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.
Fu
M
M
Wallenberg Laboratory, Sahlgren's Hospital, University of Göteborg, Sweden.
Matoba
M
M
Liang
Q M
QM
Sjögren
K G
KG
Hjalmarson
A
A
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