POTENT EFFECTS OF AP3A AND AP4A ON CORONARY RESISTANCE AND AUTACOID RELEASE OF INTACT RABBIT HEARTS

We investigated effects of platelet-derived dinucleotides diadenosine 5',5'''-P1,P4-tetraphosphate (AP4A) on coronary vasculature. In isolated rabbit hearts, saline perfused at constant flow (36 +/- 3 ml/min), AP3A and AP4A induced dose-dependent decreases in coronary perfusion pressure. Dose-effect curves of AP3A [-log M mean effective concentration (EC50) 6.2 +/- 0.1] and AP4A (EC50 6.4 +/- 0.2) were identical and not significantly different from those of adenosine, ADP, and ATP (n = 4-8). There were, however, distinct differences between both dinucleotides: pretreatment with endothelium-derived relaxing factor (EDRF)-inhibitors oxyhemoglobin (6-mu-M, n = 6) and N(G)-nitro-L-arginine (30-mu-M, n = 6) significantly reduced AP4A-induced dilation by 44 and 42% but did not affect vasomotor effects of AP3A or of sodium nitroprusside, adenosine, ATP, and ADP. Concentration of the stable hydrolysis product of prostaglandin (PG)I2, 6-keto-PGF1-alpha, increased by 173 +/- 25% in coronary effluent (n = 23) during infusion of AP3A (1-mu-M). This increase was significantly higher than during infusion of equimolar concentrations of AP4A (38 +/- 10%), ATP (23 +/- 5%), adenosine (20 +/- 10%), or an equimolar combination of AMP and ADP (52 +/- 25%), the hydrolysis products of AP3A. Luminometric and high-performance liquid chromatography analysis showed a nearly complete (94 +/- 3%) degradation of ATP during passage through the coronary bed while significant amounts of AP3A (31 +/- 5%) and AP4A (33 +/- 6%) remained uncleaved. We conclude that both dinucleotides are potent dilators of coronary resistance vessels. Compared with ATP, their survival during a passage through the coronary bed is approximately 10 times higher. Their specific effects on PGI2 and EDRF release suggest that both uncleaved dinucleotides have direct effects on cells of the vascular wall.