Acute cardioprotective effects oferythropoietin in infant rabbits are mediated by activation ofprotein kinases and potassium channels

Abstract. Erythropoietin is protective against cardiac ischemia, butthe underlying mechanisms are unknown. We determined whethererythropoietin (0.5 – 10.0 U/ml) confers acute cardioprotectionin infant rabbit hearts and the contribution of protein kinases,nitric oxide synthase and potassium channels to the underlyingmechanism. Hearts from normoxic infant New Zealand White rabbits(n=8/group) were isolated and perfused in the Langendorff mode.Biventricular function was recorded under steady-stateconditions prior to 30 min global no-flow ischemia and 35 minreperfusion. Administration of erythropoietin for 15 minimmediately prior to ischemia resulted in aconcentration-dependent increase in recovery of left and rightventricular developed pressure in rabbit hearts followingmyocardial ischemia and reperfusion. The optimal concentrationof erythropoietin that afforded maximum recovery of developedpressure was manifest at 1.0 U/ml. Erythropoietin (1.0 U/ml)treatment resulted in phosphorylation of PKC, p38 MAP kinase andp42/44 MAP kinase. The cardioprotective effects oferythropoietin were abolished by the protein kinase inhibitorsSB203580 (p38 MAP kinase), PD98059 (p42/44 MAP kinase) andchelerythrine (PKC) as well as the potassium channel blockersglibenclamide, HMR 1098, 5-HD and Paxilline. Nitrite and nitraterelease from hearts before (2.3 ± 0.9 nmol/min/g) and after (2.4± 1.9 nmol/min/g) 15 min treatment with erythropoietin (1.0U/ml) were not different. L-NAME and L-NMA did not block thecardioprotective effect of erythropoietin. We conclude the rapidactivation of potassium channels and protein kinases byerythropoietin represents an important new mechanism forincreasing cardioprotection.This work was supported in part by grants HL54075,HL66334 and HL65203 to JEB and HL61417 and HL71214 to KAP fromthe National Institutes of Health.