Inotropic effects of diadenosine monophosphate (AP1A) in isolated human cardiac preparations

Dependent on the number of phosphate residues, diadenosine polyphosphates (APnP) exert divergent inotropic effects in the human heart. We studied the inotropic effects of the smallest member of this family, diadenosine monophosphate (AP1A). Force of contraction was measured in an isometric setup in isolated electrically driven (0.5 Hz) preparations from human atria. AP1A exerted a concentration-dependent negative inotropic effect. The IC50 value was 20.2 microM and the IC50 value was 3.1 microM (n = 5-8). At 100 microM AP1A, force of contraction declined to 50% of the predrug value after 2.5 +/- 0.5 min of incubation (n = 8). AP1A antagonized the positive inotropic effect of the beta-adrenoceptor agonist isoprenaline (10 nM). For 100 microM AP1A, the time to 50% of the predrug force in the presence of isoprenaline amounted to 2.3 +/- 0.2 min (n = 5). The positive inotropic and lusitropic effects of isoprenaline were antagonized by AP1A. The direct (AP1A alone) and indirect (AP1A in the presence of isoprenaline) negative inotropic effects of AP1A were blocked by the A1-adenosine receptor antagonist 1,3-dipropyl-cyclopentyl-xanthine (DPCPX, 0.3 microM). The inotropic effect of AP1A was not blocked by adenosine deaminase. In conclusion, AP1A exerts indirect and direct negative inotropic effects in the human heart through A1-adenosine receptors. These effects might protect the heart against excessive beta-adrenergic stimulation.