The effect of the thromboxane A2 receptor antagonist SQ 29,548 on the severity of pacing-induced ischemia.
The effect of the thromboxane A2 (TXA2)/prostaglandin endoperoxide receptor antagonist, SQ 29,548 on pacing-induced ischemia was determined in anesthetized open-chest dogs. The dogs were subjected to a left anterior descending coronary artery (LAD) stenosis sufficient to result in ischemia as measured by epicardial ST-segment elevation only when the hearts were paced 70-80 beats/min above baseline. After a recovery (nonpacing) period, either 0.2 mg/kg + 0.2 mg/kg/hr SQ 29,548 or saline was infused i.v. The animals were subjected to 5 min periods of pacing before and 10, 40 or 70 min after the initiation of drug or saline treatment. Before drug treatment, pacing + LAD stenosis resulted in significant ST-elevation in both groups (11.5 +/- 1.1 mV and 12.4 +/- 0.6 mV for saline and SQ 29,548 groups, respectively). During drug treatment, SQ 29,548 significantly reduced ST-elevation during pacing + stenosis at 40 and 70 min. At 70 min, ST-elevation was 4.9 +/- 1.7 mV for the SQ 29,548 group vs 10.8 +/- 1.2 mV for the saline group (p less than 0.05). In separate experiments 0.2 mg/kg + 0.2 mg/kg/hr SQ 29,548 antagonized the activity of a TXA2 mimetic, U-46,619, for femoral vasoconstriction, causing 100-to-200 fold rightward shifts in dose response relationships. Thus, a dose of SQ 29,548 capable of strong TXA2-receptor blockade reduced the severity of ischemia, and this effect was independent of changes in arterial blood pressure and heart rate.
Grover
G J
GJ
Department of Pharmacology, Squibb Institute for Medical Research, Princeton, New Jersey.
Schumacher
W A
WA
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000787:Angina Pectoris / Q000209:etiology / Q000503:physiopathology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002304:Cardiac Pacing, Artificial; D003326:Coronary Circulation / Q000187:drug effects; D003327:Coronary Disease / Q000209:etiology / Q000503:physiopathology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D005231:Fatty Acids, Unsaturated; D005260:Female; D005263:Femoral Artery / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006834:Hydrazines / Q000494:pharmacology*; D008297:Male; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D017482:Receptors, Thromboxane; D012039:Regional Blood Flow / Q000187:drug effects; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors*
D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D011450:Prostaglandin Endoperoxides, Synthetic; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C045749:SQ 29548