Y-26763

Y-26763 protects the canine heart from a stunning injury through opening of the KATP channels.[Pubmed:9128839]

Eur J Pharmacol. 1997 Apr 4;323(2-3):197-204.

The present study describes the protective effects of the ATP-sensitive K+ (KATP) channel opener Y-26763 ((-)-(3S,4R-4-(N-acetyl-N-hydroxyamino)-6-cyano-3,4-dihydro-2,2-dimethyl -2H-1-benzopyran-3-ol), on a model of reversible ischemia/reperfusion injury ('stunned' myocardium). Stunning was caused by 10-min occlusion of the left circumflex coronary artery followed by 3-h reperfusion in pentobarbital anesthetized beagle dogs. This procedure reduced by over 80% myocardial segment function measured by sonomicrometry in control preparations. Y-26763, administered 10 min before the left circumflex coronary artery occlusion, at a dose (3 micrograms/kg, i.v.) lacking significant systemic hemodynamic effects, produced a rapid and marked (80%) recovery of the shortening of the ischemic segment. By contrast, nifedipine (1 microgram/kg plus 0.2 microgram/kg per min, i.v.) did not ameliorate postischemic function. Glibenclamide, administered before Y-26763 at a dose (0.3 mg/kg, i.v.) that did not affect adversely hemodynamics and stunning injury negated the beneficial action of Y-26763. However, glibenclamide failed to do so when administered 2 min before starting reperfusion. The ischemia/reperfusion areas, which were measured by digital image analysis with NIH image software, were similar among experimental groups. Overall, these results indicate that Y-26763 protects the canine myocardium from reversible ischemia/reperfusion injury, probably through activation of myocardial KATP channels which appear to be involved in affording protection during the ischemic insult and not at the reperfusion.

[Protection afforded by a novel K channel opener (Y-26763), against glycerol-induced acute renal failure (ARF) in rats].[Pubmed:9283211]

Nihon Jinzo Gakkai Shi. 1997 Jul;39(5):464-9.

Y-26763, a benzopyran derivative, is a newly developed ATp-sensitive K channel opener and has been reported to protect against ischemic acute renal failure (ARF). We examined the effects of Y-26763 on glycerol-induced myoglobinuric ARF in the rats. ARf was induced in 28 adult male Sprague-Dawley rats by hind-limb intramuscular injection of 50% glycerol (5 ml/kg) after 18 hrs of water deprivation. Y-26763, 7 micrograms/kg (GY group, n = 10) of vehicle (G group, n = 12) was given intravenously 15 min before glycerol injection. Glibenclamide (20 mg/kg), a K channel blocker was given prior to Y-26763 injection to see of the effects was due to the K-channel opener (GYG group, n = 6). Animals were sacrificed 24 or 96 hrs after glycerol injection. Y-26763 partially, but significantly, restored renal dysfunction 24 hrs after ARF. Pcr (mg/dl) and Ccr (ml/min), respectively were as follows: G group, 5.7 +/- 0.4, 0.015 +/- 0.006; GY group, 4.1 +/- 0.4, 0.061 +/- 0.027 (p < 0.05). These favorable effects were antagonized by glibenclamide (Pcr in GYG group, 5.4 +/- 0.3 mg/dl, p < 0.05). Renal calcium content was not statistically significant (3.5 +/- 1.2 vs. 3.4 +/- 1.2 micrograms/mg dry weight). Histological examinations revealed that extensive tubular necrosis and cast formation seen in the G group were reduced in the GY group. At the recovery phase, 96 hrs after glycerol injection, Y-26763 accelerated the recovery from ARF as shown in Pcr (mg/dl) and Ccr (ml/min): 4.3 +/- 0.2, 0.05 +/- 0.01 in the G group, 2.8 +/- 0.2, 0.13 +/- 0.02) in the GY group (p < 0.01). In conclusion, Y-26763 partially protected against glycerol-induced ARF.

Y-26763: ATP-sensitive K+ channel activation and the inhibition of insulin release from human pancreatic beta-cells.[Pubmed:14975702]

Eur J Pharmacol. 2004 Feb 20;486(2):133-9.

The effect of Y-26763 [(-)-(3S,4R)-4-(N-acetyl-N-hydroxyamino)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-be nzopyran-3-ol], a novel ATP-sensitive K(+) (K(ATP)) channel activator, was tested on insulin secretion from human pancreatic islets in vitro. Y-26763 was able to inhibit both glucose- and tolbutamide-induced insulin secretion from islets as assessed by radioimmunoassay. The mechanism for inhibition of insulin secretion was characterised using patch clamp electrophysiology on dispersed human pancreatic beta-cells which express K(ATP) channels comprised of Kir6.2 and SUR1, and the NES2Y human beta-cell line, transfected with Kir6.2DeltaC26. Y-26763 activated K(ATP) channels in a reversible manner with a similar activity to diazoxide. This required the presence of hydrolysable nucleotides and appeared to be mediated by interaction of Y-26763 with SUR1 since: (a) tolbutamide was able to reverse the actions of Y-26763 and (b) Y-26763 failed to activate Kir6.2DeltaC26 in the absence of SUR1. We conclude that Y-26763-induced inhibition of insulin release is dependent upon the activation of K(ATP) channels in human beta-cells.

Y-26763 protects the working rat myocardium from ischemia/reperfusion injury through opening of KATP channels.[Pubmed:8997613]

Eur J Pharmacol. 1996 Dec 19;317(2-3):293-9.

This investigation was undertaken to determine the possible protection against ischemia afforded by Y-26763, [(-)-(3S,4R)-4-(N- acetyl-N-hydroxyamino)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran- 3- ol], which has K+ channel-opening properties, in isolated rat hearts under working conditions. This preparation was subjected to 28 min of global ischemia followed by 30 min of reperfusion. Drugs were injected into the aortic cannula prior to ischemia. Compared to control, Y-26763 (1 microM) resulted in a significant recovery of post-ischemic cardiac functions, significant reduction of cellular enzyme loss, and preserved significantly the stocks of cellular high-energy phosphates and the myocyte ultrastructure. These effects of Y-26763 were completely prevented by glibenclamide (10 microM), a specific K+ channel blocker of KATP channels. In non-ischemic conditions, Y-26763 significantly increased coronary flow without affecting cardiac output and heart rate. The data were analyzed statistically by analysis of variance. The results clearly demonstrate that Y-26763 protects the myocardium from ischemic injury by opening KATP channels.

Y-27152, a long-acting K+ channel opener with less tachycardia: antihypertensive effects in hypertensive rats and dogs in conscious state.[Pubmed:1578381]

J Pharmacol Exp Ther. 1992 May;261(2):730-6.

(+)-(3S,4R)-4-(N-Acetyl-N-benzyloxyamino)-6-cyano-3,4-dihydro-2,2- dimethyl- 2H-1-benzopyran-3-ol (Y-27152) is a new K+ channel opener with a long duration of action and less tachycardia. In this study, Y-27152 was compared with a K+ channel opener lemakalim and a Ca++ channel blocker nifedipine for antihypertensive activity in conscious spontaneously hypertensive rats (SHR) and two-kidney, one-clip renal hypertensive dogs (RHD). In conscious SHR, Y-27152 (0.1-1 mg/kg, p.o.) produced long-lasting dose-related decreases in systolic blood pressure. At 1 mg/kg, the maximum response occurred 5 to 7 hr after dosing, and 24 hr later, the pressure was still significantly reduced. Heart rate was not changed by these doses of Y-27152, whereas equihypotensive doses of lemakalim or nifedipine were strongly tachycardic. The cardiovascular effects of Y-27152 were antagonized by glibenclamide (20 mg/kg, i.v.). In conscious unrestrained RHD, Y-27152 at doses of 0.01, 0.03 and 0.1 mg/kg lowered blood pressure with a slow onset and long duration of action and had only a minimal effect on heart rate, whereas both lemakalim and nifedipine reduced blood pressure and markedly increased heart rate. No tolerance to the antihypertensive effect of Y-27152 (0.1 mg/kg) occurred during an 8-week repeated daily dosing to RHD and plasma renin activity, and aldosterone levels were not elevated during this period. In rat aortic rings contracted with 20 mM KCl, Y-27152 did not modify the tension; however, its desbenzyl form (Y-26763) produced vasorelaxation, and this effect was antagonized competitively by glibenclamide.(ABSTRACT TRUNCATED AT 250 WORDS)