In vitro and ex vivo Ca-antagonistic effect of 2-methoxyethyl(E)-3-phenyl-2-propen-1-yl(+/-)-1,4-dihydro-2,6-dimethyl- 4-(3- nitrophenyl)pyridine-3,5-dicarboxylate (FRC-8653), a new dihydropyridine derivative.
The characteristics of calcium antagonism and vascular effect of 2-methoxyethyl(E)-3-phenyl-2-propen-1-yl(+/-)-1,4-dihydro-2,6-dime thyl-4-(3- nitrophenyl)pyridine-3,5-dicarboxylate (FRC-8653) were investigated. FRC-8653 inhibited an increase in intracellular free calcium concentration during membrane depolarization in PC12 cells. FRC-8653 also inhibited the specific binding of 3H-nitrendipine to cardiac membranes, in a similar manner to nifedipine and nicardipine. FRC-8653 inhibited KCl- and CaCl-induced contractions in isolated rabbit aorta, but failed to affect norepinephrine-induced contraction. The vasorelaxing effect of FRC-8653 in rabbit aorta developed more slowly than those of nifedipine and nicardipine. In ex vivo experiment, the inhibitory effect of orally administered FRC-8653 against KCl-contraction in rat aorta lasted longer than that of nifedipine. These findings suggest that FRC-8653 dilates blood vessels by blocking calcium influx via dihydropyridine-sensitive, voltage-dependent calcium channels and that the vascular effects are slow in development and long in duration.
Hosono
M
M
Pharmaceuticals Research Laboratories, Fujirebio Inc., Tokyo, Japan.
Iida
H
H
Ikeda
K
K
Hayashi
Y
Y
Dohmoto
H
H
Hashiguchi
Y
Y
Yamamoto
H
H
Watanabe
N
N
Yoshimoto
R
R
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004095:Dihydropyridines / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009568:Nitrendipine / Q000378:metabolism; D016716:PC12 Cells; D011189:Potassium Chloride / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D011189:Potassium Chloride; C065927:cilnidipine; D009568:Nitrendipine; D002118:Calcium