EFFECTS OF THE NOVEL WATER-SOLUBLE CALCIUM-ANTAGONIST (+ -)-3-(4-ALLYL-1-PIPERAZINYL)-2,2-DIMETHYLPROPYL METHYL METHYL-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-dimethylpro pyl methyl methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate dihydroc hloride, CAS 117241-46-0), a new water soluble diyhdropyridine derivat ive on the responses of isolated canine arteries were examined. NKY-72 2 (IC50: 5-10 x 10(-10) mol/l), nicardipine (IC50: 5-10 x 10(-10) mol/ l) and nifedipine (IC50: 44-195 x 10(-10) mol/l) relaxed four arteries in the potency order of basilar > coronary > mesenteric > intrarenal arteries. NKY-722 was nearly equipotent to nicardipine and about 10 ti mes more potent than nifedipine. [H-3]NKY-722 was accumulated in the f our arteries in the same order of amount as the vasoinhibitory effect. All three drugs inhibited the contraction induced by Ca2+ and methyl -(2-trifluoromethylophenyl)-pyridine-5-carboxylate (Bay K 8644) in the mesenteric arteries, indicating their Ca2+ antagonistic actions, NKY- 722 and nicardipine were nearly equipotent and about 100 times more po tent than nifedipine on the Ca2+-induced contraction and was about 4 t imes more potent than nicardipine and 400 times more potent than nifed ipine on the Bat K 8644-induced contraction. NKY-722, nicardipine and nifedipine relaxed the mesenteric arteries precontracted with KCl by m ore than 90%, while they relaxed the arteries contracted with PGF(2 al pha), 9,11-dideoxy-9 alpha,11 alpha-methanoepoxy-PGF(2 alpha) (U-46619 ) and endothelin-1 only by 40-70%. The IC50 values of NKY-722 and nica rdipine were similar and much smaller than that of nifedipine for all four contracting agents. At the equieffective concentrations, the rela xation induced by NKY-722 was more slowly developed than that induced by nicardipine or nifedipine in the mesenteric arteries precontracted with KCl; 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 w ash-out; t(1/2) was 3.0, 1.5 and 0.3 h, respectively. In conclusion, N KY-722 shows vasoinhibitory and vasorelaxing effects through the Ca2+- antagonistic action and its potencies were similar to those of nicardi pine and much greater than those of nifedipine. The effect of NKY-722 is slower in onset and longer-lasting than that of nicardipine or nife dipine.