flunarizine and nilvadipine

We examined the effects of an L-type Ca2+ channel blocker, nilvadipine (0.5 and 2.0 mg/kg), and that of a T-type Ca2+ channel blocker, flunarizine (10.0 and 40.0 mg/kg), on the hypnotic potency of both a benzodiazepine (BZ)-hypnotic, triazolam (1.0 mg/kg), and a non-BZ hypnotic, zolpidem (20.0 mg/kg), in rats. The polysomnogram was recorded for 6 h after administration of the vehicle solution alone, or after one of the Ca2+ channel blockers, with or without one of the hypnotics. Both Ca2+ channel blockers prolonged the increased total time of non-rapid eye movement (non-REM) sleep induced by either hypnotic. In the case of triazolam, however, the non-REM sleep-enhancing effect induced by nilvadipine was greater than that induced by flunarizine. These findings indicate that the hypnotic action of triazolam is potentiated more strongly by an L-type Ca2+ channel blocker than by a T-type Ca2+ channel blocker.

Topics: Animals; Calcium Channel Blockers; Calcium Channels; Calcium Channels, L-Type; Calcium Channels, T-Type; Drug Interactions; Flunarizine; Hypnotics and Sedatives; Male; Nifedipine; Pyridines; Rats; Rats, Wistar; Sleep, REM; Triazolam; Zolpidem

Effects of nilvadipine on the low- and high-voltage activated Ca2+ currents (LVA and HVA ICa, respectively) were compared with other organic Ca2+ antagonists in acutely dissociated rat hippocampal CA1 pyramidal neurons. The inhibitory effects of nilvadipine, amlodipine and flunarizine on LVA ICa were concentration- and use-dependent. The apparent half-maximum inhibitory concentrations (IC50s) at every 1- and 30-s stimulation were 6.3x10-7 M and 1.8x10-6 M for flunarizine, 1.9x10-6 M and 7.6x10-6 M for nilvadipine, and 4.0x10-6 M and 8.0x10-6 M for amlodipine, respectively. Thus, the strength of the use-dependence was in the sequence of nilvadipine>flunarizine>amlodipine. Nilvadipine also inhibited the HVA ICa in a concentration-dependent manner with an IC50 of 1.5x10-7 M. The hippocampal CA1 neurons were observed to have five pharmacologically distinct HVA Ca2+ channel subtypes consisting of L-, N-, P-, Q- and R-types. Nilvadipine selectively inhibited the L-type Ca2+ channel current which comprised 34% of the total HVA ICa. On the other hand, amlodipine non-selectively inhibited the HVA Ca2+ channel subtypes. These results suggest that the inhibitory effect of nilvadipine on the neuronal Ca2+ influx through both LVA and HVA L-type Ca2+ channels, in combination with the cerebral vasodilatory action, may prevent neuronal damage during ischemia.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Amlodipine; Animals; Calcium Channel Agonists; Calcium Channel Blockers; Flunarizine; Membrane Potentials; Nifedipine; Patch-Clamp Techniques; Pyramidal Cells; Rats; Rats, Wistar

We evaluated the effects of Ca2+ entry blockers, nilvadipine and flunarizine, on microcirculatory disorders of the inner ear and on blood flow in the inner ear of rats. Under sodium pentobarbital anesthesia, the middle ear was opened by a ventrolateral approach. A green light (wave length 540 nm) was applied to the cochlea or the vestibule to induce a hearing disturbance or equilibrium dysfunction as a result of inner ear microcirculatory disorders, while rose bengal solution was infused intravenously. In a hearing disturbance model, a compound cochlear nerve action potential was recorded by electrocochleography every minute after the beginning of illumination. The sound stimulus was an 8 kHz sine wave 100 dB normal hearing level. The action potential was calculated 128 times. The action potential disappeared about 12 min after the beginning of illumination. In another model of equilibrium dysfunction, the photoillumination was applied for 40 min under the infusion of rose bengal. The behavior of rats was observed in the swimming test and nystagmus was recorded 24 h after the completion of photoillumination. In a separate experiment, blood flow in the inner ear was measured with a laser Doppler flowmeter under sodium pentobarbital anesthesia. In this study, both nilvadipine and flunarizine prolonged the time required for complete suppression of the action potential, prevented equilibrium dysfunction in the swimming test and reduced the occurrence of nystagmus. Flunarizine significantly increased inner ear blood flow and nilvadipine failed to decrease blood flow in the inner ear, despite a reduced systemic blood pressure. In conclusion, Ca2+ entry blockers may prevent microcirculatory disorders of the inner ear in rats.

Topics: Acoustic Stimulation; Action Potentials; Analysis of Variance; Animals; Calcium Channel Blockers; Cochlea; Ear, Inner; Flunarizine; Hearing Disorders; Laser-Doppler Flowmetry; Nifedipine; Rats; Rats, Wistar; Regional Blood Flow; Sensation Disorders; Ultraviolet Rays