KT‐362, a Vasodilating and Antiarrhythmic Agent

Abstract

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-

Linked biaromatic compounds as cardioprotective agents

“…Potent cardioprotective effects of KT‐362 against myocardial damages during ischemia and reperfusion have also been noted. [ 245 ]…”

“…The central part of the linker also did not significantly affect the affinity of the compounds: both the Smith-93 amide compound and the Smith-44 compound with the central aminoethanol fragment had similar inhibition constants. [245] JTV-519 and analogs…”

“…Potent cardioprotective effects of KT-362 against myocardial damages during ischemia and reperfusion have also been noted. [245] In 1995, researchers from Kirin Brewery Co., Ltd. (Japan) patented a group of KT-362 analogs 70, which also combine the structural elements of diltiazem and verapamil. The difference of this group consisted in a different position of the nitrogen atom in the seven-membered heterocycle and in the presence of a pipyridine ring in the linker.…”

Effects of KT-362, a sarcolemmal and intracellular calcium antagonist, on calcium transients of cultured neonatal rat ventricular cells: A comparison with gallopamil and ryanodine

“…In fact, KT-362 prevented ouabaine-and epinephrine-induced arrhythmias due to its Na ÷ channel blocking action and inhibition of intracellular Ca 2÷ release [1]. In guinea-pig ventricular muscles perfused with low K ÷ media, KT-362 (10-300 ~M) depressed the amplitude of delayed afterdepolarization and aftercontraction caused by intracellular Ca 2÷ overload and abolished the triggered arrhythmias [29]. It has also been predicted that drugs that suppress the Ca 2+ mobilization from the intracellular store should be effective on ventricular arrhythmias [30], especially on ventricular fibrillation [31].…”