New 1,4‐benzothiazepine derivative, K201, demonstrates cardioprotective effects against sudden cardiac cell death and intracellular calcium blocking action

Abstract

In order to find drugs with suppressive effects against sudden cardiac cell dea ... UOl of the response to K t was less marked than that by diltiazem. Its inhibition of the response to NE was greater than that by diltiazem or KT362. K201 demonstrated an inhibitory effect on binding of cardiac annexin V with actin dependent on calcium concentration, but diltiazem and KT362 did not demonstrate any action to inhibit this reaction. These results indicate that K201 was a more effective cardioprotectant than propranolol, verapamil, and diltiazem in the experimental myofibrillar overcontraction model. K201 has intracellular Ca2+ blocking action in addition to weak a-.l adrenergic blocking activity and Ca" blocking activity. o 1994 \ViIey-Liss, Inc.

Inhibitory effects of JTV‐519, a novel cardioprotective drug, on potassium currents and experimental atrial fibrillation in guinea‐pig hearts

“…These IC 50 values were a few to 10 times smaller than those to inhibit I Na , I Ca and I K1 in guineapig ventricular cells (Kimura et al, 1999). In addition, the concentrations to inhibit I K and I K.ACh were comparable to or smaller than those to elicit cardioprotective e ects (Inagaki et al, 2000;Kaneko, 1994).…”

“…JTV-519 is a benzothiazepine derivative possessing protective e ects against myocardial injuries induced by Ca 2+ overload and ischaemia/reperfusion (Kaneko, 1994;Inagaki et al, 2000). The underlying mechanism(s) of the cardioprotective e ect have not been well established.…”

“…The underlying mechanism(s) of the cardioprotective e ect have not been well established. The drug inhibited the myo®brillar overcontraction induced by high extracellular Ca 2+ combined with epinephrine and/ or ca eine (Kaneko, 1994). Kaneko et al (1997) ascribed the cardioprotective e ect to the inhibitory e ect on annexin V. More recently Inagaki, et al (2000) have demonstrated that JTV-519 activates speci®cally d-isoform of protein kinese C through a receptor-independent mechanism and thereby induces pharmacological preconditioning.…”

“…It has been reported that JTV-519 produced a protective e ect against Ca 2+ overload-induced myocardial injury and the e ect was more potent than propranolol, verapamil and diltiazem (Kaneko, 1994). More recently it has been also demonstrated that this drug a ords cardioprotection against ischaemia/ reperfusion injury in isolated rat hearts through the activation of protein kinase C (Inagaki et al, 2000).…”

2APB- and JTV519(K201)-sensitive micro Ca2+ waves in arrhythmogenic Purkinje cells that survive in infarcted canine heart

“…24 JTV519(K-201) is a 1,4-benzothiazepine derivative 25 that has been shown to protect against Ca 2+ overload. 26 Two recent reports have suggested that a major effect of this annexin blocker is to improve defective ryanodine receptor gating by enhancing the coupling between FKBP and RYR2 proteins to stabilize the release channel. 11 , 27 Other reports have shown that it can affect several sarcolemmal ion channels, e.g., L-type Ca 2+ channel.…”