Effect Of Nimodipine Research Articles

Neuroprotective effects of nimodipine and nifedipine in the NGF-differentiated PC12 cells exposed to oxygen-glucose deprivation or trophic withdrawal

The goal of this study was to compare the neuroprotective properties of the l-type Ca2+ channel blockers, nimodipine and nifedipine, using nerve growth factor (NGF)-differentiated PC12 neuronal cultures exposed to oxygen-glucose deprivation (OGD) and trophic withdrawal-induced cell death. Nimodipine (1–100μM) conferred 65±13% neuroprotection upon exposure to OGD and 35±6% neuroprotection towards different trophic withdrawal-induced cell death measured by lactate dehydrogenase and caspase 3 activities. The time window of nimodipine conferred neuroprotection was detected during the first 5h but not at longer OGD exposures. Nifedipine (1–100μM), to a lower potency than nimodipine, conferred 30–55±8% neuroprotection towards OGD in PC12 cells and 29±5% in rat hypocampal slices, and 10±3% neuroprotection at 100μM towards trophic withdrawal-induced PC12 cell death. The ability to demonstrate that nimodipine conferred neuroprotection in a narrow therapeutic time-window indicates that the OGD PC12 model mimics the in vivo models and therefore suitable for neuroprotective drug discovery and development.

Nimodipine Improves Regional Cerebral Blood Flow and Suppresses Inflammatory Factors in the Hippocampus of Rats with Vascular Dementia

To study the effect of nimodipine on hippocampal regional cerebral blood flow (rCBF) and proinflammatory cytokines in rats with experimental vascular dementia. Male Sprague Dawley rats were randomly divided into four groups (n = 15/group): sham operated controls (group A); focal cerebral ischaemia (group B); vascular dementia (group C); and vascular dementia treated with 20 mg/kg nimodipine daily (group D). The Morris water maze test evaluated learning and memory, and magnetic resonance perfusion-weighted imaging was used to measure rCBF. Hippocampal levels of nuclear factor-κB (NF-κB), tumour necrosis factor-α (TNF-α) and interleukin 1β (IL-1β) were measured. Compared with group C, rats in group D demonstrated significantly improved learning ability and significantly increased hippocampal rCBF. The levels of NF-κB, TNF-α and IL-1β were significantly lower in group D than in group C. Hippocampal nerve cell morphology was abnormal in group C but near normal in group D. Nimodipine improved the symptoms of cognitive impairment, increased rCBF, reduced hippocampal cytokine levels and alleviated neuronal injury in the hippocampus of rats with experimental vascular dementia.

Preventive Effect of Nimodipine on Early Postnatal Modifications of the Protein Spectrum in the Brain of Rats Subjected to Prenatal Stress

Using electrophoretic analysis, we studied peculiarities of the spectrum of soluble proteins in the preoptic region (PR), mediobasal hypothalamus (MBH), and hippocampus of 5-day-old rats, males and females, offspring of mothers subjected to 1-h-long immobilization stress within the last week of pregnancy (daily, from day 15 to day 21). A part of the pregnant rats of the experimental group were treated with a blocker of L-type calcium channels, nimodipine (20 mg/kg perorally, 30 min before the beginning of immobilization). The rats, which were descendants of intact mothers, demonstrated clear sex-related differences of the indices of contents of proteins with the molecular mass of 14.3 and 24.0 kDa. In the PR, the contents of these proteins were higher in females, while amounts of 34.7 and 66.0 kDa proteins in this structure were greater in males. There was no sex-related dimorphism of the protein composition in the MBH and hippocampus of control animals. Prenatal stress smoothed sex-related differences in the content of 66.0 kDa protein and, simultaneously, induced such differences in the amount of 18.4 kDa protein in the PO. The formation of sexrelated dimorphism of the protein spectrum in the MBH and hippocampus was a special effect of prenatal stress. Peroral introduction of nimodipine before stressing (immobilization) of pregnant females interfered with manifestations of the influence of prenatal stress upon the content of 66.0 kDa protein in the PR of 5-day-old descendants. A protective effect of nimodipine in the MDH was manifested with respect to prenatal stress-induced changes in the content of 34.7 kDa protein, while in the hippocampus this was found for 40.0 kDa protein. The results obtained allow us to conclude that calcium signalization is significantly involved in the mechanism of realization of early effects of prenatal stress.

Artificial Cold Wave-Induced Cerebral Infarction in Rats with Carotid Atherosclerosis

To investigate the effects of cold on blood pressure, serum endothelin-1 content, serum nitric oxide content, and morbidity of cerebral infarction, as well as assess the therapeutic effect of nimodipine. A total of 200 rats were initially assigned to a normal group (n = 10), sham group (n = 10), and carotid atherosclerosis group (n = 180), and subsequently the animals in the carotid atherosclerosis group were randomly assigned to three groups: non-cold (n = 59), cold treatment (n = 58), and nimodipine (n = 58). Rats in the cold and nimodipine groups experienced an artificial cold wave. The temperature was set at 22°C for 12 h (7:00 am to 7:00 pm) and then at 4°C for another 12 h (7:00 pm to 7:00 am), representing a cycle. The animals underwent three cycles of cold. Rats in the nimodipine group were treated with nimodipine and those in the cold group with given an equal volume of intragastric normal saline for 3 days. Hematoxylin and eosin staining showed features of carotid atherosclerosis in all animals. Blood pressure fluctuated with alteration of temperature. A temperature decrease was accompanied by an increase of blood pressure and elevation of serum levels of endothelium-1 and nitric oxide. In addition, although nimodipine could prevent the cold-induced increase of blood pressure and elevation of serum endothelium-1 and nitric oxide levels, it had no effect on blood pressure fluctuation or morbidity of cerebral infarction. The results suggest that dramatic variation in temperature is one of the main causes of cold-induced fluctuation of blood pressure.

Acute Effects of Nimodipine on Cerebral Vasculature and Brain Metabolism in High Grade Subarachnoid Hemorrhage Patients

Nimodipine is the only medication shown to improve outcomes after aneurysmal subarachnoid hemorrhage (SAH). Preliminary theories regarding the mechanism by which it prevents vasospasm have been challenged. The acute physiologic and metabolic effects of oral Nimodipine have not been examined in patients with poor-grade SAH. This is an observational study performed in 16 poor-grade SAH patients undergoing multimodality monitoring who received oral Nimodipine as part of routine clinical care. A total of 663 doses of Nimodipine were observed. Changes in physiologic measurements including MAP, CPP, ICP, P(bt)O(2), and CBF were examined. Administration of oral Nimodipine was associated with a 1.33 mmHg decrease in MAP (P < 0.001) and a 1.22 mmHg decrease in CPP (P < 0.001). When administration of Nimodipine was associated with MAP decreases, P(bt)O(2) (1.03 mmHg; P < 0.001) and CBF (0.39 ml/100 g/min; P = 0.002) also decreased. Despite CPP targeted therapy with vasopressor medication, oral Nimodipine was associated with a decrease in MAP and CPP. When Nimodipine administration was associated with a decrease in MAP, there were concomitant drops in P(bt)O(2) and CBF. These findings suggest that MAP support after oral Nimodipine may be important to maintain adequate CBF in patients with poor-grade subarachnoid hemorrhage.

The therapeutic effects of melatonin and nimodipine in rats after cerebral cortical injury

Secondary brain injury starts after the initial traumatic impact and marked by an increase in the intracellular calcium concentrations.This cascadeeventually results in membrane lipid peroxidation and neuronal cell death. We investigated the neuro-protective effects of nimodipine and melatonin in 38 rats after 6 hours of head trauma using the cortical impact injury model of Marmarou. Brain water in the melatonin-given group decreased significantly comparing to that of control group the brain water in the nimodipine given group increased significantly comparing to that of trauma group. Histopathologically, brain edema was significantly low in melatonin-administered group comparing to that of control group while there were no changes in brain edema in the nimodipine given group and in the group that both nimodipine and melatonin were administered in combination. MDA levels in the brain tissues were significantly lower in the melatonin and nimodipine groups comparing to those of trauma and control group however this difference was by far significant in melatonin group comparing to nimodipine group. Melatonin appears to have neuro-protective effects on the secondary brain damage while nimodipine and nimodipine plus melatonin combination did not show such neuro-protective effects on the secondary brain injury.

POST TRAUMATIC SUB ARACHNOID HEMORRHAGE

Objective: To study the effect of Nimodipine on headache associated with post traumatic sub arachanoid hemorrhage. Study Design: prospective study Setting: This study was conducted at the Department of Neurosurgery &amp; General Surgery, District Headquarters Hospital Rawalpindi. Period: 6 months Methods: 60 Patients from both genders, undergoing hospital admissions that fulfill the inclusion criteria were included in the study. Results: 12 patients were lost due to poor patient follow up. Of the remaining 48 patients, 29 (60.4%) patients suffered road side accidents, 12 (25%) had assaults and 7(14.6%) had fall. The patients were classified according to Hunt and Hess and Fischer Grading. 34 patients had grade 1 and 14 had grade 2 injuries according Hunt and Hess classification. 31 had grade 1 injuries and 17 had grade 2 injuries according to Fischer Grading. The mean age was 34.02 years with a range of 4 to 71. The mean interval since trauma &amp; admission were 1.4 hour. The patient score on the visual analog pain scale before treatment had a mean of 4.46. The patient score on visual analog scale after treatment was 2.33 and P-value was calculated to be &lt;0.001. Conclusions: The above results signify that Nimodipine should be prescribed to patients with Grade 1 and 2 post traumatic sub arachanoid hemorrhage. Headache was considerably reduced after the use of nimodipine.

Differential Effect of Nimodipine in Attenuating Iron-Induced Toxicity in Brain- and Blood–Brain Barrier-Associated Cell Types

Metal homeostasis is increasingly being evaluated as a therapeutic target in stroke and neurodegenerative diseases. Metal dysregulation has been shown to lead to protein aggregation, plaque formation and neuronal death. In 2007, we first reported that voltage-gated calcium channels act as a facile conduit for the entry of free ferrous (Fe(2+)) ions into neurons. Herein, we evaluate differential iron toxicity to central nervous system cells and assess the ability of the typical L-type voltage-gated calcium channel blocker nimodipine to attenuate iron-induced toxicity. The data demonstrate that iron sulfate induces a dose-dependent decrease in cell viability in rat brain endothelial cells (RBE4; LC(50) = 150 μM), neuronal cells (Neuro-2α neuroblastoma; LC(50) = 400 μM), and in astrocytes (DI TNC1; LC(50) = 1.1 mM). Pre-treatment with nimodipine prior to iron sulfate exposure provided a significant (P < 0.05) increase in viable cell numbers for RBE4 (2.5-fold), Neuro2-α (~2-fold), and nearly abolished toxicity in primary neurons. Astrocytes were highly resistant to iron toxicity compared to the other cell types tested and nimodipine had no (P > 0.05) protective effect in these cells. The data demonstrate variable susceptibility to iron overload conditions in different cell types of the brain and suggest that typical L-type voltage-gated calcium channel blockers (here represented by nimodipine), may serve as protective agents in conditions involving iron overload, particularly in cell types highly susceptible to iron toxicity.

Nimodipine promotes regeneration of peripheral facial nerve function after traumatic injury following maxillofacial surgery: An off label pilot-study

BackgroundAnimal tests, retro- and prospective clinical trials in neurosurgical departments have shown a beneficial effect of nimodipine on the preservation and recovery of facial and acoustic nerve function following vestibular schwannoma surgery.Encouraged by these positive results a pilot-study of nimodipine treatment in patients with a peripheral facial nerve (FN) paresis following maxillofacial surgery was performed. The rate and time of FN recovery were analysed and compared with the results in the literature. MethodsThirteen patients (n = 13) suffering from a moderate (1/13) up to a severe (12/13) peripheral FN paresis after maxillofacial surgery were treated with orally administered nimodipine. The anatomical main course of the FN was preserved in all patients with a 2nd to 3rd degree of Sunderland-injury (Sunderland, 1951). After no evidence of a spontaneous regeneration had shown, oral medication with nimodipine was started as an “off-label” use. ResultsAn improvement of the FN function correlated to the start of the vasoactive medication and as a consequence a recovery of the FN function up to House–Brackmann (HB) grade I°–II° was observed in all the patients within a period of 2 months after the beginning of treatment (p = 0.00027). ConclusionsThe clinical observations in these patients suggest a positive effect of nimodipine on the acceleration of peripheral FN regeneration after surgically caused trauma. The results of this pilot-study are very promising. A prospective study with a larger number of patients is planned to approve the beneficial effect of nimodipine on the peripheral FN in maxillofacial or otorhinolaryngological surgery.

Nimodipine alleviates apoptosis-mediated impairments through the mitochondrial pathway after spinal cord injury

Abstract Spinal cord injury (SCI) remains an unsolved human health challenge. To alleviate the impairments of SCI, we studied the therapeutic effect of nimodipine (an L-type Ca2+ channel antagonist) on functional recovery from SCI using Nystrom’s method in a mouse model. Eighty-four mice were divided into three groups: control group in which only vertebral plates were cut off without causing any spinal injuries; SCI; and SCI with nimodipine treatment. We assessed the histopathology, apoptosis detection, cell cycle, mitochondrial transmembrane potential, bcl-2/bax and caspase-3 levels of tissue 8 h, 1 d, 3 d and 4 d after trauma to evaluate rehabilitation. Behavioral performances were also assessed before and after nimodipine treatment. Results from inclined plane tests, motor score assessment and histological observations indicated that mice in the nimodipine-treated group rehabilitated better than those in the SCI group. The ratio of apoptosis, caspase-3 and bax expression in the nimodipine-treated group were significantly lower than those in the SCI group. The mitochondrial membrane potential and bcl-2 expression were up-regulated in the nimodipine-treated group. Taken together, our results indicate that the inhibition of calcium flux by nimodipine could reduce apoptosis processes and tissue damage through a mitochondrial pathway after spinal cord trauma.

Effects of nimodipine on rabbits with symptomatic cerebral vasospasm

To investigate the effects of nimodipine on symptomatic cerebral vasospasm in rabbits. Twenty four japanese white rabbits which ligation of bilateral common carotid arteries and no neurological deficits were randomized to sham-operation, subarachnoid hemorrhage (SAH) and nimodipine which injected of nimodipine 0.1 mg/kg, continuous vein administration 5 day. The behavior scores, neurological scores were observed everyday and cerebral angiography changes were measured twice by 3D-CTA, and basilar artery was removed for pathological examination after last CTA examination. In SAH group, The basilar artery were significantly vasoconstrictive on 5 days, neurological scores were increased, and the basilar artery was found apoptosis-like changes under light microscopic and electron microscope. Nimodipine group could not dilated the basilar artery arteriospasm after SAH, but it could attenuate neurological deficit, and obviously alleviate the pathological changes of basilar artery. Nimodipine could not vasodilation of basilar artery in SCVS, but obviously could alleviate neurological changes and pathological changes of basilar artery in rabbits with symptomatic cerebral vasospasm.

Neuroprotective Effects by Nimodipine Treatment in the Experimental Global Ischemic Rat Model : Real Time Estimation of Glutamate

Glutamate is a key excitatory neurotransmitter in the brain, and its excessive release plays a key role in the development of neuronal injury. In order to define the effect of nimodipine on glutamate release, we monitored extracellular glutamate release in real-time in a global ischemia rat model with eleven vessel occlusion. TWELVE RATS WERE RANDOMLY DIVIDED INTO TWO GROUPS: the ischemia group and the nimodipine treatment group. The changes of extracellular glutamate level were measured using microdialysis amperometric biosensor, in coincident with cerebral blood flow (CBF) and electroencephalogram. Nimodipine (0.025 µg/100 gm/min) was infused into lateral to the CBF probe, during the ischemic period. Also, we performed Nissl staining method to assess the neuroprotective effect of nimodipine. During the ischemic period, the mean maximum change in glutamate concentration was 133.22±2.57 µM in the ischemia group and 75.42±4.22 µM (p<0.001) in the group treated with nimodipine. The total amount of glutamate released was significantly different (p<0.001) between groups during the ischemic period. The %cell viability in hippocampus was 47.50±5.64 (p<0.005) in ischemia group, compared with sham group. But, the %cell viability in nimodipine treatment group was 95.46±6.60 in hippocampus (p<0.005). From the real-time monitoring and Nissl staining results, we suggest that the nimodipine treatment is responsible for the protection of the neuronal cell death through the suppression of extracellular glutamate release in the 11-VO global ischemia model of rat.

Alteration in voltage-dependent calcium channels in dog basilar artery after subarachnoid hemorrhage

The L-type Ca++ channel antagonists like nimodipine have limited efficacy against vasospasm after subarachnoid hemorrhage (SAH). The authors tested the hypothesis that this is because SAH alters these channels, rendering them less responsible for contraction. Basilar artery smooth muscle cells were isolated 4, 7, and 21 days after SAH in dogs, and Ca++ channel currents were recorded in 10-mmol/L barium. Proteins for α₁ subunits of L-type Ca++ channels were measured by immunoblotting and isometric tension recordings done on rings of the basilar artery. High voltage-activated (HVA) Ca++ channel currents were significantly decreased and low voltage-activated (LVA) currents increased during vasospasm 4, 7, and 21 days after SAH (p < 0.05). Vasospasm was associated with a significant decrease in the number of cells with negligible LVA current while the number of cells in which the LVA current formed greater than 50% of the maximal current increased (p < 0.01). Window currents through LVA and HVA channels were significantly reduced. All changes correlated with the severity of vasospasm. There was an increase in protein for Ca(v)3.1 and Ca(v)3.3 α₁ subunits that comprise T-type Ca++ channels, a decrease in L-type (Ca(v)1.2 and Ca(v)1.3) and an increase in R-type (Ca(v)2.3) Ca++ channel α₁ subunits. Functionally, however, isometric tension studies showed vasospastic arteries still relaxed with nimodipine. Voltage-dependent Ca++ channels are altered in cerebral arteries after SAH. While decreased L-type channels may account for the lack of efficacy of nimodipine clinically, there may be other reasons such as inadequate dose, effect of nimodipine on other cellular targets, and mechanisms of vasospasm other than smooth muscle contraction mediated by activation of L-type Ca++ channels.

Antagonism of R-Type Calcium Channels Significantly Improves Cerebral Blood Flow after Subarachnoid Hemorrhage in Rats

The effects of R-type calcium channels on cerebral blood flow (CBF) and vasospasm pathways following subarachnoid hemorrhage (SAH) have not been well studied. The aim of this study was to investigate the role of R-type calcium channels in vasospasm development and treatment. Sixty-five rats were randomly divided into four groups: sham (n = 14), SAH (n = 17), SAH + nimodipine (n = 17), and SAH + SNX-482 (n = 17). A prechiasmatic SAH model was constructed on day 0. Then 5 μg of nimodipine (an L-type calcium channel antagonist) or 0.1 μg of SNX-482 (an R-type calcium channel antagonist) was infused intracisternally on days 1 and 2. On day 3, neurological status was evaluated and CBF was determined using fluorescent microspheres. The extent of myosin light chain-2 (MLC2) phosphorylation was determined by urea-glycerol polyacrylamide gel electrophoresis, followed by immunoblotting. The relative presence of R-type calcium channels and calponin was determined by SDS polyacrylamide gel electrophoresis, followed by immunoblotting. Numbers of R-type calcium channels increased following SAH, and neurological deficit, CBF reduction, and enhancement of MLC2 phosphorylation as well as calponin degradation were all found to be present. There were no statistically significant differences in neurological scores among the SAH, SAH + nimodipine, and SAH + SNX-482 groups. Nimodipine had no significant effect on CBF reduction compared to the SAH group (p > 0.008), whereas SNX-482 significantly inhibited CBF reduction (p < 0.008). Both MLC2 phosphorylation and calponin degradation appeared to be inhibited by SNX-482, whereas the effects of nimodipine were relatively blunted. We concluded that an R-type calcium channel antagonist may improve CBF following SAH by partially inhibiting MLC2 phosphorylation and calponin degradation, and may exceed the potential of an L-type calcium channel antagonist, which suggests a more crucial role for R-type calcium channels in the development of SAH vasospasm and its treatment.

Effects of nimodipine on brain AQP4 and ZO-1 expressions in rat’s brain after serious systemic thermal injury

Effects of nimodipine on brain AQP4 and ZO-1 expressions in rat’s brain after serious systemic thermal injury

Significance and expression of FKHR and AKT after subarachnoid hemorrhage in rat brain cortex

To study the significance and expression of FKHR and AKT after subarachnoid hemorrhage (SAH) in rat brain cortex. Twenty-four rats were randomly divided into three groups: sham, SAH and SAH plus nimodipine (n=8 each). A reliable SAH model was established by double injections of blood into cistern magna in Wistar rats. The neurological scores were measured by Loeffler and the expressions of FKHR, P-FKHR, AKT and P-FKHR detected by Western blot. Compared with sham group, the neurological score of SAH group obviously decreased (P < 0.05), the expression of FKHR became elevated in rat cortex (P < 0.01), the expression of AKT had no change and the expressions of P-AKT and P-FKHR obviously decreased (all P < 0.01). But the neurological score markedly increased (P < 0.01) and the expressions of P-AKT and P-FKHR became elevated (all P < 0.01) after administration of nimodipine. Both P-AKT and P-FKHR are involved in the process of brain cortex damage induced by SAH. The protective effects of nimodipine on brain injury induced by SAH may be related to the elevated expressions of P-AKT and P-FKHR in brain cortex.

Nimodipine Enhancement of α2 Adrenergic Modulation of NMDA Receptor via a Mechanism Independent of Ca2+Channel Blocking

To further understand alpha2 receptor signaling in the retina and the mechanisms that mediate ocular beneficial effects of brimonidine (an alpha2 agonist) and nimodipine (an L-type Ca(2+) channel blocker). The authors used in situ retinal ganglion cells (RGCs) in the isolated rat retina to characterize alpha2 modulation of NMDA receptor function and a rabbit retinal NMDA excitotoxicity model to verify in vitro findings under in vivo conditions. Electrophysiological (whole-cell patch clamp) recordings and Ca(2+) imaging were used to characterize NMDA receptor function and to verify the effect of various Ca(2+) channel blockers. In vivo drug application in rabbits was achieved by intravitreal injections. Application of NMDA elicited a robust whole-cell inward current in individual in situ RGCs voltage clamped at -70 mV. Pretreatment with brimonidine significantly reduced NMDA-elicited currents in RGCs. This suppressive effect of brimonidine was substantially enhanced by background addition of nimodipine or isradipine, but not by diltiazem, verapamil, or cadmium. This effect of nimodipine was blocked by either a selective alpha2 antagonist, a cyclic adenosine monophosphate (cAMP) analogue, or an adenylate cyclase activator, indicating that nimodipine acts through the alpha2 receptor-G(alphai)-coupled pathway. Brimonidine protects RGCs in the rabbit excitotoxicity model. This brimonidine protection is also enhanced significantly by application of nimodipine but not of diltiazem. These in vitro and in vivo findings demonstrate a novel neural mechanism involving nimodipine enhancement of alpha2 signaling in RGCs. This nimodipine effect appears to be independent of its classic L-type Ca(2+) channel-blocking action.

Neuroprotective effect of nimodipine and nooglutyl in rats with experimentally produced hemorrhagic stroke

One of the most common reasons of mortality is cerebral blood supply disturbance, ischemic and hemorrhagic strokes. Although modern pharmacology disposes of a wide range of various remedies effecting different phases of pathologic processes cascade that takes place in case of a stroke, therapy is not always successful; consequences of stroke are particularly difficult in response to treatment. This investigation was carried out with purpose to examine the neuroprotective properties of well known drug Nimodipine and a soluble form of new drug Nooglutyl (N- (5-oxinicotinoyl) l glutamic acid), an agent with nootropic and antihypoxic activity, a positive modulator of AMPA subtype of glutamatergic receptors.

A highly energetic process couples calcium influx through L-type calcium channels to insulin secretion in pancreatic β-cells

Calcium (Ca(2+)) influx is required for the sustained secretion of insulin and is accompanied by a large rate of energy usage. We hypothesize that the energy usage reflects a process [Ca(2+)/metabolic coupling process (CMCP)] that couples Ca(2+) to insulin secretion by pancreatic islets. The aim of the study was to test this hypothesis by testing the effect of inhibiting candidate Ca(2+)-sensitive proteins proposed to play a critical role in the CMCP. The effects of the inhibitors on oxygen consumption rate (OCR), a reflection of ATP usage, and insulin secretion rate (ISR) were compared with those seen when L-type Ca(2+) channels were blocked with nimodipine. We reasoned that if a downstream Ca(2+)-regulated site was responsible for the OCR associated with the CMCP, then its inhibition should mimic the effect of nimodipine. Consistent with previous findings, nimodipine decreased glucose-stimulated OCR by 36% and cytosolic Ca(2+) by 46% and completely suppressed ISR in rat pancreatic islets. Inhibitors of three calmodulin-sensitive proteins (myosin light-chain kinase, calcineurin, and Ca(2+)/calmodulin-dependent protein kinase II) did not meet the criteria. In contrast, KN-62 severed the connection between Ca(2+) influx, OCR, and ISR without interfering with Ca(2+) influx. In the presence of nimodipine or KN-62, potentiators of ISR, acetylcholine, GLP-1, and arginine had little effect on insulin secretion, suggesting that the CMCP is also essential for the amplification of ISR. In conclusion, a KN-62-sensitive process directly mediates the effects of Ca(2+) influx via L-type Ca(2+) channels on OCR and ISR, supporting the essential role of the CMCP in mediating ISR.

DOSE-RELATED EFFICACY OF A CONTINUOUS INTRACISTERNAL NIMODIPINE TREATMENT ON CEREBRAL VASOSPASM IN THE RAT DOUBLE SUBARACHNOID HEMORRHAGE MODEL

Intracisternal continuous therapy is a concept in the treatment of cerebral vasospasm after subarachnoid hemorrhage. The purpose of the current study was to investigate the effect of intracisternal nimodipine after induced vasospasm. Sixty-five male Wistar rats were randomized into 4 groups: the control sham-operated group, the control subarachnoid hemorrhage-only group, and the treatment groups receiving 5 or 10 microL/hour of intracisternal nimodipine continuously for 5 days via subcutaneously implanted Alzet osmotic pumps (Durect Corp., Cupertino, CA). Vasospasm was analyzed 5 days later by means of digital subtraction angiography. Morphological examination of the brain parenchyma was performed using Nissl-staining, c-Fos immunohistochemistry, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling. Detailed analysis of the digital subtraction angiography was possible for 31 animals. Significant angiographic vasospasm was induced in the double hemorrhage-only group compared with the sham-operated group (P = 0.002). Among the 4 groups, there were statistically significant differences of the arterial vessel caliber as measured by digital subtraction angiography (P = 0.001, Kruskal-Wallis test). The treatment group receiving 5 microL/hour of nimodipine and the control sham-operated group demonstrated the largest intracranial artery diameters with a significant difference between control subarachnoid hemorrhage-only group and the treatment group receiving 10 microL/hour of nimodipine (P = 0.0328, Wilcoxon rank-sum test). Variation in vessel calibers, however, did not result in different brain tissue alterations, even when using sensitive markers for the induction of the stress response or apoptosis. Intracisternal nimodipine lavage with 5 microL/hour, but not with 10 microL/hour leads to significant arterial relaxation. Further research is needed to elucidate the underlying cause of the decreasing nimodipine effect at higher dosage.