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 p latelet-derived compounds on myocardial perfusion and cardiac electrophysio logy. Diadenosine polyphosphates are secreted from platelets and present in the myocardium, but their electrophysiologic and vasomotor effects are inc ompletely understood. We used isolated guinea-pig hearts to study the effec ts of diadenosine triphosphate (Ap(3)A). tetraphosphate (Ap(4)A), pentaphos phate (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) tran siently reduced coronary perfusion pressure, which recovered during the con tinued presence of the compounds. At concentrations greater than 0.1 muM ef fects were maximal and sustained (perfusion pressure decreased from 36.5 +/ - 3.4 to 18.6 +/- 2.5 mm Hg, p < 0.001, with 1 <mu>M Ap(4)A). The changes i n 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 inc reased from 170.6 +/- 2.5 to 187.3 +/- 3.8 ms, p < 0.05, and refractory per iod increased from 138.5 <plus/minus> 1.6 to 147.9 +/- 2.0 ms, p < 0.05. Ap (4)A and its analog reduced QRS duration (from 24.7 <plus/minus> 1.1 to 13. 9 +/- 1.6 ms with 1 muM Ap(4)A, P < 0.05), P-2-purinergic (adenosine tripho sphate) receptor antagonism (suramin) reduced perfusion pressure but was wi thout electrophysiologic effect. Other changes in coronary perfusion pressu re and electrophysiologic variables associated with Ap(4)A were not seen in the presence of suramin. P-1-(adenosine) antagonism (8-[p-sulfophenyl]theo phylline) attenuated the electrophysiologic effects only. Diadenosine polyp hosphates have potent cardiac electrophysiologic and coronary vasomotor eff ects via purinergic receptors, suggesting an important role during platelet activation ill acute coronary syndromes.