Activity of dihydrothienopyridine S312 enantiomers on L-type Ca2+ channels in isolated rat aorta and cerebral microvessels.
The activity of the two enantiomers of the dihydrothienopyridine S312 was characterized in isolated rat aorta and cerebral microvessels. The interaction of S312 with 1,4-dihydropyridine and phenylalkylamine binding sites was also investigated in depolarized rat cerebral microvessels and in membranes from rat ileum. Both S-(+)-S312 and R-(-)-S312 dose dependently inhibited KCl-evoked contraction of the rat aorta, with IC50 values of 0.14 (0.13-0.16) and 2.98 (2.67-3.33) nM, respectively. When the aorta was preincubated with S-(+)-S312 in a depolarizing medium, the inhibitory effect was significantly increased, but this increased inhibition was not reversed by incubation in physiological medium. The effect of R-(-)-S312 was not affected by preincubation in a depolarizing medium. In rat cerebral microvessels, S-(+)-S312 inhibited the KCl-induced contraction and KCl-stimulated Ca2+ influx with similar potency. [3H](+)-PN 200-110 specific binding was competitively displaced by the two enantiomers in depolarized cerebral microvessels. The calculated Ki values were 0.12 nM for S-(+)-S312 and 2.4 nM for R-(-)-S312. Only 20% of [3H]D888 specific binding in rat ileum membranes was displaced by S-(+)-S312. The dissociation rate of [3H]D888 was markedly decreased by S-(+)-S312, and this allosteric interaction was significantly more marked than with nitrendipine. It is concluded that the dihydrothienopyridine S312 could interact with Ca2+ channels in a manner different to that of genuine dihydropyridines.
Dessy
C
C
Laboratoire de Pharmacologie, Université Catholique de Louvain, Bruxelles, Belgium.
Salomone
S
S
Morel
N
N
Godfraind
T
T
D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004095:Dihydropyridines / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D014661:Vasoconstriction / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D014665:Vasodilator Agents; C059447:S 312; D011189:Potassium Chloride; C038806:1,4-dihydropyridine; D002118:Calcium