flunarizine and Hypoxia

According to classic theory, a migraine attack is initiated by cerebrovascular spasm followed by extracranial vasodilatation. Results of recent studies support this theory and suggest that cerebral blood flow during the initial phase of migraine symptoms is, in fact, decreased and this decrease probably leads to ischemia and hypoxia. Cellular hypoxia, in turn, can cause an increase in the flow of calcium from the extracellular fluid to the intracellular space, resulting in calcium overload and cellular dysfunction. Because calcium-channel blockers selectively inhibit the intracellular influx of calcium ions, investigators have begun evaluating the efficacy of these agents for migraine prophylaxis. Nimodipine, a calcium-channel blocker that exhibits selective effects on cerebral vessels, seems to offer protection against the cerebral ischemia and hypoxia presumed to be operative during migraine attacks. In a double-blind, placebo-controlled study, nimodipine decreased the frequency and duration of migraine attacks by at least half in 69% of patients treated with this agent. Comparable reductions in migraine frequency and duration were attained in 58, 51, 41 and 52% of patients treated with methysergide maleate, pizotifen, clonidine hydrochloride and propranolol, respectively. The piperazine derivative flunarizine also has calcium-channel blocking properties. This agent prevents vasospasm in cerebral arteries and protects against cerebral hypoxia. Results of double-blind studies of migraine prophylaxis with flunarizine demonstrate the beneficial effects of this agent, particularly in younger patients. Flunarizine proved to be superior to pizotifen in decreasing the severity of migraine attacks and comparable to pizotifen in decreasing their frequency.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Calcium Channel Blockers; Cinnarizine; Double-Blind Method; Flunarizine; Humans; Hypoxia; Migraine Disorders; Nicotinic Acids; Nimodipine; Vasodilator Agents

Calcium-entry blockers inhibit contractions of vascular smooth muscle cells in response to potassium and to endogenous and exogenous vasoconstrictor stimuli in both normoxic and hypoxic conditions. In this regard, the protecting effect of flunarizine is of long duration and particularly evident on brain arteries at concentrations not affecting vascular myogenic activity or myocardial contractile force. Some calcium-entry blockers (especially flunarizine) also decrease blood hyperviscosity by improving red blood cell deformability. Both vascular and rheological effects reflect a protection against changes in permeability of the cell membrane to calcium.

Topics: Animals; Blood Viscosity; Calcium; Calcium Channel Blockers; Cinnarizine; Dogs; Erythrocytes; Flunarizine; Hypoxia; Muscle, Smooth, Vascular; Myocardial Contraction; Norepinephrine; Potassium; Prostaglandins; Rats; Serotonin; Vasoconstriction

Pharmacological agents that delay the hypoxic arrest of neuronal electrical activity, as indicated by the suppression of electroencephalogram (EEG), have previously been thought to increase brain resistance to oxygen insufficiency. On the other hand, acceleration of the EEG suppression may offer some protection against severe hypoxia by reducing neuronal energy spending on electrogenesis. In unanesthetized rats we examined the effects of several antihypoxic drugs on the time of appearance of isoelectric EEG (tiEEG), caused by normobaric hypoxia. In addition, alterations in cerebral blood flow induced by hypoxia and by some drugs were monitored using polarographic techniques to determine if cerebrocirculatory changes play a significant role in the drug effects on tiEEG. We also assessed drug effects on behavioral recovery after hypoxia by measuring the latency of restoration of the head-withdrawal reflex upon vibrissae stimulation. Pentobarbital (30 and 60 mgkg(-1)i.p.), chloralhydrate (400 mgkg(-1)i.p.) flunarizine (50-100 mgkg(-1)p.o.), hydergine (3-50 mgkg(-1)p.o.), nicergoline (50 mgkg(-1)and 85 mgkg(-1)p.o.), sabeluzole (3 and 7.5 mgkg(-1)i.p.) and vincamine (80 mgkg(-1)p.o.) reduced tiEEG (mean 27.1 +/- 3.3 min prior to drugs). In contrast, idebenone (29-85 mgkg(-1)p.o.) and vinpocetine (29-85 mgkg(-1)p.o.) had no significant effects on tiEEG. The divergent effects on cerebral blood flow suggest an insignificant role for cerebrocirculatory changes in the drug-induced reduction of tiEEG during severe hypoxia. The drug effects on recovery of the head-withdrawal reflex (mean 4.2 +/- 1.3 min prior to drugs) varied from a delay (sabeluzole) to acceleration (flunarizine) with no correlation to the effects on tiEEG, suggesting that EEG criteria alone may not predict the course of functional recovery.

Topics: Anesthesia; Animals; Cerebrovascular Circulation; Electroencephalography; Ergoloid Mesylates; Flunarizine; Hypoxia; Male; Neuroprotective Agents; Pentobarbital; Rats; Rats, Wistar; Reflex; Time Factors

Rat models of the acute and recuperative phases of hypoxic ischemic encephalopathy (HIE) were established beginning by the 7th day after birth through ischemia and hypoxia. The prophylatic and therapeutic effects on experimental HIE were studied by the application of radix salviae miltiorrhizae, flunarizine and hyperbaric oxygen. Experimental data indicated that among these measures, radix salviae miltiorrhizae gave a better result and the pathological change in the prophylactic and therapeutic groups particularly the result of the latter one were light serious than those of the control group.

Topics: Animals; Atrophy; Brain; Brain Diseases; Calcium Channel Blockers; Drugs, Chinese Herbal; Flunarizine; Hypoxia; Organ Size; Plant Extracts; Rats; Rats, Wistar; Salvia miltiorrhiza; Vasodilator Agents

Anoxic depolarization (AD) and failure of ion homeostasis play an important role in ischemia-induced neuronal injury. In the present study, different drugs with known ion-channel-modulating properties were examined for their ability to interfere with cardiac-arrest-elicited AD and with the changes in the extracellular ion activity in rat brain. Our results indicate that only drugs primarily blocking membrane Na+ permeability (NBQX, R56865, and flunarizine) delayed the occurrence of AD, while compounds affecting cellular Ca2+ load (MK-801 and nimodipine) did not influence the latency time. The ischemia-induced [Na+]e reduction was attenuated by R56865. Blockade of the ATP-sensitive K+ channels with glibenclamide reduced the [K+]e increase upon ischemia, indicating an involvement of the KATP channels in ischemia-induced K+ efflux. The KATP channel opener cromakalim did not affect the AD or the [K+]e concentration. The ischemia-induced rapid decline of extracellular calcium was attenuated by receptor-operated Ca2+ channel blockers MK-801 and NBQX, but not by the voltage-operated Ca2+ channel blocker nimodipine, R56865, and flunarizine.

Topics: Adenosine Triphosphate; Animals; Benzothiazoles; Calcium; Dizocilpine Maleate; Flunarizine; Glyburide; Heart Arrest; Hypoxia; Ion Channels; Male; Nimodipine; Piperidines; Potassium; Potassium Channels; Quinoxalines; Rats; Rats, Wistar; Sodium; Thiazoles

The anti-ischemic and anti-anoxic effects of efonidipine, a dihydropyridine calcium antagonist, were studied in several models for cerebral ischemia and anoxia in mice and rats, and the effects were compared with those of nicardipine and flunarizine. Both efonidipine and flunarizine showed protective effects in the models of KCN-induced anoxia and complete ischemia induced by decapitation in mice 6 hr after the treatment, while nicardipine did not show such a long-lasting effect. Efonidipine (1 mg/kg, i.p.), but not nicardipine and flunarizine, prolonged the tolerance times in the asphyxic anoxia model. In mice, efonidipine (4 mg/kg, i.p.) significantly reduced the cumulative mortality rate after bilateral carotid artery ligation. The survival rates at 20 hr after bilateral carotid artery ligation were 33% in the group treated with efonidipine, significantly higher than that in the control group, 0%. On the other hand, the treatment with nicardipine or flunarizine did not increase the rates at 20 hr after the ligation. Moreover, efonidipine attenuated the disturbance of cerebral energy metabolism induced by decapitation in rats. These effects of efonidipine observed in this study were on the whole superior to those of the reference drugs, strongly suggesting the improving effect of efonidipine on cerebral ischemia and anoxia.

Topics: Animals; Brain Ischemia; Calcium Channel Blockers; Dihydropyridines; Flunarizine; Hypoxia; Male; Mice; Mice, Inbred ICR; Nicardipine; Nitrophenols; Organophosphorus Compounds; Rats; Rats, Wistar

The aim of the present study was to determine whether calcium channel antagonists attenuated hypoxia/hypoglycemia- or glutamate-induced reduction in 2-deoxyglucose (2-DG) uptake of hippocampal slices obtained from ethanol withdrawal rats. Ethanol withdrawal significantly potentiated the hypoxia/hypoglycemia- and glutamate-induced reductions in 2-DG uptake of hippocampal slices. Both nifedipine and flunarizine exhibited attenuating effects on ethanol withdrawal-induced potentiation of impairment of 2-DG uptake caused by hypoxia/hypoglycemia or glutamate. Hypoxia/hypoglycemia-induced deficit of 2-DG uptake was prevented by ethanol, but chronic consumption of ethanol resulted in the development of tolerance to neuroprotective effect. These findings suggest that the increased sensitivity of neurons to ischemic damage by ischemia may involve in the increased activity of calcium channels in the hippocampus.

Topics: Animals; Calcium Channel Blockers; Deoxyglucose; Dizocilpine Maleate; Dose-Response Relationship, Drug; Ethanol; Flunarizine; Glutamic Acid; Hippocampus; Hypoglycemia; Hypoxia; Male; Nifedipine; Rats; Rats, Wistar; Substance Withdrawal Syndrome

Our purpose was to determine the diagnostic power of the T/QRS ratio of the electrocardiogram to predict fetal well-being.. In 47 fetal lambs (3 to 5 days after surgery, gestational age 123.5 +/- 3.0 days) asphyxia was induced by restriction of uterine perfusion. Fetuses were either pretreated with an adenosine transport inhibitor (n = 16) or a calcium channel blocker (n = 12) or served as controls (n = 19). Arterial oxygen content > or = 1.5 mmol/L or pH > or = 7.15 were chosen as limits for fetal well-being.. Arterial oxygen content was reduced from 3.3 (+/- 1.0) to 1.3 (+/- 0.5) mmol/L, and pH decreased to 7.03 (+/- 0.10). Mortality was 53%. Both drugs did not affect well-being, survival, or the T/QRS ratio. Maximum T/QRS ratios were reached at the peak of asphyxia. Sensitivity and specificity of the T/QRS ratio were 24.0% and 42.6% to predict hypoxemia and 25.1% and 45.3% to predict acidemia. Pearson correlation coefficients for T/QRS ratio versus oxygen content and pH were 0.169 and 0.192, respectively.. (1) In fetal lambs the T/QRS ratio failed to predict hypoxemia or acidemia. (2) Fetal survival was not correlated with the height of the T/QRS ratio during or after asphyxia.

Topics: Acids; Animals; Arteries; Asphyxia; Electrocardiography; Fetal Heart; Flunarizine; Forecasting; Health Status; Hydrogen-Ion Concentration; Hypoxia; Oxygen; Piperazines; Sensitivity and Specificity; Sheep; Survival Analysis

Long-term changes of learning behavior and of the striatal dopaminergic system were observed in a rat model of early postnatal hypoxia. Striatal dopamine (DA) concentration, K(+)-stimulated DA release from slices, and DA uptake into crude synaptosomal preparations (S1 fractions) were used as markers of the striatal DAergic system. Active avoidance learning was tested as behavioral criterion. Cyclodextrin and flunarizine were found to produce long-term effects on the DAergic system in control animals. While cyclodextrin normalized hypoxia-induced effects in DA release, flunarizine prevented those in DA uptake and improved avoidance learning.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Avoidance Learning; Catecholamines; Dopamine; Flunarizine; Homovanillic Acid; Hypoxia; In Vitro Techniques; Kinetics; Male; Neostriatum; Rats; Rats, Wistar; Synaptosomes

We investigated the changes in dopamine, homovanillic acid, 3,4-dihydroxyphenylacetic acid, and norepinephrine content in striatum of rats ventilated with 5% oxygen in nitrogen gas. We also examined the effects of flunarizine, a calcium channel blocker, on these catecholamine levels. During 10-20 min. of hypoxia, the dopamine content gradually increased and the 3,4-dihydroxyphenylacetic acid and norepinephrine levels decreased, while the concentration of homovanillic acid remained unchanged. The concentrations of these substances subsequently returned to control values after 4 hr of room air breathing. In animals pretreated with intravenous flunarizine injection, there was a slight increase in dopamine, with no appreciable change in homovanillic acid or 3,4-dihydroxyphenylacetic acid content during 10-20 min. of hypoxia. The decrease in norepinephrine which occurred during 10-20 min. of hypoxia was identical between non-treated and flunarizine-treated animals. Catecholamine levels subsequently returned to control values after 4 hr of room air breathing. These results suggest that flunarizine minimizes the alterations in striatal catecholamine contents during hypoxic ventilation.

Topics: Animals; Blood Gas Analysis; Catecholamines; Corpus Striatum; Flunarizine; Hemodynamics; Hypoxia; Male; Oxygen; Rats; Rats, Inbred Strains; Solvents; Survival Rate

21-day-old rats were subjected to unilateral carotid ligation, then, after 2 h of recovery, to 2 h of 8% hypoxia. Immediately following the insult they were treated with either flunarizine (30 mg/kg, i.p.) or with an equal volume of diluent. We have previously shown similar doses of flunarizine to be neuroprotective when given preinsult. After 5 days they were sacrificed for histological analysis. Cerebral injury was almost entirely confined to the ligated side. Full-thickness cortical infarction was noted in 55% of controls (n = 29) versus 36% of flunarizine-treated rats (n = 28; p = 0.14). Mean damage scores for all areas assessed including cortex, striatum, and hippocampus were not significantly different. These observations suggest that flunarizine is not significantly neuroprotective when given immediately after severe hypoxia-ischemia.

Topics: Animals; Animals, Newborn; Brain Ischemia; Cerebral Infarction; Dose-Response Relationship, Drug; Flunarizine; Hypoxia; Prosencephalon; Rats; Rats, Wistar

A long-term piracetam treatment leads to an improved stimulus-effect-coupling of potassium stimulated dopamine release: The maximum effect of the potassium stimulus is already obtained in presence of much lower Ca++-concentrations (Ca++-economizing effect) than normally. In consequence of the improved stimulus-effect-coupling by piracetam treatment the dose-dependent inhibitory effect of the calcium antagonist flunarizine on the fractional efflux rate of dopamine is decreased. The volume of vesicular structures is not involved in the piracetam effect.

Topics: Animals; Brain; Corpus Striatum; Dopamine; Flunarizine; Hypoxia; In Vitro Techniques; Kinetics; Piracetam; Potassium; Pyrrolidinones; Rats; Rats, Inbred Strains; Reference Values; Reserpine

Five percent oxygen was administered to rats under controlled respiration. The concentrations of catecholamines and their metabolites (dopamine, HVA, DOPAC, norepinephrine) were measured during 5% oxygen administration and subsequent recovery period. Flunarizine, a calcium channel blocker, was administered and its effects on catecholamine fluctuations were studied. Results were as follows. Dopamine increased with 5% oxygen administration. DOPAC and norepinephrine decreased and no changes were seen in HVA. After 20 min of hypoxia, catecholamine contents returned to the control levels in another 2 hours of air breathing. When flunarizine was administered in advance, changes in catecholamine content appeared to be lower during 5% oxygen administration and subsequent recovery period.

Topics: Animals; Catecholamines; Corpus Striatum; Flunarizine; Hypoxia; Male; Rats; Rats, Inbred Strains

One postulated final common pathway leading to neuronal death after hypoxic-ischemic insults is an increase in intracellular calcium concentrations. We examined the effect of pretreatment with flunarizine, a calcium channel antagonist known to pass the blood brain barrier, on the behavioral and histologic changes after an hypoxic-ischemic insult in the infant rat. The 21-d-old rats were subjected to unilateral carotid ligation, then to 2 h of hypoxia. They were pretreated with either flunarizine (30 mg/kg, intraperitoneally) or with an equal volume of diluent. After 5 days of observation they were killed for histology. Acute behavioral abnormalities were observed in more controls than treatment animals, 52 vs 11% (p less than 0.002). Cerebral injury was almost entirely confined to the ligated side and was significantly worse in the control rats. Full thickness cortical infarction was noted in 56% of controls (n = 27) vs 4% of flunarizine-treated rats (n = 24), (p less than 0.001). Mean and maximum damage scores for all areas assessed including cortex, corpus striatum, thalamus, amygdala, and hippocampus were improved markedly in treatment rats (p less than 0.005). These observations confirm that flunarizine, when given prophylactically, has a neuroprotective effect against hypoxic-ischemic injury in the developing brain.

Topics: Animals; Animals, Newborn; Brain Diseases; Brain Ischemia; Flunarizine; Hypoxia; Rats

1. The protective effects of ten slow channel inhibitor drugs against severe progressive hypoxia were investigated in rats breathing spontaneously during light anaesthesia. Respiration, heart rate, electrocorticogram (ECoG) and/or electroencephalogram (EEG) were recorded. 2. Tolerance times were monitored from hypoxia onset until cessation of respiration, ECoG, EEG synchronization, and 'background-EEG'. Drugs were administered i.v. 5 min before the onset of hypoxia. 3. Verapamil, gallopamil, and nimodipine resulted in a significant increase of tolerance times; fendiline and bepridil showed a small increase (not significant); bencyclan and prenylamine were ineffective; cinnarizine and diltiazem slightly reduced tolerance times as did flunarizine at low doses. 4. At protective doses, verapamil, gallopamil, and nimodipine significantly raised the respiration rate but had little or no cardiac depressor effects. Bencyclan showed ventilatory drive but cardiocirculatory depression. A clear-cut ventilatory drive did not occur with the other ineffective slow channel inhibitors. 5. It is suggested that the protective actions observed were not due to slow channel inhibition per se, nor to spasmolytic potency or increased cerebral blood flow. Ventilatory drive associated with other cardiopulmonary actions which secondarily raise the brain oxygen supply are likely to be responsible for this effect.

Topics: Animals; Bencyclane; Bepridil; Brain; Calcium Channel Blockers; Cinnarizine; Diltiazem; Electroencephalography; Fendiline; Flunarizine; Gallopamil; Heart Rate; Hypoxia; Nimodipine; Prenylamine; Pyrrolidines; Rats; Rats, Inbred Strains; Respiration; Verapamil

The pathophysiologic mechanism by which chronic hypoxia causes pulmonary hypertension is unknown. If anti-platelet agents, or other pharmacologic interventions, altered the pulmonary vascular changes induced by hypoxia, information concerning the pathogenesis of the pulmonary hypertension or the potential therapeutic usefulness of the drugs might be obtained. In Study 1, rats exposed to chronic hypobaric hypoxia (PB = 520 mmHg) had a pulmonary arterial medial thickness of 6.7 +/- 0.6 mu compared to 4.1 +/- 0.2 mu* for control, normoxic rats (*p less than 0.05). Administration of dipyridamole (2mg/kg/day), or sulfinpyrazone (11 mg/kg/day) in the drinking water reduced the medial thickness to 5.0 +/- 0.3 mu* and 5.4 +/- 0.5 mu* respectively, thus suggesting the possible involvement of platelets in the response of the media to chronic hypoxia. In Study 2, hypoxic rats treated with the calcium blocker, flunarizine, were found to have less medial hypertrophy than a control group of hypoxic rats. This observation suggests that a decrease in transmembrane calcium flux may also reduce medial hypertrophy.

Topics: Animals; Dipyridamole; Flunarizine; Heart; Heart Ventricles; Hypertension, Pulmonary; Hypoxia; Male; Myocardium; Platelet Aggregation Inhibitors; Pulmonary Artery; Rats; Rats, Inbred Strains; Sulfinpyrazone

Cerebral blood flow in the rat was monitored by a venous outflow technique with an extracorporeal circulation, which allows for the continuous recording of flow over periods of several hours. The bi-fluorophenyl-piperazine derivatives, lidoflazine and flunarizine, enhanced the reactive hyperemia elicited by a brief (30 s) anoxic challenge. They did not alter resting cerebral blood flow rates. Verapamil, a potent calcium slow channel blocker, decreased resting flow rates but did not alter the duration of the reactive hyperemia. As lidoflazine and flunarizine are potent inhibitors of adenosine uptake, whereas verapamil is not, the results are consistent with the hypothesis that adenosine plays a significant role in cerebral vascular autoregulation.

Topics: Animals; Blood Gas Analysis; Cerebrovascular Circulation; Cinnarizine; Extracorporeal Circulation; Flunarizine; Hyperemia; Hypoxia; Lidoflazine; Male; Piperazines; Rats; Rats, Inbred Strains; Verapamil

Flunarizine is a calcium entry blocking drug possessing antihypoxic activity in animal models of cerebral and peripheral ischemia-anoxia and has clinical usefulness in circulatory disorders of both central and peripheral origin. This report compares the activity of flunarizine and verapamil, another calcium entry blocking drug, on the central nervous system (CNS) and peripheral consequences of cytotoxic hypoxia induced by high and low doses of KCN. The lethal effect of KCN (6 mg/kg, i.p.) in rats was prevented by orally administered flunarizine (ED50 = 12 mg/kg with four-hr pretreatment) but not by verapamil (at oral doses up to 80 mg/kg with one-hr pretreatment). Since the lethal effect of KCN involves failure of respiration at the CNS level, these results suggest that flunarizine protects against the hypoxic effect of the cyanide ion by an action in brain tissue. We found also that the stimulant effect of low intravenous doses (0.5 mg/kg/min) of KCN upon respiration rate was not altered in pentobarbital- and chloralose-anesthetized rats treated with oral doses of flunarizine up to 80 mg/kg (with four hr pretreatment). In contrast, KCN-stimulated respiration rate in pentobarbital anesthetized rats was significantly attenuated by verapamil (20 and 40 mg/kg, p.o. with one hr pretreatment). Since low doses of the cyanide ion render respiration quicker and deeper by an action on chemoreceptive cells in peripheral arteries, the effect of verapamil against the hypoxic effect of KCN is mediated by an action in the periphery. In summary, we have shown that the physiological consequences of cytotoxic hypoxia can be affected by calcium entry blocking drugs having site-specific activities. Based on our results, flunarizine is more effective than verapamil against cellular anoxia involving the CNS.

Topics: Animals; Calcium Channel Blockers; Cinnarizine; Flunarizine; Hyperventilation; Hypoxia; Male; Piperazines; Potassium Cyanide; Rats; Rats, Inbred Strains; Verapamil

Transient anoxia obtained in curarized rats by momentary stopping of the artificial respiration (80 sec duration) induced a failure of the cerebral electrical activity. This effect was characterized by cessation of the spontaneous unitary discharge of cortical neurons and reduction of amplitude of somatosensory evoked potentials. Pretreatment with flunarizine (10 mg/kg/os) or suloctidil (50 mg/kg/os) induced a distinct improvement of the resistance to anoxia and of the recovery of the cerebral electrical activity.

Topics: Animals; Brain; Calcium Channel Blockers; Cinnarizine; Electrophysiology; Evoked Potentials; Flunarizine; Hypoxia; Male; Neurons; Rats; Suloctidil

Topics: Animals; Cinnarizine; Disease Models, Animal; Flunarizine; Heart Arrest; Hypoxia; Male; Piperazines; Rats; Rats, Inbred Strains; Vasodilator Agents