Effects of MCI-154, a new cardiotonic Ca2+ sensitizer, on ventricular arrhythmias and membrane ionic currents

Eto, Koji; Yi, Xue; Hashimoto, Keitaro

doi:10.1016/0014-2999(95)00776-8

Cited by 7 publications

(4 citation statements)

References 26 publications

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“…-sensitizing property (56), showed the least proarrhythmic effect on this arrhythmia. Zatebradine had no suppressing effect on the adrenaline arrhythmia (57).…”

Section: +mentioning

confidence: 93%

Arrhythmia Models for Drug Research: Classification of Antiarrhythmic Drugs

Hashimoto

2007

J Pharmacol Sci

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Abstract. The aim of this study was to classify antiarrhythmic drugs based on their effectiveness on 6 in vivo arrhythmia models, mainly using dogs. The models were produced by two-stage coronary ligation, digitalis, halothane-adrenaline, programmed electrical stimulation in old myocardial infarction dogs, coronary artery occlusion / reperfusion, or chronic atrioventricular block. Na + -channel-blocking drugs suppressed two-stage coronary ligation and digitalis arrhythmias. Ca 2+ -channel blockers and β-blockers suppressed halothane-adrenaline arrhythmia. Positive inotropic drugs aggravated halothane-adrenaline arrhythmia, but did not aggravate digitalis arrhythmia. K + -channel blockers suppressed programmed electrical stimulation induced arrhythmia, but induced torsades de pointes type arrhythmia in chronic atrioventricular block dogs and aggravated halothane-adrenaline arrhythmia. Na

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“…-sensitizing property (56), showed the least proarrhythmic effect on this arrhythmia. Zatebradine had no suppressing effect on the adrenaline arrhythmia (57).…”

Section: +mentioning

confidence: 93%

Arrhythmia Models for Drug Research: Classification of Antiarrhythmic Drugs

Hashimoto

2007

J Pharmacol Sci

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“…Concerning the induction of arrhythmia, MCI-154 did not aggravate arrhythmias generated in the two-step coronary ligation-, digitalis-, and halothane-epinephrine-induced canine arrhythmia models (13). Milrinone and vesnarinone, cAMP-dependent agents, had arrhythmogenic effects in the coronary ligation and halothane-epinephrine models (16,17).…”

Section: Effects Of Mci-154 In Heart Failure Models Effects In Acute mentioning

confidence: 97%

MCI‐154: A Second Generation Ca²⁺ Sensitizer That Does Not Impair Relaxation — A Novel Approach to the Treatment of Heart Failure

Kitada¹

2000

Cardiovascular Drug Reviews

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With the negative results of the cyclic AMP-dependent positive inotropic agents in clinical trials, great interest has been focused on the development of agents that directly activate cardiac myofilaments. These drugs are called "Ca 2+ sensitizers"; they are expected to represent a possible new pharmacological approach to the therapy of chronic heart failure. MCI-154 is one of the most powerful and promising Ca 2+ sensitizers currently in clinical trials. In preclinical studies, the positive inotropic action of MCI-154 was observed at the concentrations at which the drug did not increase intracellular Ca 2+ . In skinned cardiac muscle fiber bundles from various animal species MCI-154 shifted p Ca (-log [Ca 2+ ] M)-force relation upward and to the left, suggesting that this drug not only increases sensitivity of myofibrils to Ca 2+ , but also enhances cross-bridge interaction. In regard to the molecular mechanism of action of MCI-154, the earliest experiments showed that MCI-154 at the high concentration (10 -4 M) stimulated binding of Ca 2+ to troponin (Tn) C. However, MCI-154-(at concentrations lower than 10 -5 M)-induced increase in the affinity of TnC to Ca 2+ led to the complex formation of TnC with TnI and TnT. This effect of the drug on Ca 2+ regulation and interaction between troponin subunits was discovered using fluorescence spectroscopy. At 10 -4 M MCI-154 decreased binding of Ca 2+ to TnC. The Ca 2+ sensitizing effect of MCI-154 disappeared when cardiac TnI was exchanged for skeletal TnI. Taken together, it can be concluded that TnI may represent a target protein for the positive inotropic action of MCI-154. The long-term treatment with MCI-154 prolonged the life span of cardiomyopathic hamsters, Bio14.6, a model that resembles human heart failure. Unlike PDE inhibitors, MCI-154 did not aggravate arrhythmias generated in the two-stage coronary ligation-, digitalis-and catecholamine-induced canine arrhythmia . models. In clinical studies MCI-154 improved contractile function in patients with left ventricular dysfunction after myocardial infarction. Its effect was not associated with an increase in myocardial oxygen consumption or impaired relaxation. In conclusion, MCI-154 could be promising in the treatment of chronic heart failure. Clinical studies with MCI-154 are currently in progress.

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“…The results indicated that MCI-154 does not aggravate ventricular arrhythmias and does not act on membrane currents associated with arrhythmogenesis. Thus, MCI-154 may be useful positive inotropic agent with little arrhythmogenic effect [74]. MCI-154, has more potent positive inotropic effect than pimobendan, adibendan and sulmazole.…”

Section: Cardiovascular Activities Of Pyridazine Derivativesmentioning

confidence: 99%

Calcium Sensitizing and Phosphodiesterase-III Inhibitory Activity of Pyridazine Compounds: A Review

Asif

2019

J. Chem. Rev.

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Congestive heart disease is one of the main causes of death in the globe, affecting more than 1% of the world population. Various remedial agents are used for the treatment of cardiac diseases such as inotropics and vasodilators. Sympathomimetic drugs play an important role, but they unfortunately undergo severely from oral ineffectiveness and tachyphylaxis due to receptor desensitization. Recently, several cardiac phasphodiestrase-III (PDE-III) inhibitors have been developed with improved ventricular performance and exercise tolerances. Theoretically, PDEinhibitors combine positive inotropy and vasodilation (known as zinodilator) action and these exceptional features make them very attractive. Various pyridazine drugs act as selective PDE-III inhibitor and characterized by a positive inotropic effect combined with vasodilatory effects. The pyridazine is an important heterocyclic structure with various biologically active compounds with diverse pharmacological activities. Pyridazine hold considerable interest relative to the physiologically active cardiac compounds such as Ca +2 sensitizing and PDE-III inhibitor activity. However, some pyridazine compounds have been reported as effective agents in the treatment of several cardiovascular diseases including, acute and chronic heart failure, myocardial infarction, angina, arrhythmia, and hypertension. Pyridazinone nucleus has focus attention because of new pyridazinone compounds will design and development of novel Ca +2 sensitizing and PDE-III inhibitors as cardio tonic agents in future.

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Effects of MCI-154, a new cardiotonic Ca2+ sensitizer, on ventricular arrhythmias and membrane ionic currents

Cited by 7 publications

References 26 publications

Arrhythmia Models for Drug Research: Classification of Antiarrhythmic Drugs

Arrhythmia Models for Drug Research: Classification of Antiarrhythmic Drugs

MCI‐154: A Second Generation Ca²⁺ Sensitizer That Does Not Impair Relaxation — A Novel Approach to the Treatment of Heart Failure

Calcium Sensitizing and Phosphodiesterase-III Inhibitory Activity of Pyridazine Compounds: A Review

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Effects of MCI-154, a new cardiotonic Ca2+ sensitizer, on ventricular arrhythmias and membrane ionic currents

Cited by 7 publications

References 26 publications

Arrhythmia Models for Drug Research: Classification of Antiarrhythmic Drugs

Arrhythmia Models for Drug Research: Classification of Antiarrhythmic Drugs

MCI‐154: A Second Generation Ca2+ Sensitizer That Does Not Impair Relaxation — A Novel Approach to the Treatment of Heart Failure

Calcium Sensitizing and Phosphodiesterase-III Inhibitory Activity of Pyridazine Compounds: A Review

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MCI‐154: A Second Generation Ca²⁺ Sensitizer That Does Not Impair Relaxation — A Novel Approach to the Treatment of Heart Failure