Effects of fasudil, a Rho-kinase inhibitor, on myocardial preconditioning in anesthetized rats.
The aim of this study was to examine the effects of fasudil, a Rho-kinase inhibitor, on ischemic preconditioning and carbachol preconditioning in anesthetized rats. The total number of ventricular ectopic beats was markedly augmented with fasudil at 0.3 mg/kg and depressed with fasudil at 10 mg/kg. Fasudil at 10 mg/kg also markedly decreased the ventricular tachycardia incidence. Ischemic preconditioning, induced by 5 min coronary artery occlusion and 5 min reperfusion, decreased the incidence of ventricular tachycardia and abolished the occurrence of ventricular fibrillation. The incidences of ventricular tachycardia and ventricular fibrillation in the fasudil (10 mg/kg) + ischemic preconditioning group were found to be similar to the ischemic preconditioning group. However, low doses of fasudil (0.3 and 1 mg/kg) appeared to prevent the antiarrhythmic effects of ischemic preconditioning. Carbachol (4 microg/kg/min for 5 min) induced marked reductions in mean arterial blood pressure, heart rate and abolished ventricular tachycardia. Marked reductions in ventricular ectopic beats and ventricular tachycardia were noted in the fasudil (10 mg/kg) + carbachol preconditioning group. Lactate levels were markedly reduced in the ischemic preconditioning group and this reduction was prominently inhibited with fasudil at 1 mg/kg. Ischemic preconditioning caused a marked decrease in plasma malondialdehyde levels. Fasudil (10 mg/kg), ischemic preconditioning and carbachol preconditioning each generated marked reductions in ischemic myocardial malondialdehyde levels. Decreases in infarct size were observed with fasudil (10 mg/kg) treatment, ischemic preconditioning and carbachol preconditioning when compared to control. These results suggest that low doses of fasudil (0.3 and 1 mg/kg) appeared to prevents the effects of ischemic preconditioning and carbachol preconditioning, but a high dose of fasudil (10 mg/kg) was able to produce cardioprotective effects on myocardium against arrhythmias, infarct size or biochemical parameters and mimic the effects of ischemic preconditioning in anesthetized rats.
Demiryürek
Seniz
S
Department of Physiology, Faculty of Medicine, Gazi University, Besevler, 06510 Ankara, Turkey.
Kara
Ali F
AF
Celik
Ahmet
A
Babül
Aydan
A
Tarakçioglu
Mehmet
M
Demiryürek
Abdullah T
AT
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000758:Anesthesia; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002217:Carbachol / Q000494:pharmacology / Q000627:therapeutic use; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use; D003331:Coronary Vessels / Q000187:drug effects / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D047908:Intracellular Signaling Peptides and Proteins; D019157:Ischemic Preconditioning, Myocardial / Q000009:adverse effects / Q000379:methods*; D007773:Lactates / Q000097:blood; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D009203:Myocardial Infarction / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017180:Tachycardia, Ventricular / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D014664:Vasodilation / Q000187:drug effects; D018879:Ventricular Premature Complexes / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D054460:rho-Associated Kinases
D002316:Cardiotonic Agents; D047908:Intracellular Signaling Peptides and Proteins; D007773:Lactates; D008315:Malondialdehyde; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D002217:Carbachol; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; C049347:fasudil