Caldaret, an intracellular Ca2+ handling modulator, limits infarct size of reperfused canine heart.
The cardioprotective effect of caldaret, a novel intracellular Ca(2+) handling modulator that acts through reverse-mode Na(+)/Ca(2+) exchanger inhibition and potential sarcoplasmic reticulum (SR) Ca(2+) uptake enhancement, against reperfusion injury was investigated. We employed a canine model of myocardial infarction induced by 90-min occlusion of left circumflex (LCX) coronary artery followed by 4 h of reperfusion. Intravenously infused caldaret (3 or 30 microg/kg per hour) for 30 min at LCX-reperfusion markedly reduced infarct size (by 51.3% or 71.9%, respectively). This cardioprotection was accompanied by an acceleration of left ventricular (LV) contraction and relaxation during reperfusion, but not by an increase in ischemic regional transmural myocardial blood flow (TMBF) or endocardial/epicardial blood flow ratio (Endo/Epi ratio) or a reduction in double-product throughout the protocol. Diltiazem (2000 microg/kg per hour) also reduced infarct size (by 36.1%), but unlike caldaret, was accompanied by the significant increase in Endo/Epi ratio in the ischemic region and decrease in double-product. There were significant inverse relationships between infarct size and ischemic regional TMBF in all groups. Caldaret, but not diltiazem shifted the regression line downward with a flatter slope. These results suggest that the amelioration of intracellular Ca(2+) handling dysfunction achieved by caldaret leads to cardioprotective effects against reperfusion injury following prolonged ischemia.
Kawasumi
Hisashi
H
Research Laboratory II, Cardiovascular Section, Mitsubishi Pharma Corporation, 1000 Kamoshida, Aoba, Yokohama 227-0053, Japan. Kawasumi.Hisashi@mc.m-pharma.co.jp
Satoh
Naoya
N
Kitada
Yoshimi
Y
D000465:Algorithms; D000818:Animals; D001557:Benzenesulfonates / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects; D004110:Diltiazem / Q000494:pharmacology; D004285:Dogs; D006321:Heart / Q000187:drug effects; D009203:Myocardial Infarction / Q000209:etiology / Q000473:pathology*; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism
D001557:Benzenesulfonates; D002121:Calcium Channel Blockers; D010879:Piperazines; D019831:Sodium-Calcium Exchanger; C487217:caldaret; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D004110:Diltiazem; D002118:Calcium