title: Myocardial beta-adrenergic adenylate cyclase complex in a canine model of chagasic cardiomyopathy.
abstract: Infection of beagles with an opossum-derived strain of Trypanosoma cruzi (Tc-O) results in features of early and chronic chagasic cardiomyopathy, that is, increases in PR interval, atrioventricular block, and frequent ventricular premature contractions, ventricular tachycardia, and decreased left ventricular ejection fraction. These signs are not observed in animals infected with a canine strain of T. cruzi (Tc-D). To understand the biochemical basis for these early cardiac effects, we examined the beta-adrenergic adenylate cyclase complex in myocardial membranes prepared from animals infected with either of the two strains. In animals infected with Tc-O (symptomatic), the maximum velocity (Vmax) decreased and concentration of agonist resulting in 50% of Vmax (Kact) increased for isoproterenol-dependent adenylate cyclase activity; in animals infected with Tc-D (asymptomatic), Vmax and Kact for isoproterenol were unchanged from control, uninfected animals. beta-Receptor density decreased by 20% in symptomatic animals with no change in affinity, whereas no differences were observed between uninfected and infected asymptomatic animals. A complex pattern of changes was apparent in the guanine nucleotide binding protein, Gs, in the setting of infection. Alterations in cholera toxin-dependent ADP-ribosylation patterns as well as immunochemical detection with anti-G alpha s antisera suggested a change in the biochemical nature of the Gs species and not necessarily a physical loss of this protein. Reconstitution of adenylate cyclase activity in cyc- membranes demonstrated a decrease in hormone-sensitive Gs activity in membranes prepared from symptomatic animals without a change in activity demonstrable in the presence of Gpp(NH)p. Collectively, the results suggest that the depression in beta-adrenergic adenylate cyclase activity associated with symptomatic infection of beagles with T. cruzi occurs primarily as a result of changes in the Gs protein complex, most likely resulting in an uncoupling of the beta-adrenergic receptor from the Gs protein.
authors.affiliation: Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032.
authors.forename: S A
authors.initials: SA
authors.lastname: Morris
authors.forename: S
authors.initials: S
authors.lastname: Barr
authors.forename: L
authors.initials: L
authors.lastname: Weiss
authors.forename: H
authors.initials: H
authors.lastname: Tanowitz
authors.forename: M
authors.initials: M
authors.lastname: Wittner
authors.forename: J P
authors.initials: JP
authors.lastname: Bilezikian
mesh_terms: D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D001667:Binding, Competitive; D002598:Chagas Cardiomyopathy / Q000378:metabolism* / Q000503:physiopathology; D002772:Cholera Toxin / Q000494:pharmacology; D004285:Dogs; D004562:Electrocardiography; D019204:GTP-Binding Proteins / Q000378:metabolism; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D007106:Immune Sera / Q000276:immunology; D020120:Iodocyanopindolol; D007545:Isoproterenol / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism*; D010869:Pindolol / Q000031:analogs & derivatives / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D014345:Trypanosoma / Q000145:classification; D014349:Trypanosoma cruzi
chemical_list: D007106:Immune Sera; D011943:Receptors, Adrenergic, beta; D000246:Adenosine Diphosphate Ribose; D006165:Guanylyl Imidodiphosphate; D020120:Iodocyanopindolol; D002772:Cholera Toxin; D010869:Pindolol; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D007545:Isoproterenol