化合物信息

Description

Cardiovascular Disease

Description

Nisoldipine (Sular) is a calcium channel blocker belonging to the dihydropyridines class, specific for L-type Ca_v1.2 with IC50 of 10 nM.

Targets

IC₅₀

In Vitro

Nisoldipine is a potent blocker of L-type calcium channels. Nisoldipine binds directly to inactive calcium channels stabilizing their inactive conformation Similar to other DHP CCBs. Nisoldipine displays selectivity for arterial smooth muscle cells due to great number of inactive channels and the alpha-1 subunit of the channel. ^[1] Nisoldipine is about 30 times less selective for delayed-rectifier K+ channels than for L-type Ca²⁺ channels, which inhibits I_Kr (rapidly activating delayed-rectifier K⁺ current) with IC50 of 23 μM, and IKs (slowly activating delayed-rectifier K⁺ current)with IC50 of 40 μM in guinea-pig ventricular myocytes. ^[2] Nisoldipine also displays antioxidant potency with IC50 of 28.2 μM both before and after the addition of active oxygen. This is tested by means of rat myocardial membrane lipid peroxidation with a nonenzymatic active oxygen-generating system (DHF/FeC1₃-ADP). ^[3]

In Vivo

Nisoldipine decreases arterial smooth muscle contractility and subsequent vasoconstriction by inhibiting the influx of calcium ions through L-type calcium channels. This results in vasodilation and an overall decrease in blood pressure, based on which Nisoldipine is used to treat mild to moderate essential hypertension, chronic stable angina and Prinzmetal’s variant angina. ^[4] Nisoldipine shows some ability in patients with Timothy syndrome having Ca_v1.2 missense mutation G406R with IC50 of 267 nM, which is helpful to treat TS. ^[5]

Clinical Trials

Phase I has been completed in a single-dose fasting bioequivalence study of Nisoldipine extended-release tablets in healthy volunteers.

Features

Nisoldipine belongs to the dihydropyridine (DHP) class of calcium channel blockers (CCBs), the most widely used class of CCBs.

Binding experiments of electrophysiology

CHO cells expressing the subunit of the voltage-dependent L-type Ca²⁺ channel are cultrured in medium without serum in the presence of different concentrations of Nisoldipine. Then Ca²⁺ channel current elicited from a holding potential of -100 mV or -50 mV is recorded at room temperature with the whole-cell configuration of the patch-clamp method using the List EPC-7 patch-clamp amplifer and pClamp software. The concentration of competitor inhibiting 50% of the specific binding represents IC50.

Cell Lines

Ventricular myocytes

Concentrations

Dissolved in DMSO, final concentration 10-100 μM

Incubation Time

8-10 minutes

Methods

The myocytes are bathed in normal Tyrode’s solution, held at -80 mV, and depolarised after 200-ms prepulses (-40mV) to more positive potentials for 500 ms at 0.1 Hz, tail currents are recorded on repolarisations to -40mV. The myocytes are exposed to 10-100 mM Nisoldipine for 8-10 minutes. Then the whole-cell membrane currents are recorded using an EPC-7 amplifier.

Animal Models

Male Wistar rats with chronic intragastric ethanol exposure

Formulation

Dissolved in DMSO and diluted in saline

Doses

10 mg/kg

Administration

Oral every day