In previous work, we have shown that the chronic administration of
verapamil, a
calcium channel blocker, ameliorated the mortality, pathology, and biochemical alterations associated with acute murine
Chagas' disease. To extend these studies to an established chronic model, C3H/Hej mice were infected with the Sylvio X10/4 clone. This clone does not cause symptomatic
acute disease but does induce cardiac pathology incorporating several pathological features of human chagasic
cardiomyopathy. Cardiac pathology was assessed at 60, 90, and 180 days postinfection. There was a significant decrease in the degree of
inflammation and
fibrosis in the group infected and treated with
verapamil. Myocardial beta-
adrenergic adenylate cyclase (AC) activity was determined 180 days postinfection. In the infected group not treated with
verapamil, there was no significant change in the maximum rate of conversion of
ATP to cAMP (Vmax) or in the concentration of agonist giving 50% of Vmax (apparent Kact) for
isoproterenol (ISPN)-dependent AC activation. The increase in Vmax for ISPN determined in the presence of 5'-guanylylimidodiphosphate (
Gpp[NH]p) was consistently lower in infected than in uninfected mice, suggesting that
infection altered the potential synergistic activation of AC by the
guanine nucleotide. In the infected group treated with
verapamil, there was a slight increase in the Vmax for ISPN. However, there was a marked enhancement of the synergistic contribution of
Gpp(NH)p. These observations suggest that
verapamil had preserved that aspect of the AC complex mediating
guanine nucleotide sensitive activation of AC. Collectively, the observations in the acute and chronic models of murine
Chagas' disease suggest that
verapamil may be a useful adjunct in treatment.