Cardioprotective effects of a new vascular intracellular calcium antagonist, KT-362, in the stunned myocardium.
Reversible, prolonged functional and metabolic abnormalities result from brief coronary occlusions with subsequent reperfusion (stunned myocardium). In the present study the effects of a new antiarrhythmic, vasodilator agent with intracellular calcium antagonist properties in vascular smooth muscle, KT-362 (5-[3-[( 2,3,4-dimethoxyphenyl]-ethyl)amino-1-oxopropyl]- 2,3,4,5-tetrahydro-1,5-benzothiazepine fumarate) on postischemic functional (percentage of segment shortening) recover and regional myocardial blood flow (radioactive microspheres) in the stunned myocardium were investigated in anesthetized dogs subjected to a 15-min coronary artery occlusion followed by 3 hr of reperfusion. Saline or KT-362 (300 micrograms/kg/min i.v.) were infused 15 min before and throughout occlusion of the left anterior descending coronary artery. There were no significant differences between groups in ischemic bed size or collateral blood flow, however, during ischemia and after reperfusion, KT-362 produced a significant decrease in the heart rate-systolic pressure product, an index of myocardial oxygen demand. In addition, there was a significant decrease in the incidence of reperfusion-induced ventricular fibrillation in the drug-treated animals. KT-362-treated dogs showed a marked improvement in myocardial segment function of the ischemic-reperfused region at 1, 2, and 3 hr of reperfusion as compared to the saline-treated animals (3 hr percentage of segment shortening of pretreatment: saline group, 14 +/- 10; KT-362 group, 59 +/- 7). These results demonstrate that KT-362 has a favorable effect on the functional recovery of the ischemic-reperfused myocardium and incidence of ventricular fibrillation, and may be of potential benefit as a new therapeutic agent for the treatment of coronary heart disease.(ABSTRACT TRUNCATED AT 250 WORDS)
Farber
N E
NE
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee.
Gross
G J
GJ
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D004285:Dogs; D005260:Female; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D015222:Sodium Channels / Q000187:drug effects; D013841:Thiazepines / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D015222:Sodium Channels; D013841:Thiazepines; D014665:Vasodilator Agents; C051271:KT 362; D002118:Calcium