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Masao Endoh - One of the best experts on this subject based on the ideXlab platform.

  • investigation on sch00013 a novel Cardiotonic Agent with ca sensitizing action 1st communication phosphodiesterase iii inhibitory effect and class iii antiarrhythmic effect in guinea pig heart
    Drug Research, 2011
    Co-Authors: Masataka Hino, Hiromi Sugawara, Akira Yoshimura, Kimitomo Yoshioka, Mitsuo Sakato, Akihiko Ogura, Masao Endoh
    Abstract:

    In order to clarify the mechanism of action of 4,5-dihydro-6-[1-[2-hydroxy-2-(4-cyanophenyl)ethyl]-1,2,5,6- tetrahydropyrido-4-yl]pyridazin-3(2H)-one (SCH00013), a novel Cardiotonic Agent with Ca++ sensitizing action, its effects on contractile force, atrial rate and action potential, and on the activity of Na+, K(+)-ATPase and phosphodiesterase (PDE) I-IV were studied in the guinea-pig heart. SCH00013 exerted a positive inotropic effect (PIE) on isolated right ventricular papillary muscles in a concentration-dependent manner (EC50 = 9.2 mumol/l): the relative potency was milrinone > SCH00013 > vesnarinone. The PIE of SCH00013 was not influenced by propranolol, a beta-blocker, and SCH00013 did not affect the activity of cardiac Na+, K(+)-ATPase. The PIE of SCH00013 was partially inhibited by carbachol, a muscarinic receptor agonist, which implies a partial contribution of the cAMP-dependent mechanism to the PIE. SCH00013 inhibited the activity of PDE III selectively, but the potency was weak: the IC50 value was 64.9 mumol/l, which was 46 and 3.9 times less potent than those of milrinone and vesnarinone, respectively. SCH00013 and vesnarinone elicited a moderate decrease in the rate of beating of isolated right atria, while milrinone increased it. SCH00013 markedly prolonged the action potential duration and the effective refractory period with no change in the resting membrane potential and dV/dtmax, an indication that SCH00013 may suppress the activity of delayed rectifying K+ channels. These results indicate that SCH00013, that primarily acts as a Ca++ sensitizer, possesses a weak selective PDE III inhibitory effect. The potential positive chronotropic effect of SCH00013 due to PDE III inhibition may be offset by its effect on K+ channels.

  • Decrease in Ca2-Sensitizing Effect of UD-CG 212 Cl, a Metabolite of Pimobendan, under Acidotic Condition in Canine
    2001
    Co-Authors: Ventricular Myocardium, Reiko Takahashi, Yasuhisa Shimazaki, Masao Endoh
    Abstract:

    We studied the influence of acidosis on the positive inotropic effect of UD-CG 212 Cl {4,5-dihydro-6-[2-(4-hydroxyphenyl)-1H-benzimidazole-5-yl]-5-methyl-3(2H)-pyridazinone}, an ac-tive metabolite of pimobendan, in canine ventricular trabeculae loaded with aequorin. The positive inotropic effect of UD-CG 212 Cl was markedly suppressed under acidotic conditions. The maximal contractile response to UD-CG 212 Cl was at-tained at 105 M in the control condition at pH 7.4, but was not achieved even at 104 M during acidosis. The maximal inotro-pic effect of UD-CG 212 Cl was 18 % of the maximal response to isoproterenol (ISOmax) in association with an increase in Ca2 transients of 7 % of ISOmax in the control, while they are 8 and 6 % of ISOmax under acidosis, respectively. Acidosis abol-ished the increase in myofilament Ca2 sensitivity induced by UD-CG 212 Cl, whereas the increase in Ca2 transients in-duced by the compound was not affected by acidosis. In con-clusion, UD-CG 212 Cl elicited a positive inotropic effect even under acidosis, however, UD-CG 212 Cl was much less effec-tive as a Cardiotonic Agent under acidosis mainly due to a decrease in the Ca2-sensitizing effect under acidotic condi-tion. Cardiotonic Agents are indispensable for improvement of contractile dysfunction in heart failure. Pimobendan {UD-CG 115 BS; 4,5-dihydro-6-[2-(p-methoxyphenyl)-5-benzimida-zolyl]-5-methyl-3(2H)-pyridazinone} is a unique Cardiotonic Agent that has already been launched for treatment of pa-tients with heart failure (Hagemeijer, 1993). It has an inhib-itory action on phosphodiesterase III (Scholz and Meyer, 1986) and prolongs the action potential duration (Honerjäger et al., 1984). A part of the increase in force of contraction has been shown to be due to the myofilament Ca2 sensitization (Fujino et al., 1988; Scheld et al., 1989; Böhm et al., 1991). In addition, pimobendan is converted to the active metabolit

  • investigation on sch00013 a novel Cardiotonic Agent with ca sensitizing action 2nd communication in vivo cardiovascular effects and bioavailability in dogs
    Drug Research, 1999
    Co-Authors: Akira Yoshimura, Hiromi Sugawara, Y Koide, Kimitomo Yoshioka, Masataka Hino, Mitsuo Sakato, Masao Endoh
    Abstract:

    In vivo cardiovascular effects and bioavailability of 4,5-dihydro-6-[1-[2-hydroxy-2-(4-cyanophenyl)ethyl]-1,2,5,6- tetrahydropyrido-4-yl]pyridazin-3(2H)-one (SCH00013), a novel Cardiotonic Agent, were investigated. In anesthetized dogs, intravenous administration of SCH00013 (0.3-10 mg/kg) increased maximum rate of rise in left ventricular pressure (LVdP/dtmax) in a dose-dependent manner with no change in heart rate (HR) and, at the dose of 3 mg/kg or higher, at which the increase in LVdP/dtmax reached the maximum, it decreased blood pressure. In conscious dogs, oral administration of SCH00013 (1-10 mg/kg) also increased LVdP/dtmax dose-dependently with no change in HR. The increase in the plasma concentration of orally administered SCH00013 (3 mg/kg) was parallel to the increase in LVdP/dtmax. The areas under the plasma concentration versus time curve (AUC0-24 h) after oral and intravenous administration of SCH00013 (3 mg/kg) were essentially identical (15.3 +/- 2.0 micrograms.h/ml and 16.5 +/- 2.1 micrograms.h/ml, respectively). These results suggest that oral bioavailability of SCH00013 is notably high. In conclusion, the positive inotropic effect of SCH00013 with neither elevation of HR nor excessive hypotension, as well as the high oral bioavailability of this compound, may provide a beneficial pharmacological treatment of the patients with congestive heart failure.

  • investigation on sch00013 a novel Cardiotonic Agent with ca sensitizing action 3rd communication stereoselectivity of the enantiomers in cardiovascular effects
    Drug Research, 1999
    Co-Authors: Hiromi Sugawara, Akira Yoshimura, Kimitomo Yoshioka, Masataka Hino, Mitsuo Sakato, Masao Endoh
    Abstract:

    The cardiovascular effects of the enantiomers, (+)-SCH00013 and (-)-SCH00013, of a novel Cardiotonic Agent 4,5-dihydro-6-[1-[2-hydroxy-2-(4-cyanophenyl)ethyl]- 1,2,5,6-tetrahydropyrido-4-yl]pyridazin-3(2H)-one (SCH00013) were investigated in vitro and in vivo. The enantiomers of SCH00013 elicited an equipotent positive inotropic effect in isolated guinea-pig papillary muscles. Both of the enantiomers had a modest negative chronotropic effect in isolated guinea-pig right atria and the difference in the chronotropic effects of the enantiomers was not significant. In anesthetized dogs, both enantiomers increased LVdP/dtmax without change in heart rate and slightly decreased blood pressure. These hemodynamic effects of the enantiomers were not significantly different from each other. (+)-SCH00013 and (-)-SCH00013 increased the extent of cell shortening in association with only a small increase in the Ca++ transients in indo-1-loaded rabbit cardiomyocytes, and both the increases in cell shortening and Ca++ transients were not significantly different between the enantiomers. Both isomers equally shifted the relationships between the increases in the cell shortening and Ca++ transients to the left and upward as compared with the relationships for the elevation of extracellular Ca++ concentration and isoproterenol, which indicates that the effectiveness of the Ca++ sensitizing effects of the enantiomers are almost equivalent. The enantiomers of SCH00013 showed equipotent inhibitory effect on the phosphodiesterase (PDE) III activity. The maximal extent and the potency of prolonging effect of the two enantiomers on the effective refractory period were also the same. Thus, the efficacy and potency of the effects on the cardiovascular parameters such as myofibrillar Ca++ sensitivity, PDE III activity and the effective refractory period for the both enantiomers of SCH00013 are equivalent, indicating that the cardiovascular effects of SCH00013 may be due to equal contribution of both enantiomers.

  • investigation on sch00013 a novel Cardiotonic Agent with ca sensitizing action 4th communication influence on experimentally induced ventricular arrhythmia in dogs
    Drug Research, 1999
    Co-Authors: Akira Yoshimura, Hiromi Sugawara, Kimitomo Yoshioka, Masataka Hino, Mitsuo Sakato, Masao Endoh
    Abstract:

    Influence of 4,5-dihydro-6-[1-[2-hydroxy-2-(4-cyanophenyl)ethyl]- 1,2,5,6,-tetrahydropyrido-4-yl]pyridazin-3(2H)-one (SCH00013) and vesnarinone (CAS 81840-15-5) on the arrhythmia experimentally induced by three different methods was investigated in dogs. In digitalis-induced arrhythmia, SCH00013 (3 mg/kg i.v.) showed a tendency to improve the arrhythmia with a decrease in the arrhythmic ratio and an increase in the conducted beats (CB), though these changes did not reach a significant level; it decreased significantly the blood pressure (BP) with no change in the total heart rate (THR) and atrial rate (AR). Vesnarinone (3 mg/kg i.v.) did not affect these parameters except for BP that was decreased significantly. In two-stage coronary ligation-induced arrhythmia, SCH00013 (1 and 3 mg/kg i.v.) did not change the arrhythmic ratio, CB, AR and BP, while the THR being slightly decreased; the arrhythmic ratio showed a tendency to decrease with SCH00013 when examined at 24 h after coronary ligation. Vesnarinone (3 mg/kg i.v.) did not affect these parameters at 24 and 48 h after ligation. In epinephrine (adrenaline)-induced arrhythmia, both SCH00013 and vesnarinone showed exacerbation of arrhythmia. SCH00013 at 1 mg/kg i.v. did not elicit ventricular fibrillation (VF) in five dogs examined, but at 3 mg/kg i.v. it elicited VF in two of three dogs. Vesnarinone at 1 mg/kg i.v. induced VF in all of three dogs examined. Incidence of VF induced by optical isomers of SCH00013 was not significantly different from each other: both isomers elicited VF in two of six dogs at 1 mg/kg i.v. and at 3 mg/kg i.v. each of them induced VF in two dogs examined. The present results indicate that SCH00013 is a Cardiotonic Agent that is equivalent to or less arrhythmogenic than vesnarinone in animal models of arrhythmia, such as adrenaline- and digitalis-induced arrhythmia and the two-stage coronary ligation-induced arrhythmia. Optical isomers of SCH00013 were essentially equieffective in eliciting exacerbation of adrenaline-induced arrhythmia in the dog.

Mitsuhiro Yokoyama - One of the best experts on this subject based on the ideXlab platform.

  • oxygen saving effect of a new Cardiotonic Agent mci 154 in diseased human hearts
    Journal of the American College of Cardiology, 1997
    Co-Authors: Masuki Mori, Motoshi Takeuchi, Hideyuki Takaoka, Katsuya Hata, Yoshihiko Hayashi, Hideyuki Yamakawa, Mitsuhiro Yokoyama
    Abstract:

    Objectives. The aim of this study was to examine the left ventricular mechanoenergetic effects of a novel Ca2+sensitizing Agent, MCI-154, on diseased human hearts compared with dobutamine. Background. Unlike conventional Cardiotonic Agents, a Ca2+sensitizer that could produce a positive inotropic action by altering the responsiveness of myofilament to Ca2+could generate force with smaller amounts of Ca2+; thus, it may potentially save energy expenditure. Methods. The left ventricular pressure-volume relation and myocardial oxygen consumption per beat (Vo2) were measured by a conductance (volume) catheter and a Webster catheter. Left ventricular contractility (Emax), systolic pressure-volume area (PVA [index of left ventricular total mechanical energy]) and Vo2were assessed before and after infusion of MCI-154 or dobutamine. The PVA-independent Vo2(Vo2mainly for excitation-contraction coupling) was assessed as the Vo2at zero PVA. Results. Both Agents increased Emax comparably (dobutamine: from 3.55 ± 1.10 [mean ± SD] to 5.04 ± 1.16 mm Hg/ml per m2, p < 0.0001; MCI-154: from 3.36 ± 1.26 to 5.37 ± 2.14 mm Hg/ml per m2, p < 0.0001); dobutamine increased total Vo2(from 0.22 ± 0.08 to 0.27 ± 0.09 ml O2, p < 0.05) and PVA-independent Vo2(from 0.019 ± 0.019 to 0.091 ± 0.051 ml O2, p < 0.005); but MCI-154 did not change these variables significantly. Consequently, the oxygen cost of contractility (ΔPVA-independent Vo2/ΔEmax) was less with MCI-154 than with dobutamine (0.14 ± 0.18 vs. 1.10 ± 0.80 J/mm Hg per ml per m2, p < 0.05). Conclusions. These results suggest that the Cardiotonic action mediated by MCI-154 could provide an energetic advantage over the conventional Cardiotonic action with currently used inotropic Agents. (J Am Coll Cardiol 1997;29:613–22)

  • lusitropic effects of a ca2 sensitization with a new Cardiotonic Agent mci 154 on diseased human hearts
    Cardiovascular Research, 1995
    Co-Authors: Masuki Mori, Motoshi Takeuchi, Hideyuki Takaoka, Mitsuhiro Yokoyama
    Abstract:

    Objectives: Recognition of the problems of conventional Cardiotonic Agents has led to an interest in drugs that produce a positive inotropic action by altering the responsiveness of myofilament to Ca2+ (i.e., Ca2+ sensitizing Agents). The importance of the effects of these compounds on left ventricular (LV) systolic function has been emphasized, whereas the effect of them on LV diastolic function is still problematic. To investigate the lusitropic action of a novel Ca2+ sensitizing Agent, MCI-154, we compared the effects of MCI-154 on LV relaxation and filling dynamics with those of dobutamine in diseased human hearts. Methods: We assessed the slope of the end-systolic pressure-volume relation (Emax), the time constant of LV pressure decay (Tw) and the maximum rate of LV early filling (dV/dtmax) before and after the infusion of dobutamine ( n = 10) or MCI-154 ( n = 9). LV volume and pressure were measured by a conductance catheter and a micro-tip catheter pressure transducer. Results: When both Agents increased Emax comparably, dobutamine decreased Tw from 51 to 37 ms and MCI-154 decreased Tw from 54 to 44 ms. The decrease of Tw with MCI-154 was less than that with dobutamine (17 vs. 29%, P < 0.05). At the same time, dobutamine increased dV/dtmax per end-diastolic volume (d V /d t max/ V ) from 2.84 to 3.88 s−1, whereas MCI-154 did not. Conclusions: Diastolic properties were not compromised by MCI-154, though the alteration in them with MCI-154 was less than that with dobutamine when MCI-154 increased LV contractile state to the same extent as dobutamine. The present results suggest that MCI-154 would be an ideal Ca2+ sensitizing Agent that enhances force during systole without impairing diastolic function.

Mitsuyoshi Nakashima - One of the best experts on this subject based on the ideXlab platform.

Hiroyuki Iwamoto - One of the best experts on this subject based on the ideXlab platform.

  • effect of a Cardiotonic Agent mci 154 on the contractile properties of skinned skeletal muscle fibers
    European Journal of Pharmacology, 1998
    Co-Authors: Hiroyuki Iwamoto
    Abstract:

    We have studied the effect of a Cardiotonic Agent, MCI-154 (6-[4-(4-pyridylamino)phenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride trihydrate), on the contractile properties and adenosine triphosphatase (ATPase) activity of chemically skinned rabbit skeletal muscle fibers. As in cardiac muscle, MCI-154 potentiated isometric tension and improved isometric tension cost at full Ca2+ activation. It showed little Ca2+-sensitizing effect. In contrast to its effect on cardiac muscle, however, MCI-154 decreased all the kinetic parameters tested (shortening velocity, the rate of rise of tension, and actomyosin ATPase activity). All the results are explainable if MCI-154 acts directly on skeletal actomyosin and inhibits a reaction step(s) of the ATPase cycle later than the force-generating event. The qualitative difference between cardiac and skeletal muscles in the responsiveness to this class of Cardiotonic Agents (MCI-154 and EMD 53998, a thiadiazinone derivative) is most readily understood if the Agents have two independent actions, one on troponin and the other on actomyosin itself, the latter being dominant in skeletal muscle.

Ikuo Norota - One of the best experts on this subject based on the ideXlab platform.

  • effects of a novel Cardiotonic Agent 6 3 3 4 dimethoxybenzylamino 2 hydroxypropoxy 2 1h quinolinone opc 18790 on contractile force cyclic amp level and aequorin light transients in dog ventricular myocardium
    Journal of Cardiovascular Pharmacology, 1994
    Co-Authors: Masao Endoh, Youichi Kawabata, Yumi Katano, Ikuo Norota
    Abstract:

    We studied the effects of a novel Cardiotonic Agent OPC-18790 [(+-)-6-[3-(3,4-dimethoxybenzylamino)-2-hydroxypropoxy]-2(1H)- quinolinone] on isometric contractions, intracellular aequorin light transients, and cyclic AMP levels in isolated dog ventricular trabeculae. The positive inotropic effect (PIE) of OPC-18790 (1-30 microM) was consistently associated with an abbreviation of contractions and an increase in the amplitude of aequorin light transients. The maximum responses of Ca2+ transients and force to OPC-18790 were approximately 40% of the isoproterenol-induced maximum. Carbachol (3 microM) markedly attenuated the increases in force, light transients, and cyclic AMP accumulation induced by OPC-18790. These results indicate that OPC-18790 is a Cardiotonic Agent with moderate effectiveness, and that the PIE of OPC-18790 may be produced mainly by an increase in intracellular Ca2+ transients induced by cyclic AMP accumulation. For a given increase in amplitude of Ca2+ transients, OPC-18790 produced a more pronounced increase in force of contraction (FOC) than did isoproterenol, suggesting that OPC-18790 does not produce as great a decrease in Ca2+ sensitivity of contractile proteins as does isoproterenol. These observations indicate that among Cardiotonic Agents acting through cyclic AMP pathway, regulation of contractility produced by the selective cyclic AMP phosphodiesterase III (PDE-III) inhibitor OPC-18790 is qualitatively different from the regulation induced by isoproterenol that acts on cyclic AMP generation in intact myocardial cells.