Inotropic effects of diadenosine tetraphosphate (AP(4)A) in human and animal cardiac preparations

Diadenosine tetraphosphate (AP(4)A) is an endogenous compound and exerts di verse physiological effects in animal systems. However, the effects of AP(4 )A on inotropy in Ventricular cardiac preparations have not yet been studie d. The effects of AP(4)A on force of contraction (FOC) were studied in isol ated electrically driven guinea pig and human cardiac preparations. Further more, the effects of AP(4)A on L-type calcium current and [Ca](i) were stud ied in isolated guinea pig ventricular myocytes. In guinea pig left atria, AP(4)A (0.1-100 mu M) reduced FOC maximally by 36.5 +/- 4.3%. In guinea pig papillary muscles, AP(4)A (100 mu M) alone was ineffective, but reduced is oproterenol-stimulated FOC maximally by 29.3 +/- 3.4%. The negative inotrop ic effects of AP(4)A in atria and papillary muscles were abolished by the A (1)-adenosine receptor antagonist 1,3-dipropyl-cyclopentylxanthine. in guin ea pig ventricular myocytes, AP(4)A (100 mu M) attenuated isoproterenol-sti mulated L-type calcium current and [Ca](i). In human atrial and ventricular preparations, AP(4)A (100 mu M) alone increased FOC to 158.3 +/- 12.4% and 167.5 +/- 25.1%, respectively. These positive inotropic effects were aboli shed by the P-2-purinoceptor antagonist suramin. On the other hand, AP(4)A (100 mu M) reduced FOC by 27.2 +/- 7.4% in isoproterenol-stimulated human V entricular trabeculae. The latter effect was abolished by 1,3-dipropyl-cycl opentylxanthine. in summary, after beta adrenergic stimulation AP(4)A exert s negative inotropic effects in animal and human ventricular preparations v ia stimulation of A(1)-adenosine receptors. in contrast, AP(4)A alone can e xert positive inotropic effects via P-2-purinoceptors in human ventricular myocardium. Thus, P-2-purinoceptor stimulation might be a new positive inot ropic principle in the human myocardium.