NIMODIPINE

BACKGROUND AND OBJECTIVE Anxiety that occurs during alcohol withdrawal may be the precipitating factor for relapse of alcoholism. Earlier studies have demonstrated calcium channel activity peaks during alcohol withdrawal and calcium channel antagonists were found to decrease behavioral manifestations of alcohol withdrawal syndrome. The objective of the study was to evaluate the anxiolytic potential of calcium channel antagonists, verapamil and nimodipine during ethanol withdrawal in rats. METHODOLOGY Male wistar albino rats were fed with 10% ethanol liquid diet for 4 weeks. Ethanol was withdrawn 8 hours before test procedure. Verapamil (20mg/kg) and nimodipine (10mg/kg) were administered orally. Elevated plus maze (EPM) and Open field test (OFT) were used to assess the anxiolytic activity. RESULT In the EPM model, the time spent in the open arm and closed arm was increased and decreased respectively in rats treated with both verapamil and nimodipine as compared to control. Number of rearing in open arm and closed arm were also increased which shows increased exploratory behavior in rats. In OFT model, the time spent in central squares and peripheral squares was increased and decreased respectively in rats treated with verapamil and nimodipine as compared to control. Number of entries into the central area and the number of lines crossed in central and peripheral areas were also increased in drug treated rats as compared to control. Number of rearing was significantly increased in the central areas but not in the peripheral areas. CONCLUSION Verapamil and Nimodipine significantly reduced ethanol withdrawal induced anxiety. Calcium channel antagonists could be effectively used as alternative to benzodiazepines in ethanol withdrawal induced anxiety.

Despite intensive interest in under- standing the differentiation of vascular smooth mus- cle cells (VSMC), no information is available about differential regulation of ion channels in these cells. Since expression of the L-type Ca2/ channel can be influenced by differentiation in other cell types, we tested the hypothesis that the L-type (C class) channel is a specific differentiation marker of VSMC and that expression of these channels depends on the state of cell differentiation. We used rat aortic (A7r5) VSMC, which express functional L-type Ca2/ channels, and induced dedifferentiation by cell culture in different media. Treatment with retinoic acid was used to re- differentiate the VSMC. We characterized the dif- ferentiated state of the cells by using immunohisto- chemistry and Western blot analysis for smooth mus- cle (SM)a-actin and SM-myosin heavy chain (MHC). The number of functional Ca2/ channels was signifi-

Endocrine disrupters (EDs) continue to be the focus of extensive research. Their effects and mode of action as well as their occurrence and fate in the aquatic environment are still largely unknown and need investigation. Wastewater treatment plant effluents are for most of them the main source of contamination in water bodies. A large number of EDs are relatively polar compounds that pass easily wastewater treatments and reach the aquatic environment, where they can exert undesirable effects on both wildlife and humans. Their removal during waste-water treatment, very often inefficient, is usually estimated from the comparison of the concentrations detected at the influent and the effluent and the technique of choice for their analysis is in many cases liquid chromatography—(tandem)mass spectrometry (LC—(tandem)MS). Herein we review the analytical methods, including sample preparation and analysis, based on LC—(tandem)MS described in the literature for the determination of different classes of EDs (pesticides, phthalates, bisphenol A, alkylphenolic compounds, perfluorinated compounds, pharmaceuticals, and estrogens) in wastewater and their occurrence in this kind of matrix.

Delayed ischemic neurologic deficit (DIND) is a serious complication of acute aneurysmal subarachnoid hemorrhage (aSAH). Although oral nimodipine is accepted as standard care for the prevention of DIND, the intravenous route is preferred by several centers. In the present study we compared the clinical efficacy between enteral and intravenous nimodipine after aSAH. A total of 171 aSAH patients were randomly assigned to either the enteral (84 patients) or the intravenous (87 patients) nimodipine group and were compared regarding the incidence of DIND, number of new ischemic lesions on 12-month brain magnetic resonance image, and clinical outcome 12 months after aSAH as assessed by Glasgow Outcome scale, modified Rankin scale, and Karnofsky scale. Health-related quality of life was also assessed by the 15D questionnaire 12 months after aSAH. The incidence of DIND did not differ significantly between the groups (20% in the enteral versus 16% in the intravenous group, P=0.61), whereas n...

Endocrine disrupters (EDs) continue to be the focus of extensive research. Their effects and mode of action as well as their occurrence and fate in the aquatic environment are still largely unknown and need investigation. Wastewater treatment plant effluents are for most of them the main source of contamination in water bodies. A large number of EDs are relatively polar compounds that pass easily wastewater treatments and reach the aquatic environment, where they can exert undesirable effects on both wildlife and humans. Their removal during waste-water treatment, very often inefficient, is usually estimated from the comparison of the concentrations detected at the influent and the effluent and the technique of choice for their analysis is in many cases liquid chromatography—(tandem)mass spectrometry (LC—(tandem)MS). Herein we review the analytical methods, including sample preparation and analysis, based on LC—(tandem)MS described in the literature for the determination of different classes of EDs (pesticides, phthalates, bisphenol A, alkylphenolic compounds, perfluorinated compounds, pharmaceuticals, and estrogens) in wastewater and their occurrence in this kind of matrix.

We have recently synthesized a new series of hybrid compounds having the moieties of tacrine, a potent inhibitor of brain and peripheral acetylcholinesterase (AChE), and nimodipine, a blocker of L-type voltage-dependent calcium channels (VDCCs). These compounds were designed to target AChE and L calcium channels in the brain, as potential therapeutic agents in Alzheimer's disease. We performed the present study to determine the main peripheral side effects of two of these compounds, ITH12117 and ITH12118. We have here shown that in rat vas deferens these compounds inhibited AChE with a potency about 1000-fold lower than that of physostigmine or tacrine. Furthermore, the hybrid compounds enhanced contractions evoked by acetylcholine, with a potency about 100-fold lower than that of physostigmine or tacrine. Additionally, contractions induced by Ca2+ on depolarized vas deferens were blocked by nimodipine with greater efficacy, compared with ITH12117 and ITH12118. Compound ITH12118 (1 μM) caused a pronounced inhibition of the tonic (but not phasic) contraction elicited by electrical field stimulation. Furthermore, the same dose of nimodipine and ITH12118 blocked by 75% cytosolic Ca2+ elevations produced by acetylcholine, noradrenaline, or ATP. As a matter of comparison, we showed that rat brain cortex AChE was inhibited by ITH12118 with a potency 10 to 20-fold higher than that for vas deferens. This study shows that ITH12118 could be a paradigmatic multitarget compound having selective brain effects with smaller peripheral side effects. This may help to orient the search of new neuroprotective compounds with potential therapeutic application in Alzheimer's disease.

Comparison between evolutionarily distant receptors can provide critical insights into both structure and function. Sequence comparison between the mineralocorticoid receptors (MR) of the zebrafish (zMR) and human (hMR) reveals a high degree of sequence conservation in the major functional domains. We isolated a zMR cDNA to contrast the transcriptional response to a range of ligands and to establish whether a teleost MR exhibits the amino/carboxyl-terminal interaction (N/C-interaction) previously reported for the hMR. Aldosterone, deoxycorticosterone (DOC) and cortisol induced zMR transcriptional activity with similar efficacy to that observed with the hMR. The hMR antagonist, spironolactone, acted as an agonist with the zMR. The zMR exhibited an N/C-interaction in response to aldosterone but, in contrast to the hMR, cortisol and DOC predominantly stimulated the interaction in the zMR. Conservation of the N/C-interaction between evolutionarily distant MR provides evidence of functio...

In the present study, the effects on intracellular calcium concentration ([Ca(2+)](i)) oscillations of the blockade of ether-a-go-go-related gene (ERG) K(+) channels and of Ca(2+) influx through store-operated channels (SOC) activated by [Ca(2+)](i) store depletion have been studied in GH(3) cells by means of a combination of single-cell fura-2 microfluorimetry and whole-cell mode of the patch-clamp technique. Nanomolar concentrations (1-30 nM) of the piperidinic second-generation antihistamines terfenadine and astemizole and of the class III antiarrhythmic methanesulfonanilide dofetilide, by blocking ERG K(+) channels, increased the frequency and the amplitude of [Ca(2+)](i) oscillations in resting oscillating GH(3) cells. These compounds also induced the appearance of an oscillatory pattern of [Ca(2+)](i) in a subpopulation of nonoscillating GH(3) cells. The effects of ERG K(+) channel blockade on [Ca(2+)](i) oscillations appeared to be due to the activation of L-type Ca(2+) chann...

Calcium plays an important role in the pathophysiology of pain. A number of studies have investigated the effect of L-type calcium channel blockers on the analgesic response of morphine. However, the results are conflicting. In the present study, the antinociceptive effect of morphine (2–5 Μg) and nimodipine (1 Μg) co-administered intraspinally in mice was observed using the tail flick test. It was compared to the analgesic effect of these drugs (morphine — 250 Μg subcutaneously; nimodipine — 100 Μg intraperitoneally) after systemic administration. Nimodipine is highly lipophilic and readily crosses the blood brain barrier. Addition of nimodipine to morphine potentiated the analgesic response of the latter when administered through the intraspinal route but not when administered through systemic route. It may be due to direct inhibitory effect of morphine and nimodipine on neurons of superficial laminae of the spinal cord after binding to Μ-opioid receptors and L-type calcium channels respectively.