The vascular and cardioprotective effects of liriodenine in ischemia-reperfusion injury via NO-dependent pathway.
Liriodenine is an aporphine derivative isolated from the plant Fissistigma glaucescens. Electrophysiological action, particularly the blockage of Na+ and K+ channels, contributes to the drug's well-known anti-arrhythmic action. However, liriodenine's cardioprotective efficacy and the relation of the channel blockages to the efficacy are poorly known, as is the drug's effect on coronary flow and endothelial function. The present study evaluated the protection conveyed by liriodenine to myocardium and coronary endothelial cells under conditions of ischemia-reperfusion and to assess the involvement of a nitric oxide (NO)-dependent mechanism. In the Langendorff model utilizing Sprague-Dawley rat hearts, the left main coronary artery was occluded for 30 min and reperfusion for 120 min. Liriodenine (1 microM) significantly promoted the recovery of coronary flow and decreased myocardial infarction compared with vehicle-treated hearts. The drug attenuated the reduction of endothelial reactivity and NO release. To simulate the condition that occurs in the ischemic stage, human umbilical vein endothelial cells (HUVEC) were cultured in serum free conditions. Liriodenine showed concentration-dependent effects on cell viability associated with anti-apoptosis under serum-deprivation. Liriodenine prevented eNOS reduction in serum-deprived HUVEC and ischemia-reperfusion hearts. The vascular and cardioprotective effects were reversed by N(G)-nitro-L-arginine methyl ester. Another Na+ and K+ channel blocker with similar activities as liriodenine (quinidine) failed to protect endothelial cells and myocytes. These results demonstrate that liriodenine reduces the extent of cardiovascular injuries under ischemia-reperfusion conditions mainly by preserving the eNOS and the NO production.
Chang
Wei-Luen
WL
Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Chung
Ching-Hu
CH
Wu
Yang-Chang
YC
Su
Ming-Jai
MJ
D000818:Animals; D001060:Aporphines / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III; D011802:Quinidine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D001060:Aporphines; D002316:Cardiotonic Agents; D009569:Nitric Oxide; C026980:liriodenine; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D011802:Quinidine; D019331:NG-Nitroarginine Methyl Ester