Prevention of myocardial reperfusion injury in experimental coronary revascularization following ischemic arrest by a novel antiinflammatory drug, ONO-3144.
The cardioprotective effects of a novel antiinflammatory drug, ONO-3144 (ONO), on ischemic-reperfused myocardium were investigated using an in situ pig heart model. Heart was subjected to 2 h of regional ischemia, with the final 1 h having superimposed global cardioplegic arrest followed by 1 h of reperfusion. ONO (20 microM) was administered after the arrest at the onset of reperfusion. Left ventricular developed pressure (LVDP), maximum rate of rise of left ventricular pressure (LV dp/dt), and left ventricular end-diastolic pressure (LVEDP) were measured under isovolumic conditions to assess cardiac contractility and compliance. ONO improved LVDP and LV dp/dt, and reduced LVEDP after 60 min of reperfusion compared to control. This drug also improved segment shortening and end-diastolic length significantly after 15 and 60 min of reperfusion. Slight improvements in oxygen consumption and creatine kinase (CK) release were also noted. In addition, ONO reduced lipid peroxidation and thromboxane formation but enhanced the production of prostaglandins. In vitro studied demonstrated ONO to be effective scavengers for both hydroxyl (OH.) and hypohalite (OCL.) radicals. The results suggest that myocardial reperfusion injury that developed after ischemic arrest was reduced significantly by ONO. This drug inhibited such injury, probably by directly scavenging potentially harmful radicals such as OH. and OCI., which are generated in ischemic-reperfused myocardium.
Kimura
Y
Y
Department of Surgery, University of Connecticut School of Medicine, Farmington 06032.
Iyengar
J
J
Engelman
R M
RM
Das
D K
DK
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D003327:Coronary Disease / Q000150:complications*; D003402:Creatine Kinase / Q000378:metabolism; D005260:Female; D005609:Free Radicals; D006324:Heart Arrest, Induced; D006334:Heart Function Tests; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009204:Myocardial Revascularization; D010101:Oxygen Consumption / Q000187:drug effects; D011427:Propiophenones / Q000494:pharmacology*; D011460:Prostaglandins F / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D013552:Swine; D013929:Thromboxane B2 / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001095:Arachidonic Acids; D005609:Free Radicals; D011427:Propiophenones; D011460:Prostaglandins F; D013481:Superoxides; D016718:Arachidonic Acid; D008315:Malondialdehyde; D013929:Thromboxane B2; C037467:2-aminomethyl-4-tert-butyl-6-propionylphenol; D003402:Creatine Kinase; C100006:prostaglandin F1