Attenuation of neutrophil-mediated myocardial ischemia-reperfusion injury by a calpain inhibitor.
Calpains are ubiquitous neutral cysteine proteases. Although their physiological role has yet to be clarified, calpains seem to be involved in the expression of cell adhesion molecules. Therefore, we hypothesized that a selective calpain inhibitor could attenuate polymorphonuclear (PMN) leukocyte-induced myocardial ischemia-reperfusion (I/R) injury. We examined the effects of the calpain inhibitor Z-Leu-Leu-CHO in isolated ischemic (20 min) and reperfused (45 min) rat hearts perfused with PMNs. Z-Leu-Leu-CHO (10 and 20 microM, respectively) significantly improved left ventricular developed pressure (LVDP) (P < 0.01) and the maximal rate of development of LVDP (P < 0.01) compared with I/R hearts perfused without Z-Leu-Leu-CHO. In addition, Z-Leu-Leu-CHO significantly reduced PMN adherence to the vascular endothelium and subsequent infiltration into the postischemic myocardium (P < 0.01). Moreover, Z-Leu-Leu-CHO significantly inhibited expression of P-selectin on the rat coronary microvascular endothelium (P < 0.01). These results provide evidence that Z-Leu-Leu-CHO significantly attenuates PMN-mediated I/R injury in the isolated perfused rat heart to a significant extent via downregulation of P-selectin expression.
Ikeda
Yasuhiko
Y
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Young
Lindon H
LH
Lefer
Allan M
AM
D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors*; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology* / Q000517:prevention & control; D009504:Neutrophils / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000502:physiology
D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D002154:Calpain