ly-53857 and Coronary-Disease

The role of recurrent platelet aggregation in the development of neointimal proliferation of coronary arteries was explored in this study, and the hypothesis was evaluated that recurrent platelet aggregation and the consequent frequency and severity of cyclic coronary blood flow variations are important pathophysiologic factors in the subsequent development of neointimal proliferation. In 24 chronically instrumented dogs, variable degrees of coronary artery neointimal proliferation were observed 3 weeks after mechanical injury of the arterial endothelium and the placement of an external coronary artery constrictor. The severity of neointimal proliferation at 21 days was closely related to the frequency and severity of cyclic coronary blood flow variations during the initial 7 days after instrumentation of the animals, itself a manifestation of recurrent platelet aggregation and dislodgement. Pharmacological therapy with a dual thromboxane A2 synthetase inhibitor and receptor antagonist and with a serotonin S2 receptor antagonist frequently was successful in abolishing cyclic blood flow variations and in retarding neointimal proliferation.

Topics: Animals; Blood Pressure; Cell Division; Coronary Disease; Coronary Vessels; Dogs; Endothelium, Vascular; Ergolines; Ketanserin; Muscle, Smooth, Vascular; Platelet Aggregation; Serotonin Antagonists

The purpose of this study was to test the hypothesis that combined thromboxane A2 synthetase inhibition and receptor blockade is superior to either action alone in preventing cyclic flow variations in stenosed and endothelially injured canine coronary arteries. Forty-five dogs developed coronary cyclic flow variations after a plastic constrictor was placed around the left anterior descending coronary artery at the site where the endothelium was injured and received different interventions. In Group I, 17 dogs were treated with SQ 29,548, a thromboxane A2-prostaglandin H2 receptor antagonist. In Group II, 11 dogs received dazoxiben, a thromboxane A2 synthetase inhibitor. In Group III, R 68,070, a dual thromboxane A2 synthetase inhibitor and thromboxane A2-prostaglandin H2 receptor antagonist, was administered to 11 dogs. Group IV comprised six dogs that received aspirin before receiving R 68,070. Complete abolition of cyclic flow variations was achieved in 71% of dogs in Group I, 82% in Group II, 100% in Group III (p = 0.06 compared with Group I) and 50% in Group IV (p = 0.03 compared with Group III). Epinephrine was infused into dogs with abolished cyclic flow variations: all dogs in Group I had cyclic flow variations restored, 44% in Group II (p = 0.01 compared with Group I) and 64% in Group III (p = 0.04 compared with Group I). The plasma epinephrine levels required to restore cyclic flow variations were 2.2 +/- 0.5 ng/ml (control 0.04 +/- 0.01) in Group I, 8.7 +/- 4.5 ng/ml (control 0.05 +/- 0.02) in Group II and 7.4 +/- 2.6 ng/ml (control 0.07 +/- 0.02) in Group III.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Aspirin; Bridged Bicyclo Compounds, Heterocyclic; Coronary Circulation; Coronary Disease; Dogs; Epinephrine; Epoprostenol; Ergolines; Fatty Acids, Unsaturated; Female; Hydrazines; Imidazoles; Male; Pentanoic Acids; Pyridines; Receptors, Prostaglandin; Receptors, Thromboxane; Serotonin Antagonists; Thromboxane A2; Thromboxane-A Synthase

Dynamic changes of the thrombus after its formation due to platelet activation may affect the speed of thrombolysis. In the present study, we wanted to evaluate the role played by thromboxane A2 (TXA2) and serotonin (5HT) in mediating platelet activation during lysis of intracoronary thrombi with human recombinant tissue-type plasminogen activator (t-PA). Coronary thrombi were induced in 26 anesthetized, open-chest dogs by inserting a copper coil into the left anterior descending coronary artery (LAD). LAD blood flow was monitored throughout the experiment by means of a Doppler flow probe placed proximally to the coil. Presence of the thrombus was documented for 30 minutes. The dogs were then assigned to one of four groups as follows: group 1 dogs (n = 8), serving as controls, received a bolus of heparin (200 units/kg) and a bolus of t-PA (80 micrograms/kg) followed by a continuous infusion (8 micrograms/kg/min) for up to 90 minutes or until reperfusion was achieved; group 2 dogs (n = 10) received, immediately before heparin and t-PA, an intravenous bolus of SQ29548 (SQ) (0.4 mg/kg, a selective TXA2-receptor antagonist) and LY53857 (LY) (0.2 mg/kg, a selective serotonin S2-receptor antagonist); group 3 dogs (n = 7) received, before heparin and t-PA, an intravenous bolus of SQ alone (0.4 mg/kg); and group 4 dogs (n = 7) received, before heparin and t-PA, an intravenous bolus of LY alone (0.2 mg/kg). After thrombolysis, all dogs were monitored for 90 minutes or until a persistent reocclusion occurred.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Coronary Disease; Coronary Thrombosis; Dogs; Drug Therapy, Combination; Ergolines; Fatty Acids, Unsaturated; Hydrazines; Myocardial Reperfusion; Platelet Aggregation; Recombinant Proteins; Recurrence; Serotonin; Serotonin Antagonists; Thromboxane A2; Time Factors; Tissue Plasminogen Activator

The object of this study was to test the hypothesis that administration of both serotonin S2 and thromboxane A2-prostaglandin H2 (PGH2) receptor antagonists provides significant protection against epinephrine-induced cyclic coronary artery flow variations in open chest, anesthetized dogs with severe proximal coronary artery stenosis and endothelial injury. Three groups of dogs were studied. In Group 1 (n = 7) and Group 2 (n = 6), cyclic coronary flow variations were initiated after placement of a concentric constrictor around the left anterior descending coronary artery and were abolished by administration of either a thromboxane A2-prostaglandin H2 receptor antagonist, SQ29,548 (SQ) (Group 1), or a serotonin S2 receptor antagonist, LY53,857 (LY) (Group 2). Cyclic flow variations were restored with an epinephrine infusion and the second antagonist (LY for Group 1; SQ for Group 2) was administered to abolish epinephrine-induced cyclic flow variations. The rate of epinephrine infusion was increased until cyclic coronary flow variations returned (n = 8) or significant hemodynamic changes occurred. Plasma epinephrine concentrations were determined during a control period of cyclic coronary flow variations, after epinephrine restored cyclic flow variations in the presence of either SQ or LY, and again after epinephrine restored cyclic flow variations in the presence of both SQ and LY. A third group of dogs (Group 3, n = 9) required both SQ and LY to eliminate the initial cyclic coronary flow variations and infused epinephrine restored cyclic flow variations (n = 8). Plasma epinephrine concentrations were determined during a control period and after cyclic coronary flow variation restoration with epinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Flow Velocity; Bridged Bicyclo Compounds, Heterocyclic; Coronary Circulation; Coronary Disease; Dogs; Epinephrine; Ergolines; Fatty Acids, Unsaturated; Female; Hemodynamics; Hydrazines; Male; Receptors, Prostaglandin; Receptors, Thromboxane; Serotonin Antagonists; Yohimbine