Properties of G-protein modulated receptor-adenylyl cyclase system in myocardium of spontaneously hypertensive rats treated with adriamycin.
Properties of the receptor--G protein--adenylyl cyclase system were studied in spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar-Kyoto rats (WKY) treated with adriamycin (ADR, 1 mg/kg per week) for 12 weeks. An identical dosing schedule caused a significantly greater decline in body weight gain and a marked elevation of plasma norepinephrine level in SHR than in WKY. A significant increase in the messenger RNA encoding Gi-alpha 2 was found in SHR+ADR group. The activity of the adenylyl cyclase stimulated by guanyliminodiphosphate [Gpp(NH)p] was decreased by 49% in SHR and 73% in SHR+ADR. However, stimulated activities of adenylyl cyclase by both sodium fluoride and forskolin remained unchanged. Functional level of stimulatory G-protein (Gs) as measured by reconstitution assay in sarcolemmal membrane was unaltered among different groups. Furthermore, the density of beta-adrenoceptor was significantly decreased without change of its affinity. Muscarinic receptors exhibited a three-site affinity distribution in SHR+ADR whereas other groups displayed only two-site affinity distribution. These results suggest that SHR exhibited a depressed myocardial adenylyl cyclase signaling system which may not be due to the functional uncoupling of beta-adrenoceptors from Gs but to the increased inhibitory G-protein (Gi) activity as demonstrated by the increased mRNA of Gi-alpha 2, increased inhibition of Gpp(NH)p-mediated adenylyl cyclase and the super high affinity for carbachol of the muscarinic receptors. Decreased beta-adrenoceptor density and functional alteration of Gi might be regarded as the predisposing factors for the increased susceptibility of myocardium of SHR to ADR.
Wallenberg Laboratory, Sahlgren's Hospital, University of Göteborg, Sweden.
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M
Fu
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Matoba
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QM
Liang
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Sjögren
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Hjalmarson
D000262:Adenylyl Cyclases / Q000502:physiology*; D000818:Animals; D004317:Doxorubicin / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000235:genetics / Q000502:physiology*; D006321:Heart / Q000503:physiopathology*; D006973:Hypertension / Q000503:physiopathology*; D008297:Male; D009206:Myocardium / Q000737:chemistry; D009638:Norepinephrine / Q000097:blood; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D011976:Receptors, Muscarinic / Q000032:analysis; D012508:Sarcolemma / Q000737:chemistry
D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; D011976:Receptors, Muscarinic; D004317:Doxorubicin; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D009638:Norepinephrine