化合物信息

Description

Cardiovascular Disease

Description

Manidipine HCl is a HCl salt form of Manidipine which is a calcium channel blocker for Ca²⁺ current with IC50 of 2.6 nM.

Targets

IC₅₀

In Vitro

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]

In Vivo

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]

Clinical Trials

Features

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.

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.