Pharmacologic Profiles of YM934, a Novel Potassium Channel Opener

Uchida, Wataru; Masuda, Noriyuki; Taguchi, Taku; Shibasaki, Kumiko; Shirai, Yasuko; Asano, Masaharu; Matsumoto, Yuzo; Tsuzuki, Ryuji; Fujikura, Takashi; Takenaka, Toichi

doi:10.1097/00005344-199402000-00002

Cited by 28 publications

(24 citation statements)

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“…YM934, 2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1 ,Cbenzoxazin-4-yl) pyridine N-oxide a newly synthesized enzoxazin derivative and a novel KATp channel opener (Ishikawa et al 1994;Uchida et al 1994;Yamada et al 1993) and glibenclamide, a sulfonylurea, interact with the pore forming subunit and regulatory subunit, respectively. Since the sulfonylurea receptor is a member of the ATP-binding cassette family homologous to cystic fibrosis transmembrane conductance regulator and the multidrug resistance gene (Aguilar-Bryan et al 1995), the receptor may interact with other channels.…”

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confidence: 99%

Effects of ATP‐Sensitive Potassium Channel Opener on Potassium Transport and Alveolar Fluid Clearance in the Resected Human Lung

Sakuma

Takahashi

Ohya

et al. 1998

Pharmacology & Toxicology

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Abscruct: Since the effect of an ATP-sensitive potassium channel (KATp channel) opener on the function of alveolar epithelial cells is unknown, the effect of YM934, a newly synthesized KATp channel opener, on potassium influx into the alveolar spaces and alveolar fluid clearance was determined in the resected human lung. An isosmolar albumin solution with a low potassium concentration was instilled into the distal airspaces of resected human lungs. Alveolar fluid clearance was measured by the progressive increase in alveolar protein concentration. Net potassium transport was measured by the change in potassium concentration and alveolar fluid volume. YM934 (10-4M) increased net influx of potassium by 140% into the alveolar spaces and also increased alveolar fluid clearance by 60% in the experiments with a potassium concentration of 0.3 mEq/l. Glibenclamide ( 10-4M), a KATp channel blocker, inhibited the YM934-increased influx of potassium transport and the increase in alveolar fluid clearance. Also amiloride (10-5M), an inhibitor of apical sodium uptake, blocked the YM934 stimulated increase in net alveolar fluid clearance. These results indicate that a K A T~ channel opener can effect potassium transport and net vectorial fluid movement across the human alveolar epithelium.

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confidence: 99%

Effects of ATP‐Sensitive Potassium Channel Opener on Potassium Transport and Alveolar Fluid Clearance in the Resected Human Lung

Sakuma

Takahashi

Ohya

et al. 1998

Pharmacology & Toxicology

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“…We used 0.3 µg/kg of YM934 in the present experiment, based on our preliminary study and previous studies reporting the effect of this dose on hemodynamic variables. 3,4,16) Higher doses of YM934 induce dose-dependent decreases in aortic pressure. The NTG dose, 3 µg/kg/min, was confirmed not to induce hypotension.…”

Section: Discussionmentioning

confidence: 99%

“…This was consistent with a report by Uchida, et al confirming a potent vasodilatory effect of the agent, particularly in the coronary artery. 16) Some researchers have proposed that the increase in blood flow during reactive hyperemia after a brief period of ischemia improves segment function in the ischemic area. 20) ATP-sensitive K-ops may favorably alter the balance between myocardial oxygen supply and demand by improving perfusion and/or by decreasing oxygen consumption.…”

Section: Discussionmentioning

confidence: 99%

<b>Comparison of the Effect of the ATP-Sensitive Potassium Channel Opener YM934 With That of Nitroglycerin on Impaired Coronary Circulation in Dogs</b>

et al. 2005

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SUMMARYWe compared the effect of an ATP-sensitive potassium channel opener, YM934, with that of nitroglycerin (NTG) on impaired coronary circulation in dogs. Coronary stenosis was produced in 7 dogs by placing a hydraulic occluder around the proximal left circumflex coronary (LCx) artery and abolishing reactive hyperemia to compromise the LCx flow. The following parameters were measured: the aortic pressure, LCx flow velocity, LCx vessel diameter, LCx peripheral pressure, and segment length in the LCx area. Subsequently, we occluded the LCx artery for 15 seconds and measured the recovery-interval (time required for the segment shortening to return to the preocclusion value). The measurements were recorded under three study conditions: (1) at baseline without LCx stenosis; (2) with LCx stenosis under NTG infusion (3 µg/Kg/min); and (3) with LCx stenosis after intravenous administration of YM934 (0.3 µg/kg). The heart rate and aortic pressure were similar under the three study conditions. Mean LCx flow velocity and segment shortening did not significantly change either. However, LCx peripheral pressure decreased after the induction of stenosis (P < 0.05) and showed no response to either NTG or YM934. YM934 administration significantly increased LCx flow in the presence of LCx stenosis, (P < 0.05), whereas NTG infusion did not. YM934 significantly shortened the recovery-interval of the segment shortening after 15-sec LCx occlusion (P < 0.05), whereas NTG did not. These findings suggest that YM934 improves coronary blood flow and prevents myocardial ischemic damage in severely impaired coronary circulation. (Int Heart J 2005; 46: 501-512) Key words: ATP-sensitive potassium channel opener, Nitroglycerin, Coronary stenosis, Coronary flow, Myocardial function NITRATES and ATP-sensitive potassium channel openers (K-ops) are both effective in dilating coronary arteries and are used as agents to reduce myocardial ischemia in patients with ischemic heart disease. However, the cardiovascular From the

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“…The mechanism of vasodilator activity of these drugs is suggested to be due to the activation of ATP-sensitive potassium channels leading to a hyperpolarization of the smooth muscle membrane that causes vasorelaxation by preventing the opening of voltageactivated calcium channels [5][6][7][8][9]. Potassium channel activators are also known as potent coronary vasodilators [10][11][12], which may make them potentially useful in the treatment of angina and myocardial ischemia [13,14]. Recent studies have revealed that SKP-450 induced a concentration-dependent shortening of action potential duration with isolated rat papillary muscle, the effect being inhibited by glybenclamide [15].…”

Section: Introductionmentioning

confidence: 99%

Cardiovascular Pharmacology of SKP-450, a New Potassium Channel Activator, and Its Major Metabolites SKP-818 and SKP-310

et al. 1998

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The cardiovascular effects of SKP-450, a newly synthesized potassium channel activator, and its two major metabolites SKP-818 and SKP-310 were evaluated on isolated rat aorta and in freely moving rats and anesthetized beagle dogs. The rank order of potency in relaxing rat aorta precontracted with norepinephrine was SKP-450>SKP-818>lemakalim>SKP-310 (EC₅₀: 0.12, 0.55, 0.71 and 5.89 µmol/l, respectively). In rats, SKP-450, SKP-818 and lemakalim (3–100 µg/kg, i.v.) induced a dose-dependent decrease in mean arterial pressure (MAP; ED₂₀: 9.8, 11.7 and 22.4 µg/kg, respectively) followed by reflex tachycardia. In dogs, SKP-818 and SKP-310 (0.3–1,000 µg/kg, i.v.) had quite similar hemodynamic profiles to SKP-450 but with a smaller potency. SKP-450, SKP-818 and SKP-310 dose-relatedly decreased MAP (ED₂₀: 2.6, 4.2 and 588.8 µg/kg, respectively). They slightly increased left ventricular positive dP/dt_max with a transient decrease at the highest dose, while inducing a dose-related decrease in rate-pressure product, tension time index and systolic time. SKP-450, SKP-818 and SKP-310 induced a marked dose-dependent increase in coronary blood flow (E_max: 172.8, 257.9 and 178.7%, respectively) with less effects on blood flow through other arteries. Glybenclamide antagonized all the hemodynamic effects of SKP-450 in rats and dogs, whereas propranolol antagonized its reflex tachycardia in rats. These results indicate that SKP-450 is a potent coronary and peripheral vasodilator in rats and dogs activating ATP-sensitive potassium channels and that SKP-818 and SKP-310 exert a similar hemodynamic profile to the parent compound with equi- and weaker potency, respectively.

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Pharmacologic Profiles of YM934, a Novel Potassium Channel Opener

Cited by 28 publications

References 0 publications

Effects of ATP‐Sensitive Potassium Channel Opener on Potassium Transport and Alveolar Fluid Clearance in the Resected Human Lung

Effects of ATP‐Sensitive Potassium Channel Opener on Potassium Transport and Alveolar Fluid Clearance in the Resected Human Lung

<b>Comparison of the Effect of the ATP-Sensitive Potassium Channel Opener YM934 With That of Nitroglycerin on Impaired Coronary Circulation in Dogs</b>

Cardiovascular Pharmacology of SKP-450, a New Potassium Channel Activator, and Its Major Metabolites SKP-818 and SKP-310

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