Effects of the novel water-soluble calcium antagonist (+/-)-3-(4-allyl-1-piperazinyl)-2,2-dimethylpropyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate dihydrochloride on the responses of isolated canine arteries.

The effects of NKY-722 ((±)-3-(4-allyl-1-piperazinyl) -2,2 - dimethylpropyl methyl 1,4-dihydro - 2, 6 - dimethyl-4- (3-nitrophenyl)-3,5-pyridinedicarboxylate dihydrochloride, CAS 117241-46-0), a new water soluble diyhdropyridine derivative on the responses of isolated canine arteries were examined. NKY-722 (IC 50 : 5-16 x 10 -10 mol/l), nicardipine (IC 50 : 5-J0 x 10 -10 mol/l ) and nifedipine (IC 50 : 44-195 x 10 -1 0 mol/l) relaxed fbur arteries in the potency order of basilar > coronary > mesenteric > intrarenal arteries. NKY-722 was nearly equipotent to nicardipine and about 10 times more potent than nifbdipine. [ 3 H]NKY-722 was accumulated in the four arteries in the same order of amount as the vasoinhibitory effect. All three drugs inhibited the contraction induced by Ca 2+ and methyl 1,4-dihydro-2,6-dimethyl-3 -nitro - 4- (2 - trifluoromethylophenyl) -pyridine-5-carboxylate (Bay K 8644 ) in the mesenteric arteries, indicating their Ca 2+ antagonistic actions. NKY-722 and nicardipine were nearly equipotent and about 100 times more potent than nifedipine on the Ca2+-induced contraction and was about 4 times more potent than nicardipine and 400 times more potent than nifedipine on the Bay K 8644-induced contraction. NKY-722, nicardipine and nifedipine relaxed the mesenteric arteries precontracted with KCl by more than 90 %, while they relaxed the arteries contracted with PGF 2α 9,11-dideoxy-9a,11a-methmioepoxy-PGF 2α ( U-46619,) and endothelin-I only by 40-70%. The IC 50 values of NKY-722 and nicardipine were similar and much smaller than that of nifedipine for all four contracting agents. At the equieffective concentrations, the relaxation induced by NKY-722 was more slowly developed than that induced by nicardipine or nifedipine in the mesenteric arteries precontracted with KCI ; T 1/2 was 46, 24 and 3 min, respectively. The vasoinhibitory effect of NKY-722 on the KCl-induced contraction was sustained for a longer time than that of nicardipine or nifedipine during repetitive wash-out ; t 1/2 was 3.0, 1.5 and 0.3 h, respectively. In conclusion, NKY-722 shows vasoinhibitory and vasorelaxing effects through the Ca 2+ -antagonistic action and its potencies were similar to those of nicardipine and much greater than those of nifedipine. The effect of NKY-722 is slower in onset and longer-lasting than that of nicardipine or nifedipine. langsamer ein, halten aber langer an als die von Nicardipin und Nifedipin.