewis
Stephen J
SJ
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006614:Hindlimb / Q000098:blood supply; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011433:Propranolol / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects; D012039:Regional Blood Flow / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D013152:Splanchnic Circulation / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D004791:Enzyme Inhibitors; D018341:Receptors, Adrenergic, alpha-2; D018342:Receptors, Adrenergic, beta-1; D009569:Nitric Oxide; D011433:Propranolol; D019001:Nitric Oxide Synthase; D007545:Isoproterenol; D019331:NG-Nitroarginine Methyl Ester