Failure of nitroglycerin and diltiazem to reduce platelet-mediated vasoconstriction in dogs with coronary artery stenosis and endothelial injury: Further evidence for thromboxane A2 and serotonin as mediators of coronary artery vasoconstriction in vivo

Abstract

This study was designed to test the efficacy of nitroglycerin and diltiazem in inhibiting in vivo platelet aggregation and reducing platelet-mediated vasoconstriction in a canine model of coronary artery stenosis and endothelial injury. Coronary artery diameter was measured in vivo by means of ultrasonic crystals sutured on the left anterior descending coronary artery (LAD) immediately distal to an external constrictor (LADI), 1 cm below (LAD2), and on the left circumflex coronary artery. Coronary diameter was continuously measured before, during cyclic flow variations (progressive declines in blood flow followed by sudden restorations of flow due to recurrent intracoronary platelet aggregation), during cyclic flow variations and intravenous infusion of nitroglycerin (5 l.ig/kg per min) or diltiazem (15 μg/kg per min), and after cyclic flow variations were abolished by administration of LY53857, a serotonin receptor antagonist (n = 7), or SQ29548, a thromboxane A2 receptor antagonist (n = 7).During control cyclic flow variations, at the nadir of coronary flow (6% to 11% of the nonstenosed values), LAD1 cross-sectional area decreased by 43 ± 8% and 44 ±3% in the two groups of dogs subsequently treated with LY53857 and SQ29548, respectively. Neither nitroglycerin nor diltiazem caused changes in cyclic flow variation frequency or severity. Furthermore, neither drug significantly reduced the vasoconstriction associated with cyclic flow variations, whereas they significantly increased circumflex artery crosssectional area. In contrast, LY53857 and SQ29548 were very effective in abolishing cyclic flow variations and the coronary vasoconstriction related to them. Five additional dogs received an intracoronary infusion of nitroglycerin (21 ± 5 μkg per min) and later diltiazem (15 μg/kg per min). Again, neither drug decreased the coronary vasoconstriction associated with cyclic flow variations. A modest antiplatelet effect was observed during intracoronary infusion of nitroglycerin as cyclic flow variation frequency decreased from 7.7 ± 0.4 to 5.6 ± 0.5 cycles/30 min during control cyclic flow variations (p < 0.05).It is concluded that nitroglycerin and diltiazem are relatively ineffective in inhibiting marked in vivo platelet aggregation and platelet-mediated vasoconstriction in this experimental model. This study provides further evidence that thromboxane A2 and serotonin are mediators of platelet-mediated vasoconstriction in this experimental model.