title: 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.
abstract: We evaluated the effects of KT-362 (5-[3-([2-(3,4-dimethoxyphenyl)-ethyl]amino)-1-oxopropyl]-2,3,4,5, -tetrahydro-1,5-benzothiazepine fumarate), a putative intracellular calcium antagonist, on the intracellular free calcium concentration ([Ca2+]i) of cultured neonatal rat ventricular cells using microfluorometry of fura-2. The effects were compared with those of gallopamil (D-600), a sarcolemmal calcium channel antagonist, and ryanodine, a modulator of sarcoplasmic reticulum (SR) function. KT-362 decreased both systolic [Ca2+]i (sCa) and diastolic [Ca2+]i (dCa) in cell aggregates, in a concentration (1, 3, 10, and 30 microM) and stimulation frequency (0.2, 0.5, and 1.0 Hz) dependent manner. The time to peak of the Ca2+ transient was significantly prolonged by KT-362 at a concentration of 30 microM, while the half-life of the Ca2+ transient was prolonged at concentrations of > or = 10 microM. Gallopamil (1 microM) decreased both sCa and dCa in a frequency (0.2, 0.5, and 1.0 Hz) dependent fashion, as was the case for KT-362, but did not change the time course of Ca2+ transients. Ryanodine (10 microM) prolonged the time to peak and half-life of the Ca2+ transient, as was also the case for KT-362, while the effect of ryanodine on dCa differed from that of KT-362. Finally, the effect of KT-362 on Ca2+ transients could be mimicked by simultaneous application of gallopamil and ryanodine. These results suggest that KT-362 is a novel compound that exerts depressant effects on both sarcolemmal Ca2+ channels, and perhaps Ca2+ release channels of the sarcoplasmic reticulum, in cultured neonatal rat ventricular cells.
authors.affiliation: Department of Physiology, Oita Medical University, Hasama, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Tatsukawa
authors.forename: M
authors.initials: M
authors.lastname: Arita
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002478:Cells, Cultured; D005260:Female; D005711:Gallopamil / Q000494:pharmacology; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012433:Ryanodine / Q000494:pharmacology; D012508:Sarcolemma / Q000187:drug effects*; D013841:Thiazepines / Q000494:pharmacology*
chemical_list: D002121:Calcium Channel Blockers; D013841:Thiazepines; C051271:KT 362; D012433:Ryanodine; D005711:Gallopamil