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Arzneimittel-Forschung 1988-Nov

Effects of nilvadipine on the cardiovascular system in experimental animals.

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M Ohtsuka
Y Koibuchi
S Sakai
K Tsujioka
T Fujiwara
T Ozaki
K Maeda
I Motoyama
H Horiai
T Ono

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概要

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)

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