6533b823fe1ef96bd127f5c2

RESEARCH PRODUCT

Influence of cyclization and acyl substitution on the inotropic effects of adenine nucleotides.

subject

description

This study was designed to further elucidate relevance and mechanism of the positive inotropic action of cyclic N6-2′-O-dibutyryl-AMP (DB-c-AMP). For this purpose the effects of cyclic N6-monobutyryl-AMP (N6-MB-c-AMP), noncyclic N6-2′-O-3′-O-tributyryl-5′-AMP (TB-AMP), c-AMP, adenosine and various adenine nucleotides (ATP, ADP, AMP) on myocardial contractile force (CF) were investigated and compared to that of DB-c-AMP. The experiments were performed on isolated, electrically driven (frequency 2 Hz) rat left auricles, i.e. on a preparation in which DB-c-AMP consistently produced positive inotropic effects. The following results were obtained: From the failure of non-cyclic TB-AMP to increase contractile force it is concluded that the positive inotropic effects seen with cyclic DB-AMP and cyclic N6-MB-AMP are due to both acyl substitution and the intact cyclophosphate structure. In so far we probably have ruled out one of the objections to the view that the positive inotropic responses to acyl substituted derivatives of c-AMP are “representative” for c-AMP itself. Since the effects of cyclic DB-AMP and cyclic N6-MB-AMP were qualitatively similar and since the time course of the loss of the positive inotropic effects during washout were practically not differen with both drugs, one may further conclude that within the cell both drugs are likely to act via the same compound. This agent could be c-AMP. However, cyclic N6-MB-AMP as the active intracellular compound cannot be ruled out.