706-3 The Protein Kinase C Inhibitor Polymyxin-B does not Block Preconditioning-induced Cardioprotection in the Canine Model

Abstract

In the rabbit model, administration of protein kinase C (PKC) inhibitors such as polymyxin-B have been reported to attenuate the reduction in infarct size achieved with ischemic preconditioning. Activation of PKC has therefore been proposed to playa crucial role in the mechanism by which preconditioning protects the heart from subsequent sustained coronary occlusion (CO). However, the possible confounding effects of PKC inhibition on myocardial blood flow were not assessed in these studies. We addressed this issue in 28 dogs subjected to 1 h of sustained CO and 4–5 h of reperfusion. In Protocol I, dogs received 45-min episodes of preconditioning ischemia (PC:n = 7) or a comparable control period (n = 9) before sustained CO; Protocol II was identical except polymyxin-B (PMX: 50 mg/kg) was administered throughout the PC regimen (n = 6) or control period (n = 6). Blood flow to the ischemic subendocardium was assessed during sustained CO by injection of rauiolabeled microspheres, and area of necrosis (AN) was delineated by tetrazolium staining and expressed as a % of the area at risk of infarction (AR). Endo Flow (ml/min/g) AN/AR (%) Protocol I: Control PC 006 ± 0.02 0.09 ± 003 19 ± 3 6 ± 2 ** Protocol II: Control + PMX PC + PMX 001 ± 001 0.02 ± 001 29 ± 5 10 ± 3§ ** P < 0.01 vs Control: § p < 0.01 vs Control + PMX Protocol I confirmed the expected reduction in infarct size in preconditioned dogs vs. controls. Protocol II revealed that all PMX-treated dogs were rendered profoundly ischemic during CO. Nonetheless, treatment with PMX did not attenuate the reduction in infarct size achieved with preconditioning. Thus, the PKC inhibitor polymyxin-B may exacerbate ischemia during CO: this may contribute to the previously reported “increase” in infarct size in preconditioned rabbits treated with this agent. Polymyxin-B did not, however, block the cardioprotective effects of preconditioning in this canine model.