The protein kinase inhibitor fasudil protects against ischemic myocardial injury induced by endothelin-1 in the rabbit.
Endothelin-1 (ET-1) induces severe pathologic conditions such as coronary spasm followed by vasospastic angina pectoris and acute myocardial infarction. The related pathophysiologic mechanisms have remained obscure. Endothelin-1 receptor (ET(A) and ET(B)) is reported to couple with several types of G protein-involved pathways that participate in phospholipase C activation and atrial myofibrils organization into sarcomeric units. Here we demonstrate that ET-1 induces histologic and pathologic dysfunction in the rabbit myocardium and that such pathologic events are prevented by the Rho-kinase inhibitor fasudil. Although the bolus injection of ET-1 (1.4 nmol/kg) via the auricular vein of the rabbit induced only transient T-wave elevation, irreversible, severe histologic changes were observed in papillary muscles of the ventricle, and multifocal myocardial necrosis with infiltration of neutrophils and macrophages in the left ventricle occurred. Oral administration of fasudil (10 mg/kg) significantly reduced the occurrence of myocardial injury determinants, whereas conventional Ca2+ channel blockers (nifedipine, diltiazem) and a K+ channel opener (nicorandil; 10 mg/kg, p.o. each) showed a lesser or no effect on such determinants. These results suggest that ET-1 induces severe myocardial dysfunction based not only on the occurrence of vasospastic ischemia but also on its direct effects on the myocardium.
Yamamoto
Y
Y
Institute for Life Science Research, Asahi Chemical Industry, Co., Ltd., Fuji, Shizuoka, Japan.
Ikegaki
I
I
Sasaki
Y
Y
Uchida
T
T
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D004110:Diltiazem / Q000494:pharmacology; D004562:Electrocardiography / Q000187:drug effects; D019332:Endothelin-1 / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology; D008264:Macrophages / Q000502:physiology; D008297:Male; D008853:Microscopy; D017202:Myocardial Ischemia / Q000473:pathology / Q000517:prevention & control*; D009336:Necrosis; D009504:Neutrophils / Q000502:physiology; D020108:Nicorandil / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D010210:Papillary Muscles / Q000187:drug effects* / Q000648:ultrastructure; D011817:Rabbits; D011897:Random Allocation; D014665:Vasodilator Agents / Q000494:pharmacology
D019332:Endothelin-1; D004791:Enzyme Inhibitors; D014665:Vasodilator Agents; D020108:Nicorandil; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D004110:Diltiazem; D009543:Nifedipine; C049347:fasudil