Stereoselective pharmacodynamic action of (+)-S-12967 and (-)-S-12968, isomers of a new slow acting 1,4-dihydropyridine derivative with calcium channel agonistic and antagonistic effects on rat aorta.
The effects of (+)-S-12967 and (-)-S12968, isomers of a new dihydropyridine (1,4-DHP) derivative [2(7-amino 2,5-dioxaheptyl) 3-ethoxycarbonyl 4-(2,3-dichlorophenyl) 5-methoxycarbonyl 6-methyl 1,4-dihydropyridine] were studied on contractile responses of isolated thoracic aortas from rats and compared to that of nifedipine. The maximal relaxant effect of both isomers was reached in about 2 hr whereas the maximal relaxant effect to nifedipine was obtained within 30 min. The two 1,4-DPH isomers and nifedipine had a far more potent inhibitory effect on potassium (K+) than on noradrenaline (NA) induced contractions. They shifted the K+, Ca2+ and NA-concentration response-curves to the right and depressed the maximal vessel response to these agonists. Nifedipine was about 10 times more potent than the (-)-isomer which again was about 100 times more potent that the (+)-isomer. In contrast to nifedipine (-)-S-12968 and (+)-S-12967 had a dual action on K+ and Ca(2+)-induced contractions as both isomers in low concentrations, 3 x 10(-9)M and 3 x 10(-7)M, respectively, shifted the K(+)-concentration response curves to the left and increased the maximal response. In K(+)-depolarized preparations they increased the response to low Ca(2+)-concentrations without affecting the maximal vessel response at the highest Ca(2+)-concentrations. The result indicates that (+)-S-12967 and (-)-S-12968 possess Ca(2+)-agonistic as well as Ca-antagonistic properties. Compared to nifedipine both isomers are slow acting vasodilators. Their action as regards their potency is stereoselective and the (-)-isomer is more potent than the (+)-isomer.
Poulsen
S H
SH
Department of Pharmacology, University of Aarhus, Denmark.
Nyborg
N B
NB
Mikkelsen
E O
EO
D000818:Animals; D001011:Aorta / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects*; D004095:Dihydropyridines / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009543:Nifedipine / Q000494:pharmacology; D011189:Potassium Chloride / Q000008:administration & dosage; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014661:Vasoconstriction / Q000187:drug effects*
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; C067838:S 11568; D011189:Potassium Chloride; D009543:Nifedipine