Investigation of the vasorelaxant effects of 3-(5′-hydroxymethyl-2′-furyl)-1-benzyl indazole (YC-1) and diethylamine/nitric oxide (DEA/NO) on the human radial artery used as coronary bypass graft

Abstract

The radial artery (RA) is used as a spastic coronary bypass graft. This study was designed to investigate the mechanism of vasorelaxant effects of YC-1 (3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole), a nitric oxide (NO)-independent soluble guanylate cyclase (sGC) activator, and DEA/NO (diethylamine/nitric oxide), a NO-nucleophile adduct, on the human RA. RA segments (n = 25) were obtained from coronary artery bypass grafting patients and were divided into 3-4 mm vascular rings. Using the isolated tissue bath technique, the endothelium-independent vasodilatation function was tested in vitro by the addition of cumulative concentrations of YC-1 (10-10 to 3 x 10-7 mol/L) and DEA/NO (10-8 to 3 x 10-5 mol/L) following vasocontraction by phenylephrine in the presence or absence of 10-5 mol/L ODQ (1H-(1,2,4)oxadiazole(4,3-a)quinoxalin-1-one), the selective sGC inhibitor, 10-7 mol/L iberiotoxin, a blocker of Ca2+-activated K+ channels, or 10-5 mol/L ODQ plus 10-7 mol/L iberiotoxin. We also evaluated the effect of YC-1 and DEA/NO on the cGMP levels in vascular rings obtained from human radial artery (n = 6 for each drug). YC-1 (10-10 to 3 x 10-7 mol/L) and DEA/NO (10-8 to 3 x 10-5 mol/L) caused the concentration-dependent vasorelaxation in RA rings precontracted with phenylephrine (10-5 mol/L) (n = 20 for each drug). Pre-incubation of RA rings with ODQ, iberiotoxin, or ODQ plus iberiotoxin significantly inhibited the vasorelaxant effect of YC-1, but the inhibitor effect of ODQ plus iberiotoxin was significantly more than that of ODQ and iberiotoxin alone (p < 0.05). The vasorelaxant effect of DEA/NO almost completely abolished in the presence of ODQ and iberiotoxin plus ODQ, but did not significantly change in the presence of iberiotoxin alone (p > 0.05). The pEC50 value of DEA/NO was significantly lower than those for YC-1 (p < 0.01), with no change Emax values in RA rings. In addition, YC-1-stimulated RA rings showed more elevation in cGMP than that of DEA/NO (p < 0.05). These findings indicate that YC-1 is a more potent relaxant than DEA/NO in the human RA. The relaxant effects of YC-1 could be due to the stimulation of the sGC and Ca2+-sensitive K+channels, whereas the relaxant effects of DEA/NO could be completely due to the stimulation of the sGC. YC-1 and DEA/NO may be effective as vasodilator for the short-term treatment of perioperative spasm of coronary bypass grafts.

Involvement of Guanylate Cyclase and K+ Channels in Relaxation Evoked by Ferulate Nitrate in Rat Aorta Artery

“…This observation is in agreement with a previous study showing that nicorandil relaxed rat aorta via activation of sGC independent of NO (49). In fact, sGC activation independent of NO is not unique to nicorandil; cinaciguat (BAY58-2667) and YC-1 have also been shown to be an activator or stimulator of sGC independent of NO, and they both increase sGC activity independent of NO, causing vasorelaxation (50,51). In addition, nitroglycerin has also been shown to activate the sGC/cGMP/cGK-I pathway and produce vasodilation independently of NO in vasorelaxant concentrations (0.01 -1 μM), while nitroglycerin in suprapharmacological concentrations (10 -1000 μM) and isosorbide dinitrate exert their activity via an NOdependent activation of vascular sGC (52).…”

Endothelium-Dependent Vasoconstriction in Isolated Vessel Grafts: A Novel Mechanism of Vasospasm?

“…This agrees well with published data of YC-1 induced relaxations of animal vessels [18], although HRA relaxation by YC-1 was reported to have an EC50 of approx. 5 nmol L -1 [19]. This may be due to a higher level of endogenous NO in HRA compared to HSV, which enhances sGC stimulation by YC-1 [9].…”

Antispastic Management in Arterial Grafts in Coronary Artery Bypass Grafting Surgery

“…A few other substances were investigated that have been suggested to be potential antispastic agents, such as L-carnitine [59], botulinum toxin [60], and NO-independent soluble guanylate cyclase activator YC-1, or NO-nucleophile adduct diethylamine/nitric oxide [61]. However, these unlikely will be chosen primarily as clinical antispastic agents.…”