Improvement of ischemia-reperfusion-induced myocardial dysfunction by modulating calcium-overload using a novel, specific calmodulin antagonist, CGS 9343B.
The present paper explores the mechanism of calcium-overloaded cardiac cell exocytosis during reperfusion of ischemic myocardium. A novel specific inhibitor of calmodulin, CGS 9343B, was used to pretreat an ischemic heart in an effort to enhance myocardial preservation. The experimental model employed an isolated in situ pig heart subjected to 120 min of ischemic insult by reversibly occluding the left anterior descending coronary artery, the last 60 min being superimposed with global hypothermic cardioplegic arrest. This ischemic episode was followed by 60 min of revascularization. CGS 9343B enhanced post-ischemic myocardial recovery, as judged by improved regional as well as global myocardial functions, better preservation of high-energy phosphate compounds, and reduced release of creatine kinase. Since this compound blocks calmodulin without inhibiting protein kinase C, the results of this study suggest that calmodulin-dependent kinase, rather than protein kinase C, is primarily involved in expressing calcium-overloaded cell exocytosis, and a specific calmodulin antagonist such as CGS 9343B can be used to salvage an ischemic heart from reperfusion injury.
Das
D K
DK
Department of Surgery, University of Connecticut School of Medicine, Farmington 06032.
Engelman
R M
RM
Prasad
M R
MR
Rousou
J A
JA
Breyer
R H
RH
Jones
R
R
Young
H
H
Cordis
G A
GA
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D003326:Coronary Circulation; D003327:Coronary Disease / Q000503:physiopathology*; D006321:Heart / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism; D010101:Oxygen Consumption; D015427:Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*; D013552:Swine
D001562:Benzimidazoles; D002147:Calmodulin; C052087:CGS 9343B; D002118:Calcium