Coronary vasomotor and cardiac electrophysiologic effects of diadenosine polyphosphates and nonhydrolyzable analogs in the guinea pig

Platelet activation in heart disease is important owing to the effects of platelet-derived compounds on myocardial perfusion and cardiac electrophysiology. Diadenosine polyphosphates are secreted from platelets and present in the myocardium, but their electrophysiologic and vasomotor effects are incompletely understood. We used isolated guinea-pig hearts to study the effects of diadenosine triphosphate (Ap(3)A). tetraphosphate (Ap(4)A), pentaphosphate (Ap(5)A), and hexaphosphate (Ap(6)A) (10 pM-0.1 mM), comparing their actions to those of adenosine, adenosine triphosphate, and nonhydrolyzable Ap(4)A and Ap(5)A analogs. Diadenosine polyphosphates (0.1 nM-0.1 muM) transiently reduced coronary perfusion pressure, which recovered during the continued presence of the compounds. At concentrations greater than 0.1 muM effects were maximal and sustained (perfusion pressure decreased from 36.5 +/- 3.4 to 18.6 +/- 2.5 mm Hg, p < 0.001, with 1 M Ap(4)A). The changes in action potential duration and refractory period developed slowly but were maintained (0.1 nM-1 muM). With 1 nM Ap(4)A, action potential duration increased from 170.6 +/- 2.5 to 187.3 +/- 3.8 ms, p < 0.05, and refractory period increased from 138.5 1.6 to 147.9 +/- 2.0 ms, p < 0.05. Ap(4)A and its analog reduced QRS duration (from 24.7 1.1 to 13.9 +/- 1.6 ms with 1 muM Ap(4)A, P < 0.05), P-2-purinergic (adenosine triphosphate) receptor antagonism (suramin) reduced perfusion pressure but was without electrophysiologic effect. Other changes in coronary perfusion pressure and electrophysiologic variables associated with Ap(4)A were not seen in the presence of suramin. P-1-(adenosine) antagonism (8-[p-sulfophenyl]theophylline) attenuated the electrophysiologic effects only. Diadenosine polyphosphates have potent cardiac electrophysiologic and coronary vasomotor effects via purinergic receptors, suggesting an important role during platelet activation ill acute coronary syndromes.