Ohtsuka M, Koibuchi Y, Sakai S, Tsujioka K, Fujiwara T, Ozaki T, Maeda K, Motoyama I, Horiai H, Ono T
Product Development Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Arzneimittelforschung. 1988 Nov;38(11):1605-18.
The effects of 5-isopropyl 3-methyl 2-cyano-1,4-dihydro-6-methyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate (nilvadipine, FR 34235, FK 235) on the cardiovascular system were investigated in isolated organs and whole animals. 1. Nilvadipine inhibited Ca2+-induced contractions of isolated dog coronary artery in high-K+, Ca2+-free medium, and the pA2 value was 10.64. In this effect, nilvadipine was 18 times more potent than nifedipine and 525 times more potent than diltiazem. In contrast, its inhibitory effect on Ca2+-induced contractions of isolated guinea pig atria was weaker (pA2:8.2): only twice that of nifedipine and 25 times that of diltiazem. 2. Nilvadipine also inhibited K+-induced 45Ca2+ uptake in isolated dog coronary arteries and isolated guinea pig atria. In the coronary arteries, the IC50 value of nilvadipine was 2.7 x 10(-10) mol/l, which was, respectively 17, 8, and 589 times lower than that of nifedipine, nicardipine and diltiazem. In the atria, on the other hand, the IC50 value of nilvadipine was 4.4 x 10(-9) mol/l, almost the same as that of nifedipine or nicardipine, and 47 times lower than that of diltiazem. These 45Ca2+ uptake inhibitory effects of the drugs were consistent with their effects on mechanical response in both tissues. 3. Nilvadipine (2.6 x 10(-10) mol/l and higher) dose-dependently inhibited ergometrine (ergonovine)-, serotonin-, and norepinephrine-induced contractions of isolated dog coronary artery, and its effects were 2 to 450 times more potent than those of nifedipine, nicardipine and diltiazem. 4. Nilvadipine (2.6 x 10(-8) mol/l or more, 32 micrograms/heart or more), like nifedipine, produced negative inotropic and chronotropic effects in isolated guinea pig atria and in dog heart-lung preparation, and was more potent than nifedipine in the negative chronotropic effect. 5. Nilvadipine in intravenous doses of 1-32 micrograms/kg decreased total peripheral resistance and systemic blood pressure, and slightly increased cardiac output, pulmonary arterial blood flow and stroke volume, but had no significant effects on pulmonary vascular resistance or pulmonary arterial blood pressure. Heart rate decreased at doses of 32 micrograms/kg or more. Nifedipine had almost the same effects as nilvadipine on total peripheral resistance and blood pressure, but was more potent than nilvadipine in increasing effects on cardiac output, stroke volume and pulmonary arterial blood flow.(ABSTRACT TRUNCATED AT 400 WORDS)
研究了5-异丙基-3-甲基-2-氰基-1,4-二氢-6-甲基-4-(间硝基苯基)-3,5-吡啶二甲酸酯（尼伐地平，FR 34235，FK 235）对离体器官和整体动物心血管系统的影响。1. 在高钾、无钙培养基中，尼伐地平抑制离体犬冠状动脉由钙离子诱导的收缩，其pA2值为10.64。在此作用中，尼伐地平的效力比硝苯地平强18倍，比地尔硫䓬强525倍。相比之下，其对离体豚鼠心房由钙离子诱导的收缩的抑制作用较弱（pA2：8.2）：仅为硝苯地平的两倍，地尔硫䓬的25倍。2. 尼伐地平还抑制离体犬冠状动脉和离体豚鼠心房中钾离子诱导的45Ca2+摄取。在冠状动脉中，尼伐地平的IC50值为2.7×10(-10)mol/L，分别比硝苯地平、尼卡地平及地尔硫䓬低17倍、8倍和589倍。另一方面，在心房中，尼伐地平的IC50值为4.4×10(-9)mol/L，与硝苯地平或尼卡地平几乎相同，比地尔硫䓬低47倍。这些药物对45Ca2+摄取的抑制作用与其对两种组织机械反应的作用一致。3. 尼伐地平（2.6×10(-10)mol/L及以上）剂量依赖性地抑制麦角新碱、5-羟色胺及去甲肾上腺素诱导的离体犬冠状动脉收缩，其作用比硝苯地平、尼卡地平及地尔硫䓬强2至450倍。4. 尼伐地平（2.6×10(-8)mol/L或更高，32μg/心脏或更高），与硝苯地平一样，在离体豚鼠心房和犬心肺制备中产生负性肌力和负性变时作用，且在负性变时作用方面比硝苯地平更强。5. 静脉注射剂量为1 - 32μg/kg的尼伐地平可降低总外周阻力和体循环血压，并轻微增加心输出量、肺动脉血流量和每搏量，但对肺血管阻力或肺动脉血压无显著影响。剂量为32μg/kg及以上时心率降低。硝苯地平在总外周阻力和血压方面与尼伐地平作用几乎相同，但在增加心输出量、每搏量和肺动脉血流量方面比尼伐地平更有效。（摘要截短于400字）
