Disease relevance of Y 26763

• 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 [1].
• We examined the effect of the ATP-sensitive potassium channel activator Y-26763 on focal cerebral ischemia in rats [2].

High impact information on Y 26763

• RESULTS: Y-26763 increased GMBF, which was abolished by glibenclamide, and a CGRP-induced increase in GMBF was attenuated by glibenclamide [3].
• We examined whether the effect of Y-26763, an ATP-sensitive potassium channel opener, on cerebral blood flow is altered in stroke-prone spontaneously hypertensive rats (SHRSP) and, if altered, whether long-term antihypertensive treatment with cilazapril, an angiotensin-converting enzyme inhibitor, is capable of preventing the change [4].
• Vasodilator responses induced by ACh and Y-26763 were markedly attenuated in SHR compared to WKY rats, and treatment of SHR with genistein significantly improved the vasodilatation [5].
• After feeding the rats for 2 months, we measured wall thickness, diameter of the basilar artery and its dilator responses to acetylcholine (ACh); Y-26763, an opener of ATP-sensitive potassium channels; and Y-27632, an inhibitor of Rho-associated kinase [5].
• 4. Forskolin (0.1 microm), 8-bromoguanosin 3', 5' cyclic monophosphate (8Br-cGMP, 0.1 mm) and Y-26763 (10 microm) suppressed contractions without reducing the amplitude of either action potentials or Ca transients [6].

Biological context of Y 26763

• 3. (+/-)-Cibenzoline, RS-2135, pirmenol, lorcainide and KW-3407 (class I antiarrhythmic drugs, Na+ channel blockers) suppressed Y-26763 responses in a concentration-dependent manner with IC50 values (in microM) of 6.6, 54, 68, 71 and 370, respectively [7].
• 1. The mechanisms underlying the vasodilatation induced by (-)-(3S,4R)-4-(N-acetyl-N-hydroxyamino)-6-cyano-3,4-dihydro-2, 2-dimethyl-2H-1-benzopyran-3-ol (Y-26763) were investigated by measuring membrane potential, intracellular Ca2+ concentration ([Ca2+]i) and isometric force in smooth muscle cells of the rabbit mesenteric artery [8].
• In the single-dose study, peak concentration (Cmax) and area under the plasma concentration-time curve (AUC) of main active metabolite (Y-26763; M1) increased in parallel with dosage [9].
• In non-ischemic conditions, Y-26763 significantly increased coronary flow without affecting cardiac output and heart rate [1].
• Clonidine and idazoxan, which both bind to imidazoline-preferring binding sites with high affinity in various tissues, showed only a small inhibitory effect on Y-26763-induced K+ currents (IC50 780 microM and 955 microM, respectively) [10].

Anatomical context of Y 26763

• Conclusions: Y-26763 may directly prevent electrical excitability of bladder smooth muscles by inhibiting spike discharges and also by hyperpolarizing the membrane [11].
• 1. The novel K+ channel opener, Y-26763 induced outward K+ currents in voltage-clamped follicle-enclosed Xenopus oocytes in a concentration-dependent manner with an EC50 value of 58 microM [7].
• Y-26763 also had no apparent effect on the myofilament Ca(2+)-sensitivity in the presence of Hist in alpha-toxin-skinned smooth muscles [12].
• 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 [13].
• 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 [13].

Associations of Y 26763 with other chemical compounds

• 4. Clofilium, E-4031, MS-551 and bretylium (class III antiarrhythmic drugs which increase the action potential duration) also suppressed Y-26763 responses concentration-dependently, IC50 values (in microM) were 3.3, 660, 980 and > or = 2000, respectively [7].
• The rank order of potencies (IC50 in microM) of four isomers of diltiazem to block Y-26763-induced K+ currents was (+)-trans (4.2) > (-)-trans (13.3) > (-)-cis (35.8) > (+)-cis (75.9), which was, however, opposite to that of their potencies as Ca2+ channel antagonists [14].
• (+)-Propranolol and mexiletine also suppressed Y-26763-induced K+ currents with IC50 values of 115 microM and 789 microM, respectively [15].
• The Ca2+ channel antagonist, SD-3211 and its less potent (-)-isomer, SD-3212, suppressed Y-26763-induced K+ currents with similar IC50 values of 10.7 microM and 8.9 microM, respectively [14].
• The non-imidazoline/non-imidazolidine alpha-adrenoceptor antagonists, WB-4101 (2-(2,6-dimethoxy-phenoxyethyl)-aminomethyl-1,4-benzodioxane hydrochloride), yohimbine and rauwolscine, showed suppressive effects on Y-26763-induced K+ currents (IC50 203 microM, 813 microM and 832 microM, respectively) [10].

Gene context of Y 26763

• 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 [16].
• The results clearly demonstrate that Y-26763 protects the myocardium from ischemic injury by opening KATP channels [1].
• K+ currents induced by the K+ channel opener Y-26763 were potentiated by ANF (0.5-50 nM) in a concentration-dependent manner [17].

Analytical, diagnostic and therapeutic context of Y 26763

• 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) [13].
• Y-26763 did not affect CBF before or after occlusion compared with CBF values of the control group [2].

References