[Isoproterenol, denopamine, and atenolol-induced alterations in beta-adrenergic receptor-adenylate cyclase system of rat myocardium].
Catecholamines (CAs) had been used for the treatment of congestive heart failure (CHF). However, since continuous administration of CAs develops tolerance in hemodynamics presumably due to desensitization of beta-adrenergic receptor (beta AR)-adenylate cyclase (AC) system, beta antagonist, instead of beta agonist, has recently been employed to treat CHF, in that it may recover beta AR-AC system. In this study, the precise mechanisms of alterations in cardiac beta AM-AC system after chronic administration of beta agonist or antagonist, were investigated. The rats were treated continuously for 14 days with saline, isoproterenol (ISO), atenolol (ATENO), or denopamine (DENO), a new positive inotropic agent with beta 1 selective AR agonistic properties, which is reported to hardly cause the tolerance in clinical studies. beta AR density (Bmax) was markedly reduced by ISO and slightly increased by ATENO. Forskolin stimulated cyclase activity was reduced markedly by ISO. Total amount of the pertussis toxin substrates (inhibitory G-protein; Gi) and cholera toxin substrates (stimulatory G-protein; Gs) were not different among 4 groups. However, Gs activity measured by human platelet reconstitutive assay was reduced by ISO and DENO. These results indicate that ISO-induced desensitization in caused by the reduction in Gs and AC-catalytic activity as well as by the down-regulation of beta AR. Furthermore, it is suggested that DENO may cause slight desensitization of beta AR-AC system due to reduced Gs activity.
Department of Cardiovacular Medicine, Hokkaido University School of Medicine, Sapporo, Japan.
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Igarashi
D000262:Adenylyl Cyclases / Q000187:drug effects* / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001262:Atenolol / Q000494:pharmacology*; D004361:Drug Tolerance; D004983:Ethanolamines / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000378:metabolism
D000318:Adrenergic beta-Agonists; D004983:Ethanolamines; D011943:Receptors, Adrenergic, beta; D001262:Atenolol; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D007545:Isoproterenol; C037293:denopamine