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 µg/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.
Methods and findings in experimental and clinical pharmacology
Young, Lindon; Ikeda, Yasuhiko; and Lefer, Allan M., "Protein kinase inhibition exerts cardioprotective effects in myocardial ischemia/reperfusion via inhibition of superoxide release" (2001). PCOM Scholarly Papers. 464.