Metabolic protection of the reperfused canine endocardium by the thromboxane synthetase inhibitor, dazoxiben.
This study investigated whether dazoxiben, a thromboxane synthesis inhibitor, could reverse regional contractile dysfunction and protect against adenine nucleotide loss in the "stunned myocardium". Hearts from anesthetized dogs were "stunned" by 15 min of left anterior descending coronary artery occlusion followed by 3 hr of reperfusion. Left ventricular segment shortening (%SS) and regional myocardial blood flow (RMBF) were measured by sonomicrometry and the radioactive microsphere technique, respectively. Local coronary venous blood was withdrawn and thromboxane A2 and prostacyclin measured by radioimmunoassay. Transmural biopsies from the reperfused and nonischemic areas were taken at 3 hr following reperfusion for tissue metabolite analysis. During ischemia, %SS, RMBF and area at risk were decreased to similar levels in both control and dazoxiben-treated hearts indicating equivalent degrees of flow deprivation. During reperfusion, %SS recovered only partially and was not significantly improved by dazoxiben. Dazoxiben augmented peak prostacyclin production (123 +/- 31% vs. 292 +/- 49% of preocclusion values) following reperfusion, while it completely blocked thromboxane A2 production. Dazoxiben attenuated the decline in endocardial ATP (69 +/- 5% vs. 92 +/- 9% normalized to the nonischemic zone) and total adenine nucleotides. The results indicate that dazoxiben may elicit a cardioprotective effect on energy metabolism in the reperfused heart, but this is dissociated from any improvement in regional contractile function.
Pieper
G M
GM
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee 53226.
Farber
N E
NE
Gross
G J
GJ
D000227:Adenine Nucleotides / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000097:blood; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D004285:Dogs; D011464:Epoprostenol / Q000097:blood; D007093:Imidazoles / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects; D015425:Myocardial Reperfusion; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D009206:Myocardium / Q000378:metabolism*; D013928:Thromboxane A2 / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D000227:Adenine Nucleotides; D007093:Imidazoles; C029166:dazoxiben; D013928:Thromboxane A2; D000255:Adenosine Triphosphate; D011464:Epoprostenol; D013930:Thromboxane-A Synthase