title: Effects of a novel, potent benzothiazepine Ca2+ channel antagonist, DTZ323, on guinea-pig ventricular myocytes.
abstract: The effects of a 1,5-benzothiazepine derivative, (+)-cis-3-(acetyloxy)-5-[2-[[2-(3,4-dimethoxyphenyl)ethyl]-methyla mino]ethyl]-2,3-dihydro-2-(4-methyoxyphenyl)-1,5-benzothiazepine-4 (5H)-one (DTZ323), on membrane currents were investigated in guinea-pig ventricular myocytes using the whole-cell patch-clamp technique. DTZ323 suppressed the L-type Ca2+ channel currents (I[Ca(L)]) more selectively than the T-type Ca2+ channel and the Na+ channel currents. DTZ323 inhibited I[Ca(L)] in a use- and a voltage-dependent manner with 24 times higher potency than that of diltiazem. Rate of recovery of I[Ca(L)] from the conditioned block by DTZ323 was faster compared with diltiazem and verapamil, and was steeply dependent on the holding potential at resting membrane potential range in ventricular myocytes (-90 to -60 mV). Our results suggest that DTZ323 is a selective Ca2+ channel antagonist, the most potent among the 1,5-benzothiazepine Ca2+ channel antagonists, and that the voltage- and use-dependent effect of DTZ323 on I[Ca(L)] is due to the steep voltage dependence of the rate of dissociation from the cardiac L-type Ca2+ channels.
authors.affiliation: Department of Toxicology and Pharmacology, Faculty of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Kurokawa
authors.forename: S
authors.initials: S
authors.lastname: Adachi-Akahane
authors.forename: T
authors.initials: T
authors.lastname: Nagao
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000145:classification / Q000187:drug effects / Q000378:metabolism; D004110:Diltiazem / Q000031:analogs & derivatives* / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; C105375:DTZ 323; D015222:Sodium Channels; D014700:Verapamil; D004110:Diltiazem