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 β-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 (V(max)) decreased and concentration of agonist resulting in 50% of V(max) (K(act)) increased for isoproterenol-dependent adenylate cyclase activity; in animals infected with Tc-D (asymptomatic), V(max) and K(act) for isoproterenol were unchanged from control, uninfected animals. β-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, G(s), in the setting of infection. Alterations in cholera toxin-dependent ADP-ribosylation patterns as well as immunochemical detection with anti-G(αs) antisera suggested a change in the biochemical nature of the G(s) species and not necessarily a physical loss of this protein. Reconstitution of adenylate cyclase activity in cyc- membranes demonstrated a decrease in hormone-sensitive G(s) 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 β-adrenergic adenylate cyclase activity associated with symptomatic infection of beagles with T. cruzi occurs primarily as a result of changes in the G(s) protein complex, most likely resulting in an uncoupling of the β-adrenergic receptor from the G(s) protein.
- Adenylate cyclase
- Chagas' disease
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine