Effect Of Nimodipine Research Articles

Optical recording method for evaluation of neuronal damage in rat hippocampal slices during ischemia and reperfusion

OBJECTIVE: To develop a novel technique of optical recording and its validation for assessment of the neuroprotective effect of nimodipine, a L-type calcium channel blocker. METHODS: In vitro ischemia was induced by oxygen/glucose deprivation (OGD), the light transmittance (LT) of rat hippocampal slices undergoing OGD and reperfusion was quantitated using a simple apparatus relying on basic principles of light transmittance and a computerised image analysis system. RESULTS: OGD was associated with increased LT in the stratum radiatum of CA1 area and the dentate gyrus in hippocampal slices. Peak LT occurred (7.59 +/-1.42) min after OGD, followed by a marked decrease in LT (n=15 slices). Nimodipine administration (0.5 &mgr;mol/L, n=10 slices, 5 &mgr;mol/L, n=9 slices) appeared to protect the tissue from OGD damage by inhibiting elevation of LT, However, 50 &mgr;mol/L nimodipine resulted in increased LT (25.83 +/-6.32). min after administration (n=11 slices). CONCLUSION: LT signal measurement is a non-invasive, reliable method for determination of neuronal damage in ischemic rat brain slices Nimodipine is demonstrated opposite neuroprotective effects depending on its dose.

Role of Ca 2+ channels on the hypothermic response produced by activation of κ-opioid receptors

The effect of nimodipine (NIM) and lercanidipine (LER) 1,4-dihydropyridine (DHP) calcium channel blockers (CCBs) on the hypothermic response of selective κ-opioid receptor agonists U50,488H (U50), PD117,302 (PD) and U69,593 (U69) was determined in rats by recording colonic temperature using digital telethermometer. Intraperitoneal (ip) injections of U50 (7.5, 15, 22.5 and 40 mg/kg), PD (7.5, 15 and 22.5 mg/kg) and U69 (5 and 20 mg/kg) produced a dose-dependent hypothermic response. However, higher doses of U50 (60 and 80 mg/kg) produced hypothermia, which is less when compared to that produced by 22.5-mg/kg dose of U50. NIM (1 mg/kg ip; 15 min prior) and LER (0.3 mg/kg ip; 15 min prior) did not produce any change in basal colonic temperature. Treatment of NIM and LER potentiated the U50 (7.5, 15, 22.5 and 40 mg/kg)-induced hypothermic effect. NIM did not potentiate hypothermia produced by U50 (60 mg/kg). On the other hand, PD (7.5, 15 and 22.5 mg/kg)- and U69 (5 and 20 mg/kg)-induced hypothermia was unaffected by the pretreatment of either NIM or LER. This differential modulation of κ-opioid agonist-induced hypothermia by CCBs suggest that there may be two mechanisms, Ca 2+-sensitive and Ca 2+-insensitive, involved in κ-opioid agonist-induced hypothermic response.

Systematic Review of Nimodipine

To the Editor: I noted with interest the systematic review of nimodipine from Dr. Horn et al ( Stroke . 2001;32;2433–2438). The authors are to be complimented for a thorough review of difficult literature; their summary brings clarity to a previously confusing issue. I concur with their conclusions that preclinical data suggested nimodipine NOT be pursued in clinical trials. The authors emphasized stroke infarct volume as an outcome measure. They meta-analyzed the effect of nimodipine on infarct size (their Figure 1), in which an overall favorable effect is shown for nimodipine. The “methodological score” they used to rate the quality of the reviewed articles gave a point if the article included both behavioral and morphometric outcomes. It seems to me that this review could be taken as further indictment of morphometry as a valuable outcome measurement: infarct volume in the rodent brain seems not to predict effects either on functional outcome or in human clinical trials. This controversy has been bubbling for a while now, and this article serves to crystallize it. The only remaining arguments in favor of morphometry as an end point are (1) it is simple and (2) the data are parametric so standard statistical analysis can be used. Arguments against morphometry include (1) the variance is so huge (if it is reported honestly) that sample sizes must be increased beyond what is typically reported and (2) it has limited relevance to functional outcome. Horn et al have buttressed this latter point, perhaps unintentionally. As we struggle to resolve the paradox of positive animal/negative human trials, we would be well served to keep this review in mind. Unless a putative neuroprotectant shows effects other than reducing rodent infarct volume, it is very unlikely to prove useful in human stroke victims. I would go further and suggest that rodent …

L-type Ca 2+ channel modulation by dihydropyridines potentiates κ-opioid receptor agonist induced acute analgesia and inhibits development of tolerance in rats

The effect of 1,4-dihydropyridine (DHP) calcium channel blockers (CCBs), nimodipine (NIM) and lercanidipine (LDP) on the analgesic response of selective κ-opioid receptor agonists, U50,488H, PD117,302 and U69,593 was determined in male Sprague-Dawley rats using the tail-flick test. The effect of NIM on development of tolerance to U50,488H-induced analgesia and the status of brain DHP-sensitive Ca 2+ channel (L-type) binding sites in both U50,488H-naive and tolerant rats was determined using the highly selective DHP radioligand, [ 3H]PN200-110. Tolerance was induced by injecting U50,488H (25 mg/kg, i.p.) twice daily for 4 days. Intraperitoneal (i.p.) injection of κ-opioid receptor agonists produced a dose-dependent acute analgesic response. NIM (1 mg/kg; i.p.) and LDP (0.3 mg/kg; i.p.) used in the study produced no tail-flick analgesia. Administration of NIM and LDP (15 min prior) significantly potentiated the analgesia produced by three κ-opioid receptor agonists. Tolerance developed completely to the analgesic effect induced by U50,488H (25 mg/kg, i.p.) administered on the 5th day. NIM (1 mg/kg, i.p.) twice daily for 4 days not only completely inhibited the development of tolerance to analgesic response but also significantly potentiated it (supersensitivity). There was a significant up-regulation of DHP binding sites ( B max: +41%) in whole brain membranes of tolerant rats when compared to vehicle treated naive rats, implicating increased influx of Ca 2+ through L-type channels in κ-opioid tolerance. U50,488H (25 mg/kg, i.p.) and NIM (1 mg/kg, i.p.) twice daily for 4 days also resulted in an equivalent up-regulation of DHP binding sites (+36%) as that of U50,488H alone. These results strongly suggest a functional role of L-type Ca 2+ channels in the regulation of pain sensitivity, mechanism of κ-opioid analgesia and expression of tolerance.

Nitric oxide donor sodium nitroprusside induces neurotoxicity in cerebellar granular cell culture in rats by an independent mechanism from L-type or dantrolene-sensitive calcium channels.

The effects of sodium nitroprusside (SNP) in rat cerebellar granular cell culture were investigated in the present study. All doses of the SNP (10, 25, 50, 100, 250, 500 microM) were able to induce cell death compared with control values (p < 0.001 for all groups tested). Interestingly enough, a nonlinear dose-response curve was obtained for SNP-induced neurotoxicity. We also investigated the possible neuroprotective effects of nimodipine and dantrolene, alone or in combination. Both drugs failed to prevent neuronal cell death at the doses tested, either alone or in combination. Despite the fact that the most effective dose was a dantrolene concentration of 10 microM with SNP 500 microM and a concentration of 1 microM with SNP 50 microM, the differences were insignificant statistically. According to our results, SNP-induced cerebellar toxicity appears to be an independent reaction from L-type or endoplasmic reticulum calcium currents.

Protective effect of nimodipine on dichlorvos-induced delayed neurotoxicity in rat brain

The effect of dichlorvos (200 mg/kg body weight) with or without nimodipine (6 mg/kg body weight/day for 3 days, starting 1 day prior to the administration of dichlorvos) on calcium homeostasis was studied in the rat brain. The delayed neurotoxic potential of dichlorvos was assessed in terms of neuropathy target esterase (NTE) inhibition in the brain and the subsequent development of motor incoordination at 21 days post-exposure. NTE activity had recovered up to 84% at the time of clinical manifestations. No signs of motor deficit were present when nimodipine was given with dichlorvos. The administration of dichlorvos alone caused an increase in intrasynaptosomal Ca 2+ with a concomitant increase in calpain activity. These increases in calpain activity and in the levels of intracellular Ca 2+ were not observed when nimodipine was administered to rats treated with dichlorvos. Also, the inhibition of calcium ATPase following the exposure to dichlorvos was reduced when animals received nimodipine. This indicates that nimodipine, a centrally acting calcium channel blocker, may contribute to the amelioration of dichlorvos-induced neurotoxicity by attenuation of calcium-mediated disruption of cytoskeletal homeostasis, without preventing NTE inhibition.

Effects of nimodipine on tissue lactate and malondialdehyde levels in experimental head trauma.

We studied the effects of nimodipine on brain tissue lactate and malondialdehyde (MDA) levels one hour after experimental head trauma in 25 New Zealand rabbits. Group 1 (n=5) was the sham operated group. Group 2 (n=10) received head trauma without treatment and in group 3 (n=10) nimodipine was administered for 30 minutes intravenously (2 microg/kg/min) immediately after head trauma. In groups 2 and 3, tissue samples from the non-traumatized side was named as "a" and traumatized side as "b". The lactate and malondialdehyde contents were significantly higher in groups 2a, 2b, 3a and 3b when compared with to group 1 (P<0.05). The differences between non-treated groups (2a, 2b) and nimodipine treated groups (3a, 3b) were not significant (P>0.05). The differences between the traumatized sides (2b, 3b) and non-traumatized sides (2a, 3a) were significant (P<0.05). These results demonstrated that nimodipine is ineffective in suppressing the increase of tissue lactate and malondialdehyde levels in the early period of experimental head trauma.

Nimodipine promotes regeneration and functional recovery after intracranial facial nerve crush.

The calcium flow inhibitor, nimodipine, has been shown to promote motor neuron survival in the facial nucleus after intracranial facial nerve transection. However, it has not been known whether the neuroprotective effects primarily involve survival of nerve cell bodies or outgrowth and/or myelination of nerve fibers. Here, we studied the effects of nimodipine in a different injury model in which the facial nerve was unilaterally crushed intracranially. This lesion caused complete anterograde degeneration and partial retrograde degeneration that were studied with a combination of several stereological methods. Nimodipine did not attenuate the modest lesion-induced neuronal loss (13%) but accelerated the time course of functional recovery and axonal regrowth, inducing increased numbers and sizes of myelinated axons in the facial nerve. It is interesting to note that nimodipine also enlarged the axons and the myelin sheaths in the nonlesioned facial nerve, which points to the possibility of using this substance for new clinical applications to promote axonal growth and remyelination.

Studies on a model of long term alcohol drinking

This study investigated the effects of a dihydropyridine calcium channel antagonist in a free drinking model [7] previously reported to show increased and ‘uncontrolled’ drinking. The results showed, rather than the previously reported increase in consumption, a gradual decrease in alcohol intake over 9–18 months. When the alcohol was withdrawn from one group of rats after 55 weeks free choice, the animals showed no behavioural signs of physical withdrawal, but they did demonstrate the expected elevated ethanol intake on reintroduction to ethanol after 2 weeks abstinence. A second group of rats were given 62 weeks free choice access to ethanol in groups of four, then transferred to single housing and baseline drinking levels established. Intraperitoneal injections of nimodipine 5 mg/kg, 20 mg/kg or Tween vehicle were then given once daily. Nimodipine had no effect on ethanol intake of animals with continuous access to ethanol, or of those animals withdrawn from ethanol and then reintroduced after 2 weeks of abstinence. However the unexpectedly low alcohol intake may have prevented any effects of nimodipine being seen.

Nimodipine attenuates lipid peroxidation during the acute phase of head trauma in rats.

Oxygen free radical-mediated lipid peroxidation is one of the major mechanisms of secondary damage in traumatic brain injury. We assessed the effects of nimodipine on lipid peroxidation 1 h after head trauma in rats. Nimodipine (1.5 microg/kg IV bolus injection) was given immediately after head trauma by either the carotid artery or the jugular vein. Placebo treated rats received saline by the same routes. Control rats received head trauma only. Sham-operated rats were the group without head trauma. Malondialdehyde (MDA), which is the end product of lipid peroxidation, was measured as an indicator of oxygen free radical formation in the brain tissue. The mean values for MDA in sham operated rats were 92.4 +/- 4.9 nanomoles/gram wet weight (nmol/gww) of brain tissue. In the control group, MDA content of the brain tissue was 120.8 +/- 9.4 nmol/gww. In placebo treated rats, the results were similar. In the groups receiving nimodipine via carotid artery or jugular vein, the mean values were 101.1 +/- 6.9 and 106.5 +/- 6.0 nmol/gww, respectively. These results indicate that nimodipine caused a significant decrease in lipid peroxidation when given in the acute phase of head trauma in rats. This occurred regardless of the route of injection.

Protective effect of nimodipine on behavior and white matter of rats with hydrocephalus.

Hydrocephalus, a pathological dilation of the ventricles of the brain, causes damage to periventricular white matter, at least in part, through chronic ischemia. The authors tested the hypothesis that treatment with nimodipine, an L-type calcium channel-blocking agent with demonstrated efficacy in a range of cerebral ischemic disorders, would ameliorate the adverse effects of experimental hydrocephalus. Hydrocephalus was induced in 3-week-old rats by injection of kaolin into the cisterna magna. The rats were treated by continuous administration of nimodipine or control vehicle for 2 weeks, beginning 2 weeks after induction of hydrocephalus. During the treatment period, the animals underwent repeated tests of motor and cognitive behavior. At the end of the treatment period, the rat brains were analyzed by histopathological and biochemical means. Nimodipine treatment prevented the declines in motor and cognitive behavior that were observed in untreated control rats. During the treatment period, ventricular enlargement, determined by magnetic resonance imaging, was equal in the two groups, although the corpus callosum was thicker in the treated rats. Myelin content in white matter and synaptophysin content in gray matter, an indicator of synapses, did not differ. The protective effect of nimodipine is most likely based on improved blood flow, although prevention of calcium influx-mediated proteolytic processes in axons cannot be excluded. Adjunctive pharmacological therapy may be beneficial to patients with hydrocephalus.

Radioprotective and locomotor responses of mice treated with nimodipine alone and in combination with WR-151327.

The effect of combining a radiation-protective phosphorothioate with another agent was investigated in an attempt to increase radioprotection and reduce toxicity. The calcium channel blocker nimodipine (NIMO) was administered alone (1 or 10 mg kg-1) or in combination with 200 mg kg-1 of the phosphorothioate radioprotector WR-151327 (WR) (S-3-(3-methylaminopropylamino)propylphosphorothioic acid). Radioprotection as measured (30-day survival) of mice treated i.p. 30 min before (60)Co irradiation at a dose rate of 1 Gy min-1 was evaluated in CD2F1 male mice. The effects of nimodipine and WR-151327 on locomotor activity were investigated also in a separate group of non-irradiated mice. The LD(50/30) for the Emulphor vehicle control group was 8.56. For nimodipine alone (1 or 10 mg kg-1) the LD(50/30)was 8.39 and 10.21 Gy, respectively, yielding dose modification factors (DMFs) of 0.98 and 1.19, respectively. When WR-151327 was given alone, the <LD(50/30) was 12.48 Gy (DMF = 1.46; P < 0.05 from vehicle). WR-151327 combined with 1 or 10 mg kg-1 nimodipine resulted in an LD(50/30) of 12.73 Gy (DMF 1.49, P < 0.05 from vehicle), and when WR-151327 was combined with 10 mg kg-1 nimodipine the LD(50/30) was 14.29 Gy (DMF = 1.67, P < 0.001 from WR-151327). For either dose of nimodipine, locomotor activity did not differ from vehicle. WR-151327 and WR-151327 + 1 mg kg-1 nimodipine resulted in locomotor decrements for up to 4 h post-administration (P < 0.05 from vehicle), and WR-151327 + 10 mg kg-1 nimodipine for up to 6 h (P < 0.05 from WR-151327). Therefore, although there was an additive radioprotective effect when the higher dose of nimodipine was combined with WR-151327, the locomotor decrement was also enhanced. These results demonstrate that a combination of nimodipine and a phosphorothioate such as WR-151327 may be useful as a clinical setting where behavioral and physiological side-effects can be monitored. Published in 2001 by John Wiley & Sons, Ltd.

The effects of the pre-treatment of intravenous nimodipine on Na+ -K+/Mg+2 ATPase, Ca+2/Mg+2 ATPase, lipid peroxidation and early ultrastructural findings following middle cerebral artery occlusion in the rat

Excessive calcium influx has been implicated in the pathophysiology of ischemic cerebral damage. The effects of nimodipine, a calcium antagonist, on the Na+ -K+/MG+2 ATPase activity, Ca+2/Mg+2 ATPase, lipid peroxidation, and early ultrastructural findings were examined at the acute stage of ischemia in the rat brain. Ischemia was produced by permanent unilateral occlusion of the middle cerebral artery. In Group I, the rats which had no ischemia and not received medication were used for determining Na+ -K+/Mg+2 ATPase, Ca+2/Mg+2 ATPase, the extent of lipid peroxidation by measuring the malondialdehyde content and normal ultrastructural findings. In Group II, the rats which had only subtemporal craniectomy without occlusion and received saline solution were used for determining the effect of the surgical procedure on the biochemical indices and ultrastructural findings. In Group III, the rats received saline solution following the occlusion in the same amount of nimodipine and in the same duration as used in Group IV. In Group IV, nimodipine pre-treatment 15 min before occlusion (µgkg-1 min-1 over a 10 min period) was applied i.v. Na+ -K+/Mg+2 ATPase and Ca+2/Mg+2 ATPase activities decreased significantly and promptly as early as 10 min and remained at a lower level than the contralateral hemisphere in the same group and at the normal level in Group I. Nimodipine pre-treatment immediately attenuated the inactivation of Na+ -K+/Mg+2 ATPase (p < 0.05) but there was no change on Ca+2/Mg+2 ATPase activity (p < 0.05). Malondialdehyde content increased significantly in Group III following ischemia as early as 30 min. Nimodipine pre-treatment decreased the malondialdehyde level in Group IV (p < 0.05). This study supports the possibility that nimodipine pre-treatment effects the membrane stabilizing properties via inhibiting the lipid peroxidation and subsequently restoring some membrane bound and lipid dependent enzymes' activity such as Na+ -K+/Mg+2 ATPase and the ultrastructural findings. [Neurol Res 2001; 23: 96-104]

Acute protective effect of nimodipine and dimethyl sulfoxide against hypoxic and ischemic damage in brain slices

Nimodipine and dimethyl sulfoxide (DMSO) were tested (alone and in combination) regarding their ability to increase hypoxic tolerance of brain slices under ‘hypoxic’ (deprivation of oxygen) or ‘ischemic’ (hypoxia+withdrawal of glucose) conditions. Direct current (DC) and evoked potentials were recorded in the CA1 region of hippocampal slices of adult guinea pigs. After induction of hypoxia or ischemia, the latency of anoxic terminal negativity (ATN) of the DC potential was determined during superfusion with artificial cerebrospinal fluid alone (aCSF), and during superfusion with aCSF containing DMSO [0.1% (14.1 mmol/l) and 0.4% (56.3 mmol/l)] with the addition of nimodipine (40 μmol/l). Latencies of ATN with first hypoxia were 6.7±3.7 min in the control group, 9.3±4.2 min in the 0.4% DMSO group and 12.3±5.5 min ( P=0.007) in the nimodipine/0.4% DMSO group. Latencies of ATN with first ischemia were 2.9±2 min in the control group, 4.1±1.6 min in the 0.1% DMSO group, 7.1±3.9 min in the 0.4% DMSO group ( P=0.006), 5.3±1.5 min in the nimodipine/0.1% DMSO group and 7.6±3 min ( P<0.001) in the nimodipine/0.4% DMSO group. DMSO (0.4%), either alone or in combination with nimodipine, increase the latency of the ATN after acute onset of hypoxia and ischemia.

Treatment with nimodipine or mannitol reduces programmed cell death and infarct size following focal cerebral ischemia.

The present study was conducted to evaluate the effects of nimodipine and mannitol on infarct size and on the amount of apoptosis after transient focal cerebral ischemia. Focal cerebral ischemia was induced in male Sprague-Dawley rats (weight 300-380 g) by transient occlusion of the right middle cerebral artery (MCAO) using an intraluminal thread model. All animals underwent ischemia for 2 h, followed by 24 h of reperfusion. Group I (n=16) was untreated. Group II (n=16) received 15% mannitol (1 g/kg as bolus) and group III (n=9) received 15 microg/kg/h nimodipine intravenously beginning 15 min prior to MCAO. Twenty-four hours after reperfusion, the brain was taken and sectioned in coronal slices. The slices were stained with H&E and with the transferase dUTP nick-end labeling (TUNEL) technique. Histopathological analysis revealed a significant (P<0.05) decrease in infarct size in the striatum with both drugs: mannitol (group II) 25.4+/-5.9% and nimodipine (group III) 21.5+/-11.0% versus control (group I) 34.9+/-7.0% and in the cortex 2.7+/-2.0% (group II) and 6.3+/-2.4% (group III) versus control 14.4+/-9.0% (group I). The number of apoptotic cells was statistically lower in the therapy groups (group III 9.6, group II 25.8) versus control (group I 57.9) (Mann-Whitney-Wilcoxon U-test Z>1.96, P<0.05). This study indicates that mannitol and nimodipine provide neuroprotection by preventing both the necrotic and apoptotic components of cell death after transient focal cerebral ischemia and may be effective as neuroprotective drugs for cerebrovascular surgery.

Opposite effects of T- and L-type Ca 2+ channels blockers in generalized absence epilepsy

The role of the T-type Ca 2+ channel blocker, ethosuximide, the L-type Ca 2+ channel blocker, nimodipine and L-type Ca 2+ channel opener, BAY K8644 (1,4 Dihydro-2,6-dimethyl-5-nitro-4-[trifluoromethyl)-phenyl]-3-pyridine carboxylic acid methyl ester), was investigated on spike-wave discharges in WAG/Rij rats. This strain is considered as a genetic model for generalized absence epilepsy. A dose-dependent decrease in the number of spike-wave discharges was found after i.c.v. ethosuximide, an increase after i.p. nimodipine and a decrease after i.c.v. BAY K8644. BAY K8644 was also able to antagonise the effects of nimodipine. Preliminary data were obtained with two conotoxins, MVIIC and GVIA, which block P/Q-type and N-type Ca 2+ channels, respectively. Only after i.c.v. administration of ω-conotoxin GVIA were the number and duration of spike-wave discharges reduced, but animals showed knock-out lying. The latter suggests behavioural or toxic effects and that the decrease in spike-wave activity cannot unequivocally be attributed to blockade of N-type Ca 2+ channels. It can be concluded that T- and L-type Ca 2+ channel blockers show opposite effects on spike-wave discharges. Furthermore, these effects are difficult to explain in terms of a model for spindle burst activity in thalamic relay cells proposed by McCormick and Bal [Sleep and arousal: thalamocortical mechanisms. Ann. Rev. Neurosci. 20 (1997) 185].

Nimodipine improves the disruption of spatial cognition induced by cerebral ischemia

The direct neuroprotective effect of nimodipine, a central Ca antagonist, was investigated in in vitro experiments. Also, in in vivo experiments, the effects of nimodipine and amlodipine, a noncentral Ca antagonist, on rat cerebral ischemia models developing by different mechanisms were compared. In an in vitro ischemic model using acidotic and hypoglycemic rat cerebellar granule cells, nimodipine directly protects against brain neuronal cell damage. In in vivo models of single (one 10-min, four-vessel occlusion) and repeated rat cerebral ischemia (two 10-min, four-vessel occlusions; a 50-min interval), the impairment observed 24 h after the single ischemic procedure was likely to be prevented by nimodipine (0.1–5mg/kg, i.p.). At 7 days after the repeated cerebral ischemia, the disruption of spatial cognition was significantly prevented by nimodipine (5 mg/kg, i.p.) but not amlodipine (5 mg/kg, i.p.), which was given after each ischemia. These results indicated that nimodipine may protect neuronal cells by a more persistent mode of action, that is, nimodipine may enter into the cell and control the intracellular Ca ion cascade by inhibiting excessive Ca 2+ influx into the mitochondria.

The Effect of Nimodipine on Opioid Antagonist-Induced Upregulation and Supersensitivity

Regulation of calcium flux has been suggested to play a role in acute and chronic effects of opioids. Previous studies have shown calcium channel blockers can inhibit opioid agonist-induced downregulation of μ-opioid receptors and may reduce the magnitude of tolerance. In the present study, we determined if calcium channel blockade would affect increases in opioid receptor density and functional supersensitivity produced by chronic opioid antagonist treatment in the mouse. Mice were implanted subcutaneously with a 15-mg naltrexone (NTX) or placebo pellet. Mice also were implanted with an osmotic minipump that infused nimodipine (100 μg/kg/day) or a second placebo pellet. This protocol yielded four groups: nimodipine–NTX; nimodipine–placebo; placebo–NTX; placebo–placebo. On the seventh day, pumps and pellets were removed. Twenty-four hours later, a morphine dose–response study was conducted (tail flick); or mice were sacrificed and saturation binding studies ([ 3H]DAMGO) were performed in whole brain. NTX treatment significantly increased the analgesic potency of morphine by ∼60%. Nimodipine increased the potency of morphine by ∼50%. For mice treated with both nimodipine and NTX, there was an additive effect on morphine potency (∼120% increase). In binding studies, NTX increased the density of μ-opioid receptors similarly (∼60–70%) in the presence and absence of nimodipine treatment, with no change in affinity. No effect of chronic nimodipine alone on μ-opioid receptor binding was observed. These data indicate that NTX-induced upregulation and supersensitivity are independent of calcium channel blockade by nimodipine. These results contrast with those from tolerance and downregulation studies, and confirm suggestions that different substrates mediate chronic opioid agonist and antagonist-induced effects in vivo. Finally, in a separate study, morphine potency was unaffected by acute nimodiopine (100 μg/kg; SC), suggesting that prolonged exposure to this calcium channel blocker is required to increase morphine potency.

The effects of nimodipine on vecuronium-induced neuromuscular blockade

Nimodipine, a calcium channel blocking drug, is used in the treatment of cerebral arterial spasm after subarachnoid haemorrhage due to bleeding from an intracranial aneurysm. The purpose of this study was to evaluate the effects of nimodipine on neuromuscular blockade after vecuronium had been given to facilitate tracheal intubation and maintenance of muscle paralysis in patients undergoing clipping of intracranial aneurysm. Twenty patients were divided into two groups: a control group (n = 10) who received no calcium channel blocking drug, and a nimodipine group (n = 10) consisting of patients treated with nimodipine at clinically used doses of 0.03 mg kg(-1) h(-1) pre- and perioperatively. Anaesthesia was induced with atropine 10 microg kg(-1), dehydrobenzperidol 5 mg, fentanyl 5 microg kg(-1), thiopental 5 mg kg(-1) and maintained with a mixture of N2O and isoflurane (0.5-1% inspired concentration) in O2, and additional doses of fentanyl 2.5 microg kg(-1). Neuromuscular responses were monitored by acceleromyograpy. The first twitch of the train-of-four response (T1) was considered as twitch height. After a stabilization period, an intubating dose of vecuronium 0.1 mg kg(-1) was administered. The onset of action, the time of first appearance of T1 and clinical duration of action were recorded. Then, maintenance doses of vecuronium 0.03 mg kg(-1) were administered twice more when T1 had recovered to 25% of control twitch height. The study ended when the recordings of the 3rd 25% T1 recovery had been obtained. There were no statistical differences in the onset time (120+/-44 s in the control group, 141+/-33 s in the nimodipine group), in the first appearance time of T1 (28+/-6 min in the control group, 30+/-8 min in the nimodipine group), and in the times for 25% recovery in T1 (41+/-11, 32+/-2, 40+/-13 min in the control group, respectively, and 44+/-16, 36+/-15, 38+/-15 min in nimodipine group, respectively) between the groups studied. The time between the injection of the intubating dose of vecuronium and the third recovery of T1-25% of control was not significantly different between the control group (113+/-34 min) and the nimodipine group (117+/-42 min). This study indicates that nimodipine does not have any significant effect on the time course of action of vecuronium including the onset time and its clinical duration of action after the initial and the two maintenance doses in these patients.

The effects of nimodipine on vecuronium-induced neuromuscular blockade

Nimodipine, a calcium channel blocking drug, is used in the treatment of cerebral arterial spasm after subarachnoid haemorrhage due to bleeding from an intracranial aneurysm. The purpose of this study was to evaluate the effects of nimodipine on neuromuscular blockade after vecuronium had been given to facilitate tracheal intubation and maintenance of muscle paralysis in patients undergoing clipping of intracranial aneurysm. Twenty patients were divided into two groups: a control group (n = 10) who received no calcium channel blocking drug, and a nimodipine group (n = 10) consisting of patients treated with nimodipine at clinically used doses of 0.03 mg kg−1 h−1 pre- and perioperatively. Anaesthesia was induced with atropine 10 μg kg−1, dehydrobenzperidol 5 mg, fentanyl 5 μg kg−1, thiopental 5 mg kg−1 and maintained with a mixture of N2O and isoflurane (0.5-1% inspired concentration) in O2, and additional doses of fentanyl 2.5 μg kg−1. Neuromuscular responses were monitored by acceleromyography. The first twitch of the train-of-four response (T1) was considered as twitch height. After a stabilization period, an intubating dose of vecuronium 0.1 mg kg−1 was administered. The onset of action, the time of first appearance of T1 and clinical duration of action were recorded. Then, maintenance doses of vecuronium 0.03 mg kg−1 were administered twice more when T1 had recovered to 25% of control twitch height. The study ended when the recordings of the 3rd 25% T1 recovery had been obtained. There were no statistical differences in the onset time (120 ± 44 s in the control group, 141 ± 33 s in the nimodipine group), in the first appearance time of T1 (28 ± 6 min in the control group, 30 ± 8 min in the nimodipine group), and in the times for 25% recovery in T1 (41 ± 11, 32 ± 2, 40 ± 13 min in the control group, respectively, and 44 ± 16, 36 ± 15, 38 ± 15 min in nimodipine group, respectively) between the groups studied. The time between the injection of the intubating dose of vecuronium and the third recovery of T1-25% of control was not significantly different between the control group (113 ± 34 min) and the nimodipine group (117 ± 42 min). This study indicates that nimodipine does not have any significant effect on the time course of action of vecuronium including the onset time and its clinical duration of action after the initial and the two maintenance doses in these patients.