Anti-ischemic effects of fasudil, a specific Rho-kinase inhibitor, in patients with stable effort angina.
Epicardial coronary stenosis causes myocardial ischemia; however, the role of coronary microvessels is poorly understood in the pathogenesis of effort angina. We have previously demonstrated that Rho-kinase pathway is substantially involved in coronary arterial hyperconstriction in patients with vasospastic angina and those with microvascular angina. In the present study, we tested our hypothesis that Rho-kinase is involved in coronary microvascular constriction in patients with effort angina. Intracoronary administration of fasudil (300 microg/min for 15 min), a specific Rho-kinase inhibitor, significantly increased oxygen saturation in coronary sinus vein from 37 +/- 3% to 41 +/- 3% (P < 0.05) but not in six age-matched controls (from 42 +/- 3% to 43 +/- 3%, P = NS). Furthermore, the fasudil treatment significantly ameliorated pacing-induced myocardial ischemia in patients with effort angina (magnitudes of symptom: 1.5 +/- 0.6 to 0.6 +/- 0.4, P < 0.01; ischemic ST-segment depression, 1.8 +/- 0.3 to 1.0 +/- 0.2 mm, P < 0.01; percent lactate production, 50 +/- 17% to 0.4 +/- 7%, P < 0.01) without significant hemodynamic changes. These results provide the first evidence that Rho-kinase is substantially involved in coronary microvascular dysfunction associated with myocardial ischemia in patients with effort angina, suggesting that Rho-kinase can be a novel therapeutic target in ischemic heart disease.
Fukumoto
Yoshihiro
Y
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan. fukumoto@cardio.med.tohoku.ac.jp
Mohri
Masahiro
M
Inokuchi
Kosuke
K
Ito
Akira
A
Hirakawa
Yoji
Y
Masumoto
Akihiro
A
Hirooka
Yoshitaka
Y
Takeshita
Akira
A
Shimokawa
Hiroaki
H
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000368:Aged; D000787:Angina Pectoris / Q000188:drug therapy* / Q000503:physiopathology; D002304:Cardiac Pacing, Artificial; D003251:Constriction, Pathologic / Q000188:drug therapy; D003326:Coronary Circulation / Q000187:drug effects*; D023921:Coronary Stenosis / Q000503:physiopathology; D003331:Coronary Vessels / Q000187:drug effects; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D010100:Oxygen / Q000378:metabolism; D010101:Oxygen Consumption; D005082:Physical Exertion; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D054460:rho-Associated Kinases
D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; C049347:fasudil; D010100:Oxygen