Cardioprotective effect with carbon monoxide releasing molecule-2 (CORM-2) in isolated perfused rat heart: Role of coronary endothelium and underlying mechanism

Although the cardioprotective role of carbon monoxide (CO) has been studied against myocardial ischemia-reperfusion (I/R) injury, the role of coronary endothelium and underlying mechanism in carbon monoxide-induced cardioprotection is not well understood in isolated heart. The present study was designed to determine the role of coronary endothelium in CORM-2-mediated cardioprotection during I/R injury in isolated rat heart. Preconditioning with 30 µM/l and 50 µM/l of CORM-2 for 10 min markedly reduced lactate dehydrogenase (LDH) and creatinin kinase (CK) levels in coronary effluent after global ischemia. There was also a significant improvement in coronary flow rate, heart rate, cardiodynamic parameters and marked attenuation in infarct size. However, protective effect was abolished when hearts were pretreated with 100 µM CORM-2. We observed that pretreatment with L-NAME (100 µM/l), a nitric oxide synthase (NOS) inhibitor did not affect protection by CORM-2 (50 µM/l). On the other hand pretreatment with Triton X-100 (0.05% for 20 s) to denude endothelium before CORM-2 treatment followed by I/R injury showed similar cardioprotection. Moreover, pretreatment with KATP channel inhibitor, glibenclamide almost completely reversed the cardioprotective effect of CORM-2 in endothelium-denuded hearts. These results indicate that cardioprotection by CORM-2 is highly concentration-dependent, independent of coronary endothelium and cardioprotective effect might be attributed to the activation of KATP channel present on vascular smooth muscle cell (VSMC).

The diagram illustrates the possible signaling pathways affected by CORM-2. Cardioprotective effect of CORM-2 is not dependent on NO or coronary endothelium. CORM-2 may cause activation of KATP channel of vascular smooth muscle cells (VSMC) and significantly protect the heart, which suggests that CORM-2 can mimic preconditioning effect by KATP channel activation. CORM-2 = carbon monoxide releasing molecule-2, NOS = nitric oxide synthase, NO = nitric Oxide, sGC = soluble guanylyl cyclase, GTP = Guanosine triphosphate, and cGMP = cyclic Guanosine monophosphate.Figure optionsDownload as PowerPoint slide