PREVENTION OF ISCHEMIC PRECONDITIONING ONLY BY COMBINED INHIBITION OFPROTEIN-KINASE-C AND PROTEIN-TYROSINE KINASE IN PIGS

In rabbits, inhibition of either protein kinase C or protein tyrosine kinase abolishes the infarct size reduction achieved by ischemic preco nditioning. In pigs, however, inhibition of protein kinase C does not attenuate ischemic preconditioning. The present study tested whether i nhibition of protein tyrosine kinase alone or in combination with inhi bition of protein kinase C interferes with ischemic preconditioning in pigs. In 29 enflurane-anesthetized pigs, the LAD was cannulated and p erfused from an extracorporeal circuit. Protein tyrosine kinase and pr otein kinase C were inhibited by continuous intracoronary infusion of genistein (5 x 10(-6) mol/l) and staurosporine (10(-7) mol/l), respect ively. Subendocardial blood now (ENDO) was measured with microspheres, Infarct size was analysed by TTC staining (% of LV area at risk) foll owing 90 min low-now ischemia and 120 min reperfusion, In the presence of genistein, 90 min ischemia at an ENDO of 0.06+/-0.01 (+/-S.E.M.) m l/min/g resulted in an infarct size of 16.7+/-4.2% (n=8). With geniste in, ischemic preconditioning by 10 min ischemia and 15 min reperfusion still reduced infarct size to 6.5+/-2.7% (ENDO: 0.05+/-0.01 ml/min/g, n = 7, P<0.05). In the presence of both genistein and staurosporine, infarct size following 90 min ischemia was 14.1+/-3.64% (ENDO: 0.06+/- 0.01 ml/min/g, n=7), With genistein and staurosporine, ischemic precon ditioning no longer reduced infarct size significantly (11.5+/-3.1%, E NDO: 0.06+/-0.01 ml/min/g, n=7). The effective attenuation of ischemic preconditioning only by simultaneous inhibition of both, protein kina se C and protein tyrosine kinase, suggests a complex signal cascade in volving both protein kinases. (C) 1998 Academic Press Limited.