Rho-kinase inhibitors Y-27632 and fasudil prevent agonist-induced vasospasm in human radial artery.
Radial artery (RA) vasospasm remains a potential cause of early graft failure after coronary artery bypass graft surgery, despite pretreatment with alpha-adrenergic or calcium channel blockers. Our aim was to investigate the mechanism of the vasorelaxant effects of Rho-kinase inhibitors (Y-27632 and fasudil) on the human RA. Segments were obtained from 30 patients undergoing coronary artery bypass graft and were divided into 3-4 mm vascular rings. The rings were stimulated with 10(-5) mol/L phenylephrine (PE) by using the isolated tissue bath technique and were relaxed with 10(-6) mol/L acetylcholine. Relaxation responses were recorded for Y-27632 (10(-9)-10(-4) mol/L), fasudil (10(-9)-10(-4) mol/L), and sodium nitroprusside (SNP) (10(-9)-10(-5) mol/L). Y-27632 and fasudil relaxation responses were repeated in either N(G)-nitro-L-arginine (L-NNA), which is a specific endothelial nitric oxide synthase inhibitor, or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), which is a guanylate cyclase inhibitor. SNP relaxation responses were repeated in 10(-8) mol/L Y-27632 and 10(-8) mol/L fasudil. Y-27632 and fasudil caused concentration-dependent vasorelaxation in RA rings precontracted with PE, and maximal relaxation (100%) was recorded at the highest concentration used (10(-4) mol/L). The vasorelaxant effects of Y-27632 and fasudil were significantly reduced in the presence of L-NNA and ODQ, and the pD2 values of Y-27632 and fasudil were not changed. The vasorelaxant effects of SNP were significantly increased in the presence of Y-27632 and fasudil, and the pD(2) values of SNP were not changed. These findings indicate that Y-27632 and fasudil caused concentration-dependent vasorelaxation in the RA rings. Because this effect was decreased in a dose-dependent manner by L-NNA and ODQ, the relaxant effects of Y-27632 and fasudil could be due to stimulation by nitric oxide that is being released. Rho-kinase inhibitors may have an important role in preventing vasospasm in arterial grafts used for coronary artery surgery.
Disli
Olcay Murat
OM
Department of Cardiovascular Surgery, Cumhuriyet University School of Medicine, Sivas 58140, Turkey. eozdemir@cumhuriyet.edu.tr
Ozdemir
Ercan
E
Berkan
Ocal
O
Bagcivan
Ihsan
I
Durmus
Nedim
N
Parlak
Ahmet
A
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000819:agonists / Q000031:analogs & derivatives* / Q000494:pharmacology; D000368:Aged; D000577:Amides / Q000819:agonists / Q000494:pharmacology*; D003251:Constriction, Pathologic / Q000201:enzymology / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019335:Nitroarginine / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000819:agonists* / Q000494:pharmacology*; D011725:Pyridines / Q000819:agonists / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D017534:Radial Artery / Q000187:drug effects* / Q000201:enzymology; D044169:Receptors, Calcium-Sensing / Q000819:agonists / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology
C494582:1H-(1,2,3)oxadiazolo(4,4-a)quinoxalin-1-one; D000577:Amides; D010069:Oxadiazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011810:Quinoxalines; D044169:Receptors, Calcium-Sensing; C108830:Y 27632; D009599:Nitroprusside; D019335:Nitroarginine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C049347:fasudil