Effects of fasudil, a Rho-kinase inhibitor, on myocardial preconditioning in anesthetized rats


Demiryurek S., Kara A., Celik A., Babul A., Tarakcioglu M., Demiryurek A.

EUROPEAN JOURNAL OF PHARMACOLOGY, vol.527, pp.129-140, 2005 (Journal Indexed in SCI) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 527
  • Publication Date: 2005
  • Doi Number: 10.1016/j.ejphar.2005.10.018
  • Title of Journal : EUROPEAN JOURNAL OF PHARMACOLOGY
  • Page Numbers: pp.129-140
  • Keywords: arrhythmia, fasudil, infarct size, preconditioning, Rho-kinase, CORONARY-ARTERY SPASM, PROTEIN-KINASE, SMOOTH-MUSCLE, ISCHEMIA/REPERFUSION INJURY, MECHANISM, PHOSPHORYLATION, ACTIVATION, ISCHEMIA, HEART, MODEL

Abstract

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 I mg/kg) appeared to prevent the antiarrhythmic effects of ischemic preconditioning. Carbachol (4 mu g/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 I 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 I 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. (c) 2005 Elsevier B.V. All rights reserved.