Protein kinase inhibition exerts cardioprotective effects in myocardial ischemia/reperfusion via inhibition of superoxide release.
Staurosporine, a selective inhibitor of protein kinase C (PKC) in the low nanomolar range suppresses superoxide production from polymorphonuclear leukocytes (PMNs). Therefore, we hypothesized that staurosporine could attenuate PMN-induced cardiac dysfunction by inhibiting superoxide production from PMNs. We examined the effects of staurosporine in isolated ischemic (I) (20 min) and reperfused (R) (45 min) rat hearts perfused with PMNs. Staurosporine given at 5 or 20 nM to hearts at R significantly improved left ventricular developed pressure (LVDP) (p < 0.01) and the maximal rate of development of LVDP (+dP/dtmax) (p < 0.05, 5 nM, and p < 0.01, 20 nM) compared to similar hearts perfused in the absence of staurosporine. Recombinant human superoxide dismutase (hSOD, 4 micrograms/ml) restored LVDP and +dP/dtmax to that of initial baseline at 45 min postreperfusion. Staurosporine also significantly reduced PMN adherence to the endothelium and infiltration into the myocardium by 38 to 48% (p < 0.01), whereas hSOD attenuated PMN infiltration and adherence by 74% (p < 0.001). These results provide clear evidence that inhibition or scavenging of superoxide release from PMNs significantly attenuates PMN-induced cardiac contractile dysfunction in the ischemic-reperfused rat heart and that a significant component of superoxide release from PMNs is mediated by PKC.
Young
L H
LH
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA.
Ikeda
Y
Y
Lefer
A M
AM
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002448:Cell Adhesion / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D016166:Free Radical Scavengers / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009504:Neutrophils / Q000187:drug effects; D009924:Organ Culture Techniques; D010477:Perfusion; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019311:Staurosporine / Q000494:pharmacology / Q000627:therapeutic use*; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology; D017725:Ventricular Pressure / Q000187:drug effects
D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D013481:Superoxides; D013482:Superoxide Dismutase; D011493:Protein Kinase C; D019311:Staurosporine