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M Endoh

Publications and source records attributed to M Endoh.

At least 73 records · Page 4Linked to original sources
PubMed2000

All B cells are progeny of endothelial cells: a new perspective.

We present here a speculative view of embryonic hematopoiesis. We do this with the hope of finding directions for future study, keeping in mind that our model may diverge from the real situation. However, we want to emphasize that previous models have neglected the possibility that endothelial cells (EC) represent a progenitor of hematopoietic cells (HPC). Emerging evidence, including our own, and previous histological studies argue for the presence of hemogenic EC. We discuss seemingly contradictory points of view of embryonic hematopoiesis, such as the origin of lymphogenic progenitors, and have shown that they may be resolved more satisfactorily by introducing this notion. Obviously, a good model should be a testable one, so we are currently developing experimental systems to demonstrate that all B cells are, indeed, the progeny of EC.

Animals↗
PubMed2000

Measurement of serum IgA and C3 may predict the diagnosis of patients with IgA nephropathy prior to renal biopsy.

The levels of serum IgA and C3 in patients with IgA nephropathy were determined using international standard serum (IFCC/CRM470) in a multicenter trial in Japan. The ratio of serum IgA to C3 (serum IgA/C3 ratio) without any information from renal biopsy was used for the diagnosis of IgA nephropathy. Three hundred and six patients with IgA nephropathy and other glomerular diseases, and 418 healthy adults were examined. The new diagnostic standardized criterion in patients with IgA nephropathy, obtained by nephelometric immune assay based on the international reference preparation CRM470, was 315 mg/dl. The serum IgA/C3 ratio was a more useful marker for distinguishing IgA nephropathy from non-IgA nephropathy together with serum IgA levels. This suggests that the measurement of serum IgA and C3 may predict the diagnosis of patients with IgA nephropathy prior to renal biopsy.

Adult↗
PubMed1999

Tight coupling between the rate of rise of Ca2+ transient and peak twitch contraction in guinea-pig papillary muscle.

We evaluated the relationship between cytoplasmic Ca2+ concentration ([Ca2+]i) and force in guinea-pig papillary muscles loaded with a fluorescent Ca2+ indicator, fura-PE3. In the absence of ryanodine, [Ca2+]i transient and force were altered by changing extracellular Ca2+ concentration and stimulation frequency, and also by adding methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyri dine-5-carboxylate (Bay K 8644) or ouabain. Under these conditions, the peak force correlated linearly with the maximal rate of rise of [Ca2+]i (gamma = 0.948) more than the peak [Ca2+]i transient (gamma = 0.737). Ryanodine inhibited the increase in the maximal rate of rise of [Ca2+]i resulting in abolishment of the correlation between force and the maximal rate of rise of [Ca2+]i. These results suggest that the maximal rate of rise of [Ca2+]i reflects Ca2+ release from the sarcoplasmic reticulum, and this fraction of [Ca2+]i is crucial for determining the amplitude of twitch contractions when the sarcoplasmic reticulum is intact in guinea-pig papillary muscle.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1999

Muscarinic regulation of Ca2+ signaling in mammalian atrial and ventricular myocardium.

The differential regulation of the contractility of mammalian atrial and ventricular myocardium upon activation of muscarinic receptors can be ascribed, for the most part, to alterations in intracellular Ca2+ transients. However, alterations in myofibrillar sensitivity to Ca2+ ions also contribute to such regulation. In atrial muscle, the following actions are all associated with the corresponding alterations in the amplitude of Ca2+ transients in the same direction as those in the strength of the contractile force: (1) the direct inhibitory action on the basal force of contraction; (2) the increase (recovery) in force that is induced during the prolonged stimulation of muscarinic receptors; and (3) the rebound increase in force induced by washout of muscarinic receptor agonists. In addition, for a given decrease in force induced by muscarinic receptor stimulation in atrial muscle, the amplitude of Ca2+ transients is decreased to a smaller extent than the decrease in amplitude induced by reduction of extracellular Ca2+ concentration ([Ca2+]o), an indication that muscarinic receptor stimulation might increase myofibrillar sensitivity to Ca2+ ions simultaneously with the reduction in the amplitude of Ca2+ transients during induction of the direct inhibitory action. In mammalian ventricular myocardium, the direct inhibitory action of muscarinic receptor stimulation exhibits a wide range of species-dependent variation. A pronounced direct inhibitory action is induced in ferret papillary muscle, which is also associated with a definite increase in myofibrillar sensitivity to Ca2+ ions. By contrast, in the ventricular myocardium of other species including the rabbit and the dog, muscarinic receptor stimulation scarcely affects the baseline Ca2+ transients and the force, but it results in a pronounced decrease in Ca2+ transients and force when applied in the presence of beta-adrenoceptor stimulation, a phenomenon known as 'accentuated antagonism' or the 'indirect inhibitory action' of muscarinic receptor stimulation in mammalian ventricular myocardium. During induction of the indirect inhibitory action in mammalian ventricular myocardium, muscarinic receptor stimulation reverses all the effects induced by beta-adrenoceptor stimulation, including the increase in Ca2+ transients, the positive inotropic and lusitropic effects, and the decrease in myofibrillar sensitivity to Ca2+ ions. The relationship between the amplitude of Ca2+ transients and force is unaffected during induction of the indirect inhibitory action in rabbit and dog ventricular myocardium. The direct and indirect inhibitory actions of muscarinic receptor stimulation on Ca2+ transients have clearly different dependences on frequency: the former is more pronounced at a higher rate of stimulation, while the latter is more pronounced at a lower rate. The more complex interaction of muscarinic receptor and beta-adrenoceptor stimulation in mammalian atrial muscle and ferret ventricular muscle might be explained by the contribution of both the direct and the indirect regulatory mechanisms to the interaction.

Animals↗
PubMed1999

No effect of anti-leprosy drugs in the prevention of Alzheimer's disease and beta-amyloid neurotoxicity.

There is continuing controversy as to whether or not anti-leprosy drugs prevent Alzheimer's disease (AD). Therefore, we examined the effect of anti-leprosy drugs on the prevalence of AD in leprosy patients, and also investigated the effect of anti-leprosy drugs on amyloid beta-protein (Abeta)-induced neurotoxicity in vitro. The present study suggests that anti-leprosy treatments do not prevent the onset of AD. None of our data found anti-leprosy drugs (dapsone, rifampicin, clofazimine, minomycin or ofloxacin) had any effect on Abeta neurotoxicity. It is now important to examine the infection of Mycobacterium leprae in the central nervous system to clarify the reason for the low prevalence of senile dementia, and low frequency of Abeta deposition in leprosy patients.

Aged↗
PubMed1999

Pharmacological characterization of effects of UK-1745, a novel cardiotonic agent with beta-adrenoceptor-blocking action, in aequorin-loaded canine right ventricular muscle.

UK-1745, a derivative of furoindolinone, is a novel cardiotonic agent that was designed to have both beta-adrenoceptor-blocking and cardiotonic activity. The aim of this study was to clarify the mode of action of UK-1745 in the canine and rabbit myocardium. UK-1745 elicited a weak but definite concentration-dependent positive inotropic effect in association with a decrease in the total duration of contraction: in particular, a decrease in the relaxation time in isolated canine right ventricular trabeculae. The maximum positive inotropic effect of UK-1745 was achieved at 3x10(-5)m and amounted to approximately 15% of the maximum response to isoproterenol. The EC50 for the positive inotropic effect of UK-1745 was 3.3x10(-6)m. Carbachol, a muscarinic receptor agonist, at 3x10(-6)m completely inhibited the positive inotropic effect of UK-1745. UK-1745 shifted the concentration-response curve for isoproterenol to the right with pA2 value of 5.70. By contrast, UK-1745 at 3x10(-7)to 3x10(-5)m shifted the concentration-response curve for forskolin to the left. In aequorin-loaded ventricular trabeculae, UK-1745 induced a positive inotropic effect that was accompanied by an increase in Ca2+ transients. It did not affect the relationship between the amplitude of Ca2+ transients and peak force as compared with that associated with elevation of the extracellular concentration of Ca2+ ions ([Ca2+]o). The level of cyclic AMP in tissue was not significantly increased at 3x10(-5)m UK-1745. The present results indicate that UK-1745 exerts a positive inotropic effect mainly via a cyclic AMP-dependent mechanism but, in addition, it has beta-adrenoceptor-blocking activity over the same range of concentrations. A drug with such a pharmacological profile might have the potential advantage of avoiding Ca2+ overload and superfluous oxygen consumption, which may contribute to the unfavorable effects of novel cardiotonic agents that act purely by inhibition of phosphodiesterase III.

Adrenergic beta-Agonists↗
PubMed1999

Influence of a Na+-H+ exchange inhibitor ethylisopropylamiloride, a Na+-Ca2+ exchange inhibitor KB-R7943 and their combination on the increases in contractility and Ca2+ transient induced by angiotensin II in isolated adult rabbit ventricular myocytes.

In rabbit, ventricular myocytes loaded with indo-1/AM, angiotensin II (0.1 nM-0.1 microM) exerted a positive inotropic effect with a significant increase in the amplitude of Ca2+ transients. For a given increase in cell shortening, the increase in Ca2+ transients induced by angiotensin II was less than that induced by elevation of extracellular Ca2+ concentration ([Ca2+]0) or isoprenaline, an indication that both the increase in mobilization of intracellular Ca2+ ions and myofibrillar sensitivity to Ca2+ ions contribute to the positive inotropic effect of angiotensin II. The effects of angiotensin II on Ca2+ transients and cell shortening were inhibited by the AT1 receptor antagonist losartan. A Na+ -H+ exchange inhibitor EIPA [5-(N-ethyl-N-isopropyl)amiloride] at 1 and 3 microM did not affect the Ca2+ transients and cell shortening, but it inhibited the angiotensin-II-induced responses in a concentration-dependent manner more effectively than the responses to elevation of [Ca2+]0, indicating that EIPA elicited a selective inhibitory action on the effects of angiotensin II. The observation that EIPA at 10 microM abolished the positive inotropic effect of angiotensin II without a significant depression of the inotropic response to elevation of [Ca2+]0 supports the selective action of EIPA at the high concentration on the response to angiotensin II. A novel selective Na+ -Ca2+ exchange (reverse mode) inhibitor KB-R7943, 2-[2-[4-(-nitrobenzyloxy)phenyl]ethyl] isothiourea methanesulphonate, at 0.3 and 1 microM inhibited also the responses to angiotensin II more effectively than the response to elevation of [Ca2+]0; however, over the same concentration range it suppressed significantly the amplitude of Ca2+ transients and cell shortening. Combination of EIPA (3 microM) and KB-R7943 (0.3 microM), each of which attenuated partially the angiotensin-II-induced responses, abolished the positive inotropic effect and the increase in Ca2+ transients induced by angiotensin II with much less depressant effect on the responses to elevation of [Ca2+]0. Thus, these ion exchange inhibitors exerted selective actions on the respective targets. The results with these selective inhibitors indicate that the activation of Na+ -H+ exchanger and subsequent modulation of the activity of Na+ -Ca2+ exchanger may be responsible for the increase in [Ca2+]i and the myofilament Ca2+ sensitization induced by stimulation of AT1 receptors by angiotensin II in rabbit ventricular myocytes.

Amiloride↗
PubMed1999

Characterization of the endothelin-1-induced regulation of L-type Ca2+ current in rabbit ventricular myocytes.

The effects of endothelin-1 (ET-1) on the L-type Ca2+ current (I(Ca)) and the interaction of ET-1 with beta-adrenoceptor stimulation were investigated in rabbit ventricular myocytes by the whole-cell patch-clamp technique. ET-1 (10(-8) M) had a biphasic effect on I(Ca) (direct effect), causing a transient decrease that was followed by a long-lasting increase which is much smaller than the increase induced by isoprenaline (ISO). The effect of ET-1 on I(Ca) was abolished by a selective ET(A) receptor antagonist, FR139317 (10(-6) M). The increase in I(Ca) induced by ET-1 (10(-8) M) was enhanced by a selective ET(B) receptor antagonist, BQ-788 (10(-6) M), as the transient decrease but not the increase in I(Ca) induced by ET-1 (10(-8) M) was suppressed by BQ-788. In the presence of ISO (10(-6) M), ET-1 elicited a more pronounced inhibitory effect: at 10(-9)-10(-7) M ET-1 inhibited the ISO-induced increase in I(Ca) in a concentration-dependent manner (anti-adrenergic effect). The maximum inhibition induced by ET-1 at 10(-7) M was approximately 80% of the ISO-induced response, and the IC50 value for anti-adrenergic effect of ET-1 was 4.2x10(-9) M. The anti-adrenergic effect of ET-1 (10(-8) M) was antagonized by the ET(A) antagonist FR139317 (10(-9)-10(-6) M) in a concentration-dependent manner and was partially inhibited by the ET(B) antagonist BQ-788 (10(-6) M). The anti-adrenergic effect of ET-1 was markedly attenuated by pretreatment of ventricular myocytes with pertussis toxin. The increases in I(Ca) induced by forskolin (10(-6) M), 3-isobutyl-1-methylxanthine (10(-4) M), and 8-bromo-cyclic AMP (3x10(-4) M) were also suppressed by ET-1 (10(-8) M). In summary, ET-1 has a differential effect on I(Ca) in the absence and in the presence of ISO: ET- I has a feeble biphasic action on the baseline I(Ca) and, in addition, it elicits a pronounced anti-adrenergic effect on the ISO-induced increase in I(Ca). Pertussis toxin-sensitive G protein is responsible for the anti-adrenergic effect of ET-1 on I(Ca), but the anti-adrenergic effect of ET-1 may involve also the regulation at the level of signaling process beyond the cyclic AMP generation. Anti-adrenergic effect of ET-1 on I(Ca) is mainly due to activation of ET(A) receptors but ET(B) receptors are also involved partially in the anti-adrenergic effect of ET-1 on I(Ca) in rabbit ventricular myocytes.

1-Methyl-3-isobutylxanthine↗
PubMed1999

Hemodynamic effects of carbon dioxide insufflation under single-lung ventilation during thoracoscopy.

BACKGROUND: The hemodynamic effects of carbon dioxide insufflation under single-lung ventilation were studied in 22 consecutive thoracoscopic harvests of the left internal mammary artery, which was used for minimally invasive coronary artery bypass grafting. METHODS: An electrocardiograph, arterial catheter, Swan-Ganz catheter, and transesophageal echocardiograph were used to monitor seven hemodynamic variables. Baseline data were obtained during ventilation of both lungs and the measurements were repeated after the left lung was collapsed and at 5 and 30 minutes after hemithorax insufflation with low-flow (2 to 3 L/minute) carbon dioxide gas was begun. The intrapleural pressure was maintained at 8 to 10 mm Hg. RESULTS: Thoracoscopic harvest of the internal mammary artery was completed in all cases with a mean insufflation time of 44+/-12 minutes. There were no significant changes in the mean arterial pressure, heart rate, cardiac index, and left ventricular ejection fraction throughout the procedure, whereas the central venous pressure, mean pulmonary arterial pressure, and pulmonary capillary wedge pressure (p < 0.05 for each variable) during insufflation. CONCLUSIONS: Low-flow carbon dioxide insufflation into the left hemithorax with an intrapleural pressure of 8 to 10 mm Hg under selective right-lung ventilation does not compromise the human heart with normal to moderately depressed function and can be an efficacious adjunct in specific thoracoscopic procedures.

Aged↗
PubMed1999

Differential regulation of intracellular Ca2+ signalling induced by high K+ and endothelin-1 in single smooth muscle cells of intact canine basilar artery: detection by means of confocal laser microscopy.

Changes in intracellular calcium concentration ([Ca2+]i) in smooth muscle cells play the key role in regulation of vascular smooth muscle tone and pathogenesis of cerebral vasospasm. In this study, we adopted the confocal laser microscopy to detect the fluorescence signals arising from the individual smooth muscle cells of canine basilar artery. Ring preparations were made, loaded with fluo-3 and changes in fluorescence induced by high K+ and endothelin-1 (ET-1) were measured by confocal laser microscopy. In some unstimulated smooth muscle cells Ca2+ waves arising from discrete region of the cell propagated to the whole cell with a velocity of approximately 10 microm/s. High K+ (80 mmol/L) induced a rapid rise in [Ca2+]i, the peak level being consistently reached approximately 10 s after stimulation. In contrast, the time to peak level of [Ca2+]i induced by ET-1 (0.3 micromol/L) varied widely between 13 and 26 s among individual cells, an indication that the extent of nonuniform coordination of increases in [Ca2+]i in individual cells may be partly responsible for the different time courses of tension development of vascular smooth muscle in response to the vasoactive stimulants. The increase in [Ca2+]i induced by ET-1 was transient but a pronounced and sustained contraction developed further in response to ET-1. Thus ET-1 has a biological property as a potential candidate to elicit cerebral vasospasm. Confocal laser microscopy could be a useful tool to measure the changes in [Ca2+]i in individual smooth muscle cells of cerebral artery.

Animals↗
PubMed1999

Role of Na+/Ca2+ exchange in endothelin-1-induced increases in Ca2+ transient and contractility in rabbit ventricular myocytes: pharmacological analysis with KB-R7943.

1. The effects of endothelin-1 (ET-1) on intracellular Ca2+ ion level and cell contraction were simultaneously investigated in rabbit ventricular cardiac myocytes loaded with indo-1/A1. The role of Na+/Ca2+ exchange in ET-1-induced positive inotropic effect (PIE) was examined by using KB-R7943 (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea methanesulphonate), a selective inhibitor of reverse mode Na+/Ca2+ exchange. 2. ET-1 at 0.3 pM - 1 nM increased cell contraction and Ca2+ transient (CaT) with EC50 values of 2.9 pM and 1.2 pM, respectively, and the increase in amplitude of CaT was much smaller relative to the PIE: ET-1 at 1 nM increased peak cell shortening by 237%, while it increased peak CaT by 167%. For a given level of PIE, ET-1-induced increase in CaT was much smaller than that induced by elevation of [Ca2+]o and by isoprenaline. Therefore, ET-1 shifted the relationship between peak CaT and cell shortening to the left relative to the relationship for increase in [Ca2+]o, an indication that ET-1 increased myofibrillar Ca2+ sensitivity. 3. KB-R7943 at 0.1 microM and higher inhibited contraction and CaT induced by 0.1 nM ET-1 and at 0.3 microM it abolished the increase in CaT while inhibiting the PIE by 48.1%. Over concentration range of 0.1-0.3 microM, KB-R7943 neither inhibited baseline contraction and CaT nor the isoprenaline-induced response, although at 1 microM and higher it had a significant inhibitory action on these responses. 4. These results indicate that in rabbit ventricular myocytes both increases in CaT and myofibrillar Ca2+ sensitivity contribute to the ET-induced PIE, and the activation of reverse mode Na+/Ca2+ exchange may play a crucial role in increase in CaT induced by ET-1 in rabbit ventricular cardiac myocytes.

Animals↗
PubMed1999

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.

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.

Action Potentials↗
PubMed1999

Investigation on SCH00013, a novel cardiotonic agent with Ca++ sensitizing action. 2nd communication: in vivo cardiovascular effects and bioavailability in dogs.

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.

Administration, Oral↗
PubMed1999

Investigation on SCH00013, a novel cardiotonic agent with Ca++ sensitizing action. 3rd communication: stereoselectivity of the enantiomers in cardiovascular effects.

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.

Anesthesia↗
PubMed1999

Investigation on SCH00013, a novel cardiotonic agent with Ca++ sensitizing action. 4th communication: influence on experimentally induced ventricular arrhythmia in dogs.

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.

Animals↗
PubMed1999

Induction of glomerular lesions in the kidneys of mice infected with vero toxin-producing Escherichia coli by lipopolysaccharide injection.

Lipopolysaccharide was injected into germ-free mice after they had been infected with Vero toxin-producing Escherichia coli. Microscopic examination of the kidneys of these mice showed an increased number of mesangial cells and a vacancy in the glomerular capillary lumen. A significant elevation in the expression level of interferon (IFN)-gamma in the kidney may have played a key role in the induction of glomerular lesions, because the administration of neutralizing antibody to IFN-gamma markedly alleviated such lesions.

Animals↗