Heterologous desensitization of beta-adrenoceptor signal transduction in vivo.
The hemodynamic actions of pituitary adenylate cyclase-activating polypeptide (PACAP-27) rapidly diminish upon repeated i.v. injection in rats treated with the nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME). We now report that the beta-adrenoceptor agonist isoproterenol (0.5 microg/kg, i.v.) produces pronounced hypotensive and vasodilator effects in anesthetized rats pretreated with L-NAME (100 micromol/kg, i.v.). However, the hypotensive and vasodilator actions of isoproterenol were markedly diminished in L-NAME-treated rats in which tachyphylaxis to PACAP was induced immediately prior to the injection of the beta-adrenoceptor agonist. This suggests that a reduction in tissue concentrations of nitric oxide-containing factors allows tachyphylaxis to PACAP-27-mediated vasodilation to occur in vivo and that this process leads to the heterologous desensitization of beta-adrenoceptor-mediated responses.
Travis
M D
MD
The Department of Pharmacology and Cardiovascular Center, The University of Iowa, Iowa City 52242, USA.
Whalen
E J
EJ
Lewis
S J
SJ
D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000633:toxicity; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007545:Isoproterenol / Q000008:administration & dosage / Q000494:pharmacology*; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage / Q000633:toxicity; D009479:Neuropeptides / Q000008:administration & dosage / Q000633:toxicity; D018377:Neurotransmitter Agents / Q000008:administration & dosage / Q000633:toxicity; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013618:Tachyphylaxis; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
C495403:Adcyap1 protein, rat; D000318:Adrenergic beta-Agonists; D004791:Enzyme Inhibitors; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011943:Receptors, Adrenergic, beta; D019001:Nitric Oxide Synthase; D007545:Isoproterenol; D019331:NG-Nitroarginine Methyl Ester