title: Rho-kinase inhibitors Y-27632 and fasudil prevent agonist-induced vasospasm in human radial artery.
abstract: 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.
authors.affiliation: Department of Cardiovascular Surgery, Cumhuriyet University School of Medicine, Sivas 58140, Turkey. eozdemir@cumhuriyet.edu.tr
authors.forename: Olcay Murat
authors.initials: OM
authors.lastname: Disli
authors.forename: Ercan
authors.initials: E
authors.lastname: Ozdemir
authors.forename: Ocal
authors.initials: O
authors.lastname: Berkan
authors.forename: Ihsan
authors.initials: I
authors.lastname: Bagcivan
authors.forename: Nedim
authors.initials: N
authors.lastname: Durmus
authors.forename: Ahmet
authors.initials: A
authors.lastname: Parlak
mesh_terms: 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
chemical_list: 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