Abstract

Diadenosine tetraphosphate (AP₄A) is an endogenous compound and exerts diverse physiological effects in animal systems. However, the effects of AP₄A on inotropy in ventricular cardiac preparations have not yet been studied. The effects of AP₄A on force of contraction (FOC) were studied in isolated electrically driven guinea pig and human cardiac preparations. Furthermore, the effects of AP₄A on L-type calcium current and [Ca]_i were studied in isolated guinea pig ventricular myocytes. In guinea pig left atria, AP₄A (0.1–100 μM) reduced FOC maximally by 36.5 ± 4.3%. In guinea pig papillary muscles, AP₄A (100 μM) alone was ineffective, but reduced isoproterenol-stimulated FOC maximally by 29.3 ± 3.4%. The negative inotropic effects of AP₄A in atria and papillary muscles were abolished by the A₁-adenosine receptor antagonist 1,3-dipropyl-cyclopentylxanthine. In guinea pig ventricular myocytes, AP₄A (100 μM) attenuated isoproterenol-stimulated L-type calcium current and [Ca]_i. In human atrial and ventricular preparations, AP₄A (100 μM) alone increased FOC to 158.3 ± 12.4% and 167.5 ± 25.1%, respectively. These positive inotropic effects were abolished by the P₂-purinoceptor antagonist suramin. On the other hand, AP₄A (100 μM) reduced FOC by 27.2 ± 7.4% in isoproterenol-stimulated human ventricular trabeculae. The latter effect was abolished by 1,3-dipropyl-cyclopentylxanthine. In summary, after betaadrenergic stimulation AP₄A exerts negative inotropic effects in animal and human ventricular preparations via stimulation of A₁-adenosine receptors. In contrast, AP₄A alone can exert positive inotropic effects via P₂-purinoceptors in human ventricular myocardium. Thus, P₂-purinoceptor stimulation might be a new positive inotropic principle in the human myocardium.