Effects of KT-362, a New Calcium Release Blocker, on Vascular Selectivity and Hemodynamic Actions in Anesthetized Dogs

Wakabayashi, Shigeru; Mochizuki, Seiichiro; Tomiyama, Akira; Shibata, Shoji

doi:10.1254/jjp.54.23

Cited by 4 publications

(3 citation statements)

References 19 publications

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“…EC 50 values for negative inotropy, chronotropy and dromotropy were about 25, 3 and 3 times lower for verapamil compared to those with KT-362 [42]. Verapamil was again more potent than KT-362 in anesthetized dogs as prolongation of PQ interval on the electrocardiogram was observed with 0.1 mg/kg verapamil but KT-362 even at 10 mg/kg evoked no negative dromotropic action [332] [333]. In anesthetized ischemic dogs KT-362 (0.3 mg/kg/min intravenously started 10-15 min before and continued throughout the occlusion) but not diltiazem (15 and 30 µg/kg/min) produced a significant decrease in HR and dP/dt max [333].…”

Section: Kt-362mentioning

confidence: 89%

Class IV Antiarrhythmic Agents: New Compounds Using an Old Strategy

Szentandrássy

Nagy²,

Hegyi³

et al. 2014

CPD

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Cardiac arrhythmias are a major cause of morbidity and mortality in the industrialized world. Among their treatment regimens one can find the calcium channel antagonists (CCAs), the class IV agents. In the cardiovascular system Land T-type calcium channels are found on vascular smooth muscle cells and cardiac myocytes with well defined physiological roles. Inhibition of calcium channels by CCAs has widely been used in clinical practice for several decades. Cardiovascular disorders are one of the many fields of medicine in which CCAs are used for various reasons and conditions. The three main indications of them are hypertension, angina and various cardiac arrhythmias. The most important classes of CCAs are dihydropyridines, phenylalkylamines and benzothiazepines but some newer compounds do not fall into any of these major classes. Dihydropyridines are not used in the antiarrhythmic therapy but are good vasodilators and antianginal agents. In contrast, phenylalkylamines and benzothiazepines exert cardiac actions in vivo and therefore these are one choice of antiarrhythmic drugs. This review focuses on phenylalkylamines, benzothiazepines and on new drugs with potential antiarrhythmic action in the heart as well as the mechanisms how calcium channels antagonism can lead to an antiarrhythmic action.

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Section: Kt-362mentioning

confidence: 89%

Class IV Antiarrhythmic Agents: New Compounds Using an Old Strategy

Szentandrássy

Nagy²,

Hegyi³

et al. 2014

CPD

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“…Indeed, KT-362 at concentrations ranging from 3 to 300 p M did not change the APD in guinea pig ventricular papillary muscles (2,14). Furthermore, in electrocardiograms (ECGs) recorded from anesthetized dogs, KT-362 administered intravenously at a dose of 10 mg/kg significantly lengthened the QT interval (26). at 10 pM did not depress the transient depolarization (Fig.…”

Section: The Effect Of Kt-362 On Other Currentsmentioning

confidence: 93%

KT‐362, a Vasodilating and Antiarrhythmic Agent

Kiyosue

Ito

Cheng

et al. 1996

Cardiovascular Drug Reviews

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Key Words: Antiarrhythmic effect-KT-362-L-type Ca2+ channel-Myocardium-Na+ channel-Sarcoplasmic reticulum-Vascular smooth muscle. 3,4-dimethoxyphenyl]ethyl)amino] -1 -oxopropyl)-2,3,4,5-tetrahydro-1,5-benzothiazepine fumarate} is a vasodilating and antiarrhythmic agent synthesized at the Kotobuki Pharmaceutical Co., Ltd. (Nagano, Japan). Its chemical structure resembles that of diltiazem (left half of the chemical structure shown in Fig. 1) and verapamil (the right half). KT-362 is a white powder (molecular weight 516) and is fairly soluble in water. PHARMACOLOGY Hemodynamic EffectsKT-362 decreases the heart rate in anesthetized laboratory animals (26) and increases the heart rate in conscious animals by autonomic reflex (7). Fig. 2 shows an example of the cardiovascular effects of in an anesthetized open-chest dog (26). Intravenously administered KT-362 (0.3-10 mg/kg, a bolus injection) decreased the left ventricular and mean arterial blood pressures and total peripheral resistance. As cardiac output increased, vasodilating and after-load reducing effects probably opposed the intrinsic negative inotropic effect of this drug on the myocardium. Similar results were obtained with verapamil at an effective dose more than 10 times lower than that of KT-362. Continuous infusion of KT-362 (150-300 kg/kg/min) decreased the heart rate, left ventricular pressure, and dP/dt , but these changes were not statistically significant (5 ,6918). Mechanism of Vasodilating ActionThe vasodilating action of KT-362 is attributed not only to inhibition of Ca2+ entry via voltage-gated Ca2+ channels, but also to inhibitory effects on Ca2+ release from nor-

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“…drug administration to conscious dogs, although there were no changes in the QRS or QT interval [30]. Similarly, intravenous verapamil administration at 0.1 and 0.3 mg/kg induced significant prolongation (8.9% and 20.0%, respectively) of the PQ interval in anesthetized dogs, whereas no changes were seen in the QRS or QT interval [31]. In addition, dose-dependent decreases in heart rate and LVdP/dt max were observed with verapamil (−12.3% and −23.1%, respectively, at 0.3 mg/kg) [31].…”

Section: Open Access Ppmentioning

confidence: 99%

Beat-to-Beat Variability in Field Potential Duration in Human Embryonic Stem Cell-Derived Cardiomyocyte Clusters for Assessment of Arrhythmogenic Risk, and a Case Study of Its Application

Yamazaki¹,

Hihara²,

Kato³

et al. 2014

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We established a QT interval assessment system that uses human embryonic stem cell-derived cardiomyocyte clusters (hES-CMCs) in which the field potential duration (FPD) or corrected FPD (FPDc) was measured as an indicator of drug-induced QT interval prolongation. To investigate the applicability of the hES-CMC system to drug safety assessment, we investigated short-term variability in FPDc (STV FPDc ) (beat rate rhythmicity) as a marker of torsadogenic risk. We investigated the FPDc and STV FPDc of hES-CMCs treated with hERG channel blockers (E-4031 or cisapride) or with our proprietary compounds X, Y, and Z. We also evaluated the electrocardiograms and hemodynamics of dogs treated with compound X, Y, or Z. The torsadogenic hERG channel blockers increased STV FPDc and prolonged FPDc. Compounds X, Y, and Z had hERG inhibitory activity. Compound X prolonged FPDc with increased STV FPDc , whereas compounds Y and Z tended to shorten FPDc in the hES-CMC system. In the in vivo canine study, compound X prolonged corrected QT (QTc), and compounds Y and Z tended to shorten QTc, showing a good correlation with the results in hES-CMCs. These findings suggest that combined assessment of FPDc and STV FPDc in the hES-CMC system increases the predictability of torsadogenic risk.

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Effects of KT-362, a New Calcium Release Blocker, on Vascular Selectivity and Hemodynamic Actions in Anesthetized Dogs

Cited by 4 publications

References 19 publications

Class IV Antiarrhythmic Agents: New Compounds Using an Old Strategy

Class IV Antiarrhythmic Agents: New Compounds Using an Old Strategy

KT‐362, a Vasodilating and Antiarrhythmic Agent

Beat-to-Beat Variability in Field Potential Duration in Human Embryonic Stem Cell-Derived Cardiomyocyte Clusters for Assessment of Arrhythmogenic Risk, and a Case Study of Its Application

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