JTV-519, a novel cardioprotective agent, improves the contractile recovery after ischaemia-reperfusion in coronary perfused guinea-pig ventricular muscles.
A newly synthesized benzothiazepine derivative, JTV-519 (JT) has been reported to be cardioprotective. However, the precise mechanism underlying the cardioprotective effect of this drug is unknown. Coronary-perfused guinea-pig ventricular muscles were subjected to 20-min no-flow ischaemia followed by 60-min reperfusion (I/R). I/R significantly decreased the contraction in untreated preparations (control group, 34+/-4% of baseline value, n=6). Brief administration of JT (1.0 microM) prior to ischaemia significantly improved the postischaemic contractile recovery (63+/-5% of baseline value, n=4), as compared to the control group. JT (1.0 microM) slightly prolonged action potential duration before ischaemia and induced conduction disturbance (2 : 1 block) after the initiation of ischaemia. The cardioprotective effect of JT was antagonized by chelerythrine (CH, 5.0 microM), an inhibitor of protein kinase C (PKC) or by 5-hydroxydecanoic acid (5-HD, 400 microM), an inhibitor of mitochondrial ATP-sensitive K(+) (K(ATP)) channels. These results suggest that the protective effect of JT is due to the opening of mitochondrial K(ATP) channels, which, in turn, is linked to PKC activation.
Ito
K
K
Department of Physiology, Oita Medical University, 1-1 Idaigaoka, Hasama, Oita 879-5593, Japan.
Shigematsu
S
S
Sato
T
T
Abe
T
T
Li
Y
Y
Arita
M
M
D000200:Action Potentials / Q000187:drug effects; D000255:Adenosine Triphosphate / Q000502:physiology; D000470:Alkaloids; D000818:Animals; D053119:Benzophenanthridines; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003652:Decanoic Acids / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000187:drug effects*; D006880:Hydroxy Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D008929:Mitochondria, Heart / Q000187:drug effects / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects*; D017202:Myocardial Ischemia / Q000150:complications; D015425:Myocardial Reperfusion / Q000009:adverse effects; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000517:prevention & control*; D010477:Perfusion; D010617:Phenanthridines / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D013841:Thiazepines / Q000494:pharmacology*; D016276:Ventricular Function
D000470:Alkaloids; D053119:Benzophenanthridines; D002121:Calcium Channel Blockers; D003652:Decanoic Acids; D004791:Enzyme Inhibitors; D006880:Hydroxy Acids; D010617:Phenanthridines; D015221:Potassium Channels; D013841:Thiazepines; C109183:K201 compound; C052853:5-hydroxydecanoic acid; D000255:Adenosine Triphosphate; C016299:chelerythrine; D011493:Protein Kinase C