Protective effect of l-cis-diltiazem on hypercontracture of rat myocytes induced by veratridine.
The protective effect of l-cis-diltiazem, the stereoisomer of d-cis-diltiazem, was studied against the veratridine-induced hypercontracture of rat myocytes. Veratridine increased both [Na+]i and [Ca2+]i, but did not cause hypercontracture in the absence of extracellular Ca2+. Both l-cis-diltiazem (0.1-10 microM) and d-cis-diltiazem (10-30 microM) inhibited the hypercontracture and the increase in [Ca2+]i in a concentration-dependent manner. However, l-cis-diltiazem did not exert a negative inotropic effect in K+ (20 mM)-depolarized rat papillary muscles even at a dose of 10 microM. As seen in the case of tetrodotoxin, l-cis-diltiazem and d-cis-diltiazem also suppressed the increase in [Na+]i. The results show that l-cis-diltiazem prevents the veratridine-induced hypercontracture of myocytes by suppression of the [Ca2+]i increase. The attenuation of the [Ca2+]i increase by l-cis-diltiazem was not dependent on inhibition of Ca2+ channels, but was partly due to inhibition of excessive Na+ entry via veratridine-modified Na+ channels.
Itogawa
E
E
Lead Optimization Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama, Japan.
Kurosawa
H
H
Yabana
H
H
Murata
S
S
D000818:Animals; D001572:Benzofurans; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004110:Diltiazem / Q000494:pharmacology*; D005456:Fluorescent Dyes; D016257:Fura-2; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D010210:Papillary Muscles / Q000187:drug effects; D010795:Phthalic Acids; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism; D013237:Stereoisomerism; D014701:Veratridine / Q000494:pharmacology*
D001572:Benzofurans; D002121:Calcium Channel Blockers; D005456:Fluorescent Dyes; D010795:Phthalic Acids; C103805:sodium binding benzofuran isophthalate acetoxymethyl ester; D014701:Veratridine; D012964:Sodium; D004110:Diltiazem; D002118:Calcium; D016257:Fura-2