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Research Area
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Description
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Cardiovascular Disease |
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Biological Activity
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Description
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Manidipine HCl is a HCl salt form of Manidipine which is a calcium channel blocker for Ca2+ current with IC50 of 2.6 nM. |
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Targets
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Ca2+ current |
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IC50 |
2.6 nM [1] |
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In Vitro
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At a holding potential of ?37 mV, Manidipine decreases the Ca2+ current at concentrations above 0.1 nM, and abolishes it at 100 nM. [1] Manidipine concentration-dependently inhibits the calcium concentration response curves. Manidipine inhibits coronay artery and renal artery with pIC50 of 9.3 nM and 9.1 nM, respectively. [2] Manidipine partly inhibits sympathetic nerve activity and suppresses the mean arterial pressure response to infused norepinephrine. Manidipine also inhibits aldosterone secretion. Manidipine increases in both urinary calcium and uric acid. [3] In addition, Manidipine, at nanomolar concentrations, is efficacious in modulating gene transcriptions that are involved in proinflammatory changes of mesangial cells. [4] |
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In Vivo
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Manidipine (3 mg/kg and 10 mg/kg, p.o.) dose-dependently decreases systolic blood pressure in the three types of hypertensive rats. At the dose of 10 mg/kg, Manidipine decreases the blood pressure to the normotensive level between 1 hour and 3 hours after Manidipine is administered; the antihypertensive effect lasted for at least 8 hours. [5] When Manidipine is administered at 10 μg/kg, the hypotensive action is markedly augmented. [6] Manidipine potently inhibits the Ca inward current, When the potential is at -60 mV. Manidipine consistently inhibits the Ca current evoked by depolarization to 0 mV. However, a low concentration of Manidipine (1-3 nM) enhances the Ca current evoked by the depolarizing pulse of -20 mV, when the membrane potential is held at -80 mV. Inhibition of the Ca current induced by Manidipine develops slowly and over 10 minutes is required to reach the maximum inhibition. [7] |
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Clinical Trials
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Features
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Protocol
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Cell Assay
[4]
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| Cell Lines |
Mesangial cells |
| Concentrations |
10 nM |
| Incubation Time |
Days 1, 3 and 5 |
| Methods |
The mitogenic effect is measured by the amout of [3H]thymidine incorporated into DNA of human MCs and by assessment of cell proliferation. In brief, 1 × 105 quiescent cells is seeded into a 25-mL cell culture bottle and kept in low serum medium (0.1% FCS). On the following day, the cells are preincubated for 3 hours with Manidipine (10 nM) followed by stimulation with PDGF-BB (10 ng/mL) or incubated with low serum medium abone. The medium is replaced each day, and the cells are counted at days 1, 3 and 5. |
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Animal Study
[5]
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| Animal Models |
Normotensive male Wistar-Kyoto rats and male stroke-prone SHR |
| Formulation |
Saline |
| Doses |
1 mg/kg, 3 mg/kg and 10 mg/kg |
| Administration |
Administered via p.o. |
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References |
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[1] Tohse N, et al. Eur J Pharmacol, 1993, 249(2), 231-233.
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[2] Pfaffendorf M, et al. Am Heart J, 1993, 125(2 Pt 2), 571-577.
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[3] Iimura O, et al. Am Heart J, 1993, 125(2 Pt 2), 635-641.
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[4] Roth M, et al. Proc Natl Acad Sci, 1992, 89(9), 4071-4075.
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[5] Kakihana M, et al. Jpn J Pharmacol, 1988, 48(2), 223-228.
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[6] Morimoto S, et al. Jpn J Pharmacol, 1989, 51(2), 257-265.
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[7] Okabe K, et al. J Pharmacol Exp Ther, 1987, 243(2), 703-710.
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