dihydropyridines and Brain-Ischemia

Possible strategies for treating ischemic stroke include neuroprotection (preventing injured neurons from undergoing apoptosis in the acute phase of cerebral ischemia) and stem cell therapy (the repair of disrupted neuronal networks with newly born neurons in the chronic phase of cerebral ischemia). First, we estimated the neuroprotective effect of glial cell line-derived neurotrophic factor (GDNF) by administration of GFNF protein. GDNF protein showed a direct protective effect against ischemic brain damage. Pretreatment of animals with adenoviral vector containing GDNF gene (Ad-GDNF) 24 h before the subsequent transient middle cerebral artery occlusion (MCAO) effectively reduced infarcted volume. Secondly, we studied the neuroprotective effect of a calcium channel blocker, azelnidipine, or a by-product of heme degradation, biliverdin. Both azelnidipine and biliverdin had a neuroprotective effect in the ischemic brain through their antioxidative property. Lastly, we developed a restorative stroke therapy with a bioaffinitive scaffold, which is able to provide an appropriate platform for newly born neurons. In the future, we will combine these strategies to develop more effective therapies for treatment of strokes.

Topics: Animals; Antioxidants; Azetidinecarboxylic Acid; Biliverdine; Brain Ischemia; Dihydropyridines; Disease Models, Animal; Genetic Therapy; Glial Cell Line-Derived Neurotrophic Factor; Humans; Models, Biological; Neuroprotective Agents; Stem Cell Transplantation

The authors reviewed the pathogenesis of cocaine-related cerebral ischemia, appraised current knowledge of its sequelae, and assessed the role of putative therapeutic agents, particularly dihydropyridine-class calcium channel antagonists.. The authors performed an OVID-based literature review of all indexed journals between 1966 and 2000.. Cocaine abuse significantly increases the risk of ischemic stroke. The principal mechanism of cocaine-induced cerebral ischemia is vasospasm of large cranial arteries or within the cortical microvasculature. Increased levels of extracellular monoamines, particularly dopamine, mediate vasospasm. Neuroanatomical and labeling studies also have shown that dopamine-innervated neurons may regulate cerebral blood flow. Indeed, dopamine-rich brain regions appear to be relatively specific targets for cocaine-induced cerebral ischemia. Neuroimaging studies show that cocaine-induced hypoperfusion can persist even after 6 months of abstinence. Hypoperfusion can result in deficits on complex and simple psychomotor tasks but perhaps not on memory or attention. Severe cerebral ischemia can directly precipitate neuronal death and degradation, a condition exacerbated by liberation of the excitatory amino acid glutamate. Dihydropyridine-class calcium channel antagonists inhibit cocaine-mediated dopamine release on neurons involved in vasospasm and the control of cortical circulation. Other causes of cerebral ischemia include thrombogenesis and vasculitis. Although antithrombotic agents have potential in alleviating cocaine's neurotoxic effects, their use may be limited by the risk of spontaneous hemorrhage.. Cocaine abuse can result in stroke, neuroischemia, and cognitive deficits that can persist even after prolonged abstinence. Dihydropyridine-class calcium channel antagonists, such as isradipine, show promise as therapeutic agents for preventing cocaine-induced cerebral ischemia.

Topics: Brain Ischemia; Calcium Channel Blockers; Cocaine-Related Disorders; Dihydropyridines; Humans; Isradipine; Stroke; Tomography, Emission-Computed; Tomography, Emission-Computed, Single-Photon; Vasospasm, Intracranial

Topics: Animals; Brain Ischemia; Calcium Channel Blockers; Calcium Channels; Cerebrovascular Disorders; Dihydropyridines; Flunarizine; Humans; Neuroprotective Agents; Verapamil

The aim of this study was to compare the efficacy and safety of lercanidipine and amlodipine in the treatment of hypertensive patients with acute cerebral ischemic stroke.. An open label, controlled, randomized, parallel-group study was conducted on 104 hypertensive patients (blood pressure [BP] >130/80 mmHg) diagnosed with ischemic stroke. Enrolled subjects were randomly assigned to a 4 week treatment with lercanidipine 20 mg/day or amlodipine 10 mg/day. The treatment was administered during the acute phase of the stroke, either immediately after the diagnosis or during an observation period of maximum 6 days.. Both lercanidipine and amlodipine were able to significantly reduce mean clinical systolic BP (SBP)/diastolic BP (DBP), mean 24 h ambulatory BP and day-time and night-time BP. In particular, mean clinical SBP/DBP was reduced from 168.9 ± 21.6/96.2 ± 13.6 mmHg to 147.1 ± 22.0/87.1 ± 14.0 mmHg in the lercanidipine group (p < 0.001 for SBP and p < 0.01 for DBP) and from 167.1 ± 19.9/97.8 ± 14.5 mmHg to 143.3 ± 21.9/82.8 ± 14.1 mmHg in the amlodipine-treated group (p < 0.001 for both SBP and DBP). No statistical difference was observed between the two treatments in the reduction of clinical BP. The response and normalization rates registered in the two groups of patients were also similar, with no significant difference between the two drugs. In addition, both treatments reported comparable results in terms of early morning BP surge reduction and BP stabilization, measured through trough-peak ratio and smoothness index. However lercanidipine showed a better tolerability profile than amlodipine, with fewer adverse events and a lower percentage of patients suffering from side effects.. Lercanidipine is as effective as amlodipine in the reduction and stabilization of BP in hypertensive patients after a stroke, and presents some advantages in terms of safety. Larger studies are necessary to further evaluate these preliminary findings.

Topics: Aged; Amlodipine; Antihypertensive Agents; Blood Pressure Monitoring, Ambulatory; Brain Ischemia; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged; Stroke; Treatment Outcome

Azelnidipine, a long-acting calcium channel blocker, is highly lipid soluble and selective for the vascular wall, and is expected to have an increasing effect on cerebral blood flow (CBF). The aim of this study is to investigate its safety and efficacy in stroke patients in the chronic stage as far as CBF is concerned using N-isopropyl-p-(123)I-iodo amphetamine ((123)I-IMP) single-photon emission computed tomography (SPECT). The patients were orally administered 8 or 16 mg of azelnidipine. Regional CBF was evaluated by (123)I-IMP SPECT using three-dimensional stereotactic region-of-interest (ROI) template (3D-SRT), a technique using anatomical standardization and ROI template consisting of 636 ROIs for the whole brain. Mean hemispheric CBF was defined as the mean value of the corpus callosum, and the precentral, central, parietal, angular and temporal gyri. Mean hemispheric and regional CBF after 1, 3 and 6 months were analyzed using a one-way repeated-measures analysis of variance. Ten post-ischemic stroke patients with hypertension were enrolled between October 2005 and October 2007, and all of them were well controlled with normal blood pressure (before: 172.3+/-16.6/88.4+/-14.0 mm Hg; 6 months: 128.7+/-15.9/70.9+/-10.1 mm Hg). No vascular events were observed during the study period. The mean hemispheric CBF was maintained during the study period (before: 46.0+/-9.7 ml per 100 g per min; 6 months: 49.3+/-11.1 ml per 100 g per min). The regional CBF was also maintained. In the chronic stage of ischemic stroke, azelnidipine could safely decrease systemic blood pressure without decreasing CBF.

Topics: Aged; Azetidinecarboxylic Acid; Blood Pressure; Brain Ischemia; Calcium Channel Blockers; Cerebral Infarction; Cerebrovascular Circulation; Dihydropyridines; Female; Follow-Up Studies; Functional Laterality; Heart Rate; Humans; Hypertension; Image Processing, Computer-Assisted; Iofetamine; Male; Middle Aged; Prospective Studies; Radiopharmaceuticals; Stroke; Tomography, Emission-Computed, Single-Photon

The aim of this study was to compare the effects of antihypertensive agents on cerebral blood flow (CBF) in hypertensive patients with previous ischemic stroke.. In this double-blind, multi-center, non-inferiority trial, 196 patients were randomized to cilnidipine 10-20 mg or losartan 50-100 mg once daily for 4 weeks. Baseline and follow-up CBF as measured by single photon emission computed tomography were obtained in 167. The primary endpoint was the global CBF change. The secondary endpoints were the CBF change in the hemisphere ipsilateral to the index stroke, non-impairment of global CBF and blood pressure (BP) reduction.. Global CBF increased significantly in the cilnidipine arm (9.0 +/- 29.6%, P = 0.0071) and the losartan arm (11.4 +/- 31.4%, P = 0.0012), and these changes were not different between the two groups (P = 0.607). However, the estimated difference in percentage global CBF change between the two groups was -2.43% (97.5% CI, -13.06% to 8.21%), which crossed the predetermined non-inferiority margin of -8.6%. Ipsilesional hemispheric CBF change, non-impairment of global CBF and BP reduction were similar in the two groups.. This trial failed to prove the non-inferiority of cilnidipine to losartan regarding global CBF change. Both the treatments, however, increase the global CBF despite BP lowering.

Topics: Acute Disease; Aged; Angiotensin II Type 1 Receptor Blockers; Brain; Brain Ischemia; Calcium Channel Blockers; Cerebrovascular Circulation; Dihydropyridines; Double-Blind Method; Drug Administration Schedule; Female; Humans; Hypertension; Losartan; Male; Middle Aged; Tomography, Emission-Computed, Single-Photon

Calcium channel blockers have been widely used for the treatment of hypertension because several clinical trials have demonstrated their strong action on lowering blood pressure and their role in preventing cardiovascular events such as stroke and coronary heart disease. However, there have been few reports on the effects on cerebral hemodynamics when blood pressure is lowered with this class of drug. In this study, we used positron emission tomography and acetazolamide challenge tests to measure cerebral blood flow and cerebrovascular reserve before and after administration of a novel calcium channel blocker, azelnidipine, in nine hypertensive patients (mean age, 66.1 years) with ischemic white matter lesions. Systemic blood pressure was significantly decreased from baseline (153.8+/-15.5/92.1+/-8.5 mmHg) after treatment with azelnidipine (138.4+/-16.3/81.8+/-6.2 mmHg). The baseline global cerebral blood flow values before and after treatment were 40.1+/-7.2 mL/min/100 g and 39.2+/-8.2 mL/min/100 g, respectively. The cerebrovascular reserve values before and after treatment were 58.6+/-21.7% and 56.3+/-21.3%, respectively. Differences in these parameters were not significant. A regional analysis showed no statistical differences in regional cerebral blood flow or cerebral perfusion reserve throughout the brain before and after treatment. No associations between the decreased blood pressure and the changes in cerebral blood flow or cerebrovascular reserve were found in the whole brain or in the deep white matter with ischemic lesions. In conclusion, we found that the cerebral blood flow and cerebral vascular reserve were preserved after blood pressure lowering with azelnidipine administration in hypertensive patients with ischemic white matter lesions. Azelnidipine, a novel calcium channel blocker, could be a feasible antihypertensive regimen in terms of cerebral circulation in patients with ischemic white matter lesions.

Topics: Acetazolamide; Aged; Aged, 80 and over; Azetidinecarboxylic Acid; Blood Pressure; Brain Ischemia; Calcium Channel Blockers; Cerebrovascular Circulation; Dihydropyridines; Diuretics; Female; Humans; Hypertension; Male; Middle Aged; Positron-Emission Tomography; Regional Blood Flow

Cilnidipine is reported to show antihypertensive and neuroprotective actions in a rat brain ischemia model, but is barely distributed to normal brain, suggesting that its uptake into normal brain is inhibited by efflux transporter(s), such as P-glycoprotein (P-gp). Here, we investigated whether P-gp regulates the brain distribution of cilnidipine. Intracellular accumulation of cilnidipine was decreased in P-gp-overexpressing porcine kidney epithelial cells (LLC-GA5-COL150 cells) compared with control LLC-PK1 cells and the decrease was markedly inhibited by verapamil, a P-gp inhibitor. Further, cilnidipine concentration in the brain of P-gp knockout mice was significantly increased after cilnidipine administration, compared with that in wild-type mice. Moreover, when cilnidipine was administered to male spontaneously hypertensive rats (SHR) with tandem occlusion of the distal middle cerebral and ipsilateral common carotid artery, its concentration in the ischemic hemisphere was 1.6-fold higher than that in the contralateral hemisphere. This result was supported by visualization of cilnidipine distribution using matrix-assisted laser desorption/ionization-time of flight/mass spectrometry (MALDI-TOF/MS) imaging. Our results indicated that cilnidipine is normally excluded from the brain by P-gp-mediated efflux transport, but P-gp function is impaired in ischemic brain and consequently cilnidipine is distributed to the ischemic region.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Brain; Brain Ischemia; Carotid Arteries; Cell Line; Dihydropyridines; LLC-PK1 Cells; Male; Mice; Middle Cerebral Artery; Rats; Rats, Inbred SHR; Swine

The ischemic stroke cascade is composed of several pathophysiological events, providing multiple targets for pharmacological intervention. JM-20 (3-ethoxycarbonyl-2-methyl-4-(2-nitrophenyl)-4,11-dihydro-1H-pyrido[2,3-b][1,5]benzodiazepine) is a novel hybrid molecule, in which a benzodiazepine portion is covalently linked to a dihydropyridine ring, forming a new chemical entity with potential multisite neuroprotective activity. In the present study, JM-20 prevented PC-12 cell death induced either by glutamate, hydrogen peroxide or KCN-mediated chemical hypoxia. This molecule also protected cerebellar granule neurons from glutamate or glutamate plus pentylenetetrazole-induced damage at very low micromolar concentrations. In rat liver mitochondria, JM-20, at low micromolar concentrations, prevented the Ca2+-induced mitochondrial permeability transition, as assessed by mitochondrial swelling, membrane potential dissipation and organelle release of the pro-apoptotic protein cytochrome c. JM-20 also inhibited the mitochondrial hydrolytic activity of F1F0-ATP synthase and Ca2+ influx. Therefore, JM-20 may be a multi-target neuroprotective agent, promoting reductions in neuronal excitotoxic injury and the protection of the mitochondria from Ca2+-induced impairment as well as the preservation of cellular energy balance.

Topics: Animals; Benzodiazepines; Brain Ischemia; Calcium; Cell Death; Cerebellum; Cytochromes c; Dihydropyridines; Glutamic Acid; Hydrogen Peroxide; Hydrolysis; Liver; Membrane Potential, Mitochondrial; Mitochondria; Mitochondrial Proton-Translocating ATPases; Mitochondrial Swelling; Neurons; Neuroprotective Agents; Niacin; Oxidative Stress; PC12 Cells; Pentylenetetrazole; Phosphates; Potassium Cyanide; Rats; Stroke

C5-unsubstituted-C6-aryl-1,4-dihydropyridines were prepared by a CAN-catalyzed multicomponent reaction from chalcones, β-dicarbonyl compounds, and ammonium acetate. These compounds were able to block Ca(2+) entry after a depolarizing stimulus and showed an improved Cav1.3/Cav1.2 selectivity in comparison with nifedipine. Furthermore, they were able to protect neuroblastoma cells against Ca(2+) overload and oxidative stress models. Their selectivity ratio makes them highly interesting for the treatment of neurological disorders where Ca(2+) dyshomeostasis and high levels of oxidative stress have been demonstrated. Furthermore, their low potency toward the cardiovascular channel subtype makes them safer by reducing their probable side effects, in comparison to classical 1,4-dihydropyridines. Some compounds afforded good protective profile in a postincubation model that simulates the real clinical situation of ictus patients, offering a therapeutic window of opportunity of great interest for patient recovery after a brain ischemic episode. Good activities were also found in acute ischemia/reperfusion models of oxygen and glucose deprivation.

Topics: Animals; Brain Ischemia; Calcium; Calcium Channels, L-Type; Calcium Signaling; Cell Line, Tumor; Dihydropyridines; Hippocampus; Humans; Models, Molecular; Molecular Docking Simulation; Neuroprotective Agents; Oxidative Stress; Rats; Rats, Inbred WKY; Reperfusion Injury

The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial compared the dihydropyridine T/L-type calcium channel blocker benidipine-based therapies when combined with an angiotensin receptor blocker (ARB), a β-blocker (BB) or a thiazide diuretic (TD). The results suggested that benidipine combined with a BB appeared to be less beneficial in reducing the risk of stroke compared with the benidipine-TD combination (hazard ratio (HR): 2.31, P=0.0109). We further evaluated the treatment effects on different stroke subtypes among the three benidipine-based regimens. The COPE trial was an investigator-initiated, multicenter study with PROBE design. Patients with atrial fibrillation or flutter were excluded from the study. All stroke events were subclassified with the Trial of Org 10,172 in Acute Stroke Treatment (TOAST) criteria. The total incidence of stroke was 4.7, hemorrhagic stroke was 1.6 and ischemic stroke was 2.5 per 1000 person-years. The incidence of lacunar stroke was 1.1, large-artery stroke was 0.6, cardioembolic stroke was 0.3, unknown ischemic type was 0.6 and transient ischemic attack was 0.6 per 1000 person-years. Although few differences in stroke subtypes were observed among the three treatment groups, multi-adjusted HRs for the incidence rates of all types of stroke, hemorrhagic stroke and ischemic stroke were significantly higher with the benidipine-BB regimen than with the benidipine-TD regimen. The incidence of both hemorrhagic and ischemic stroke in the benidipine-ARB regimen was not different compared with the other two treatment regimens. This prespecified sub-analysis suggested that a blood pressure-lowering therapy with a benidipine-TD regimen might be beneficial for hypertensive patients to prevent both hemorrhagic and ischemic stroke.

Topics: Adult; Aged; Aged, 80 and over; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Atrial Fibrillation; Atrial Flutter; Blood Pressure; Brain Ischemia; Dihydropyridines; Diuretics; Drug Therapy, Combination; Female; Follow-Up Studies; Heart Rate; Humans; Hypertension; Intracranial Hemorrhages; Kaplan-Meier Estimate; Male; Middle Aged; Risk Factors; Stroke; Survival Analysis; Vasodilator Agents

Possible strategies for treating ischemic stroke include: (1) Neuroprotection: preventing damaged neurons from undergoing apoptosis in the acute phase of cerebral ischemia; (2) Stem cell therapy: the repair of broken neuronal networks with newly born neurons in the chronic phase of cerebral ischemia. Firstly, we studied the neuroprotective effect of a calcium channel blocker, azelnidipine, or a by-product of heme degradation, biliverdin, in the ischemic brain. These results revealed both azelnidipine and biliverdin had a neuroprotective effect in the ischemic brain through their anti-oxidative property. Secondly, we investigated the role of granulocyte colony-stimulating factor (G-CSF) by administering G-CSF to rats after cerebral ischemia and found G-CSF plays a critical role in neuroprotection. Lastly, we developed a restorative stroke therapy with a bio-affinitive scaffold, which is able to provide an appropriate environment for newly born neurons. In the future, we will combine these strategies to develop more effective therapies for treatment of strokes.

Topics: Animals; Azetidinecarboxylic Acid; Biliverdine; Brain Ischemia; Dihydropyridines; Free Radical Scavengers; Granulocyte Colony-Stimulating Factor; Neuroprotective Agents; Rats; Stem Cells; Stroke; Tissue Scaffolds

Platelet-activating factor (PAF) is a bioactive phospholipid that accumulates during ischemia-reperfusion and is involved in the activation of platelets, neutrophils, and pro-inflammatory signaling. PAF has been suggested to enhance brain ischemia-reperfusion damage. LAU-0901, a novel PAF receptor antagonist, was examined in models of focal cerebral ischemia in rats and mice. Sprague-Dawley rats were anesthetized and received 2-hour middle cerebral artery occlusion (MCAo) by intraluminal suture. LAU-0901 (30, 60, 90 mg/kg; n=9-11) or vehicle (n=11) was administered i.p. at 2 h after onset of MCAo. The neurological status was evaluated at 60 min, and on days 1, 2, 3 and 7 after MCAo. In the dose-response study in mice, C57BL/6 mice were anesthetized and received 1 h MCAo by intraluminal suture. LAU-0901 (15, 30, 60 mg/kg; n=7-9) or vehicle (n=8) was given i.p. at 1 h after onset of MCAo. Local cerebral blood flow (LCBF) was measured at 1, 2, 4, and 6 h after MCAo in mice. LAU-0901 treated rats showed improved neurological score throughout the 7-day survival period. LAU-0901 treatment (30, 60 and 90 mg/kg) reduced total corrected infarct volume compared to vehicle rats by 76, 88 and 90%, respectively. Mice treated with LAU-0901 (30 and 60 mg/kg) reduced total infarction by 29% and 66%, respectively. LCBF was improved by treatment with LAU-0901 (30 mg/kg) by 77% of baseline at 6 h. In conclusion, we demonstrate for the first time that LAU-0901 improves behavioral scores, LCBF and reduces infarct volume after focal cerebral ischemia in rats and mice. Thus, this PAF receptor antagonist exhibits potent and sustained neuroprotection that may be of value for the design of stroke therapies.

Topics: Acute Disease; Animals; Behavior, Animal; Brain Ischemia; Cerebrovascular Circulation; Dihydropyridines; Dose-Response Relationship, Drug; Infarction, Middle Cerebral Artery; Male; Mice; Mice, Inbred C57BL; Neocortex; Neuroprotective Agents; Platelet Activating Factor; Rats; Rats, Sprague-Dawley

The combined effects of a calcium-channel blocker (CCB) with an angiotensin (Ang) II type 1 (AT1) receptor blocker were investigated in focal brain ischemia induced by middle cerebral artery (MCA) occlusion.. In male C57BL/6J mice, permanent occlusion of the MCA-induced focal cerebral ischemia and neurological deficit after 24 h, accompanied by a reduction of cerebral blood flow and an increase in superoxide production in the ischemic area. Administration of azelnidipine, a CCB, at 1.0 mg/kg per day for 10 days significantly suppressed these changes after MCA without affecting systolic blood pressure. Such inhibitory effects of azelnidipine on brain ischemia could be observed in AT1a receptor-deficient mice. In addition, olmesartan, an AT1 receptor blocker, at 3.0 mg/kg per day also diminished the ischemic brain area and neurological score, as well as superoxide production and the reduction of cerebral surface blood flow in C57BL/6 mice. The combination of lower doses of azelnidipine (0.1 mg/kg per day) and olmesartan (0.5 mg/kg per day) significantly attenuated the ischemic brain area, neurological score, superoxide production and the reduction of cerebral surface blood flow after MCA occlusion in C57BL/6 mice, whereas either of these agents alone at these doses did not affect brain ischemia.. These results indicate that azelnidipine inhibited ischemic brain damage induced by MCA occlusion, at least in part, through suppression of blood flow change and oxidative stress via a signaling mechanism independent of AT1 receptor stimulation. Moreover, azelnidipine synergistically enhanced the inhibitory action of olmesartan on brain ischemia, suggesting beneficial combined effects of a CCB with an AT1 receptor blocker on ischemic brain damage.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Azetidinecarboxylic Acid; Brain Ischemia; Calcium Channel Blockers; Cerebrovascular Circulation; Dihydropyridines; Disease Models, Animal; Drug Therapy, Combination; Imidazoles; Male; Mice; Mice, Inbred C57BL; Tetrazoles

Topics: Acetylcholine; Adenosine A3 Receptor Antagonists; Animals; Brain; Brain Ischemia; Calcium Channels; Central Nervous System; Dihydropyridines; Dizocilpine Maleate; Electrophysiology; Inosine; Ischemia; Neuroprotective Agents; Rats; Receptors, N-Methyl-D-Aspartate

Although a blockade or lack of N-type Ca(2+) channels has been reported to suppress neuronal pathological processes in several animal models of pain and ischemic brain injury, information is still limited regarding the neuroprotective effects of a dual L/N-type Ca(2+) channel blocker, cilnidipine. In this study, we assessed the effects of cilnidipine in the rat focal brain ischemia model to analyze its potential utility for hypertensive patients with cerebral infarction. In an anesthetized rat model, cerebral vasodilator actions of cilnidipine were detected at hypotensive doses, which was less potent than those of an L-type Ca(2+) channel blocker, nilvadipine. In the rat focal brain ischemia model, an anti-hypertensive and anti-sympathetic dose of cilnidipine could reduce the size of cerebral infarction, whereas an equipotent hypotensive dose of nilvadipine failed to affect it. These results suggest that N-type Ca(2+) channel-blocking profile of cilnidipine may contribute its neuroprotective action in the animal focal brain ischemia model. Thus, treatment of hypertension with cilnidipine may prevent severe consequences after brain attack.

Topics: Animals; Brain Ischemia; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Cerebral Infarction; Dihydropyridines; Dose-Response Relationship, Drug; Male; Nifedipine; Rats; Rats, Sprague-Dawley

1. AE0047 is a new dihydropyridine calcium antagonist with protective effects against cerebral ischaemia and the occurrence of stroke in several animal models. 2. In the present study we investigated whether AE0047 would improve the reduced cerebral blood flow (CBF) and oedema formation in cats subjected to middle cerebral artery (MCA) occlusion and compared it for efficacy with other dihydropyridine calcium antagonists with different moieties, such as nilvadipine and nicardipine. 3. Middle cerebral artery occlusion reduced local CBF (ICBF), as measured by the hydrogen clearance method, while dry weight measurement showed that water content in the cortical tissues surrounding each ICBF measurement electrode had increased after 4 h ischaemia. 4. Both AE0047 (10 micrograms/kg) and nilvadipine (30 micrograms/kg), given intravenously 20 min after MCA occlusion, produced an approximate 10% hypotensive response and significantly increased ICBF in severely and moderately ischaemic regions, grouped according to the initial reduced flow values. However, nicardipine (5 micrograms/kg bolus followed by infusion of 3 micrograms/kg per min for 60 min) failed to mitigate the reduction in ICBF despite an increase in the ICBF of the contralateral cortex. In addition, AE0047 tended to prevent an increase in cortical water content in severely ischaemic regions, whereas water content in both nilvadipine- and nicardipine-treated groups tended to increase. 5. These results suggest that dihydropyridine calcium antagonists act differently on cerebral ischaemia and oedema formation in a manner dependent on their side-chain structures and that AE0047 effectively attenuates ischaemic brain damage without aggravating oedema.

Topics: Animals; Blood Pressure; Body Water; Brain Ischemia; Calcium Channel Blockers; Cats; Cerebral Arteries; Cerebral Cortex; Dihydropyridines; Male; Regional Blood Flow

Calcium is involved in the physiopathology of cerebral ischemia. Calcium antagonists might prevent the calcium overload and death of cells from ischemically compromised tissue. We compare the neuroprotective effect of various doses (0.2, 0.5 and 1 mg/kg) of two dihydropyridines, nimodipine and the novel 1,4-dihydropyridine derivative PCA50938, and flunarizine in the gerbil model of global ischemia. Improvements in morbidity were observed 2 h after the end of carotid occlusion (McGraw's scale) with 0.5 mg/kg of flunarizine, all doses of PCA50938 and 0.2 mg/kg nimodipine. Neuronal loss in the CA1 sector of the hippocampus was examined. The animals treated with 0.5 mg/kg flunarizine and those treated with 1 mg/kg PCA50938 showed a significant reduction in the percentage of damaged neurons in the hippocampal CA1 area, 72 h after transient ischemia. None of the animals treated with 0.5 mg/kg flunarizine had more than 80% of the evaluated neurons altered. We conclude that PCA50938 and flunarizine may act as neuroprotective drugs with different patterns of dose-response and neuroprotective-morbidity-mortality relationships, in the model of global cerebral ischemia in the gerbil. Flunarizine has a narrow therapeutic range.

Topics: Animals; Brain Ischemia; Calcium Channel Blockers; Dihydropyridines; Female; Flunarizine; Gerbillinae; Male; Neuroprotective Agents; Nimodipine

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

Topics: Animals; Brain Ischemia; Dihydropyridines; Male; Rats; Rats, Wistar

Topics: Animals; Brain Ischemia; Cerebrovascular Circulation; Dihydropyridines; Electroencephalography; Male; Rats; Rats, Wistar

SM-6586 (SM) is a new derivative of dihydropyridine with potent calcium blocking activity and inhibitory activity of the Na+/H+ and Na+/Ca++ exchange transport. The effect of SM on survival rate, brain edema and metabolites was evaluated using two different models in spontaneously hypertensive rat (SHR). Global ischemia was induced by bilateral common carotid artery ligation (BLCL) and focal ischemia was induced by middle cerebral artery occlusion. The survival rate after BLCL was higher in the SM-treated group. The brain water content was lower, the ATP level was higher and lactate level was lower in the SM-treated group compared to the control group. In focal ischemia models, the SM-treated group showed a reduction of T1 relaxation time. The brain water content was significantly decreased in the SM-treated group. These results indicate that SM was effective in ameliorating the ischemic insult in global and focal cerebral ischemia models.

Topics: Animals; Blood-Brain Barrier; Brain Damage, Chronic; Brain Edema; Brain Ischemia; Calcium Channel Blockers; Dihydropyridines; Dose-Response Relationship, Drug; Energy Metabolism; Male; Oxadiazoles; Rats; Rats, Inbred SHR; Water-Electrolyte Balance

Voltage-dependent calcium channels (VDCCs) are thought to play a major role in the alteration of calcium homeostasis during ischemia. Tissue functional state as well as responsiveness to therapy with calcium channel blockers may be a function of regional changes in the density of VDCCs. This study determined whether VDCCs are altered by global ischemia in infant and adolescent swine.. We employed the radioligand 3HPN200-110 to quantify the binding characteristics of VDCCs in cerebral cortex, caudate, and hippocampus by equilibrium binding analysis. Adolescent and infant pigs underwent 3, 5, 10, and 20 minutes of global cerebral ischemia without reperfusion by ligation of the brachiocephalic and left subclavian arteries combined with hypotension to a mean arterial blood pressure of 50 mm Hg. Brain cortex, hippocampus, and caudate samples were taken during ischemia and frozen immediately in liquid nitrogen, and crude synaptosomal membranes were isolated by differential centrifugation/filtration. 3HPN200-110 equilibrium binding assays were performed in the presence or absence of 1.0 mumol/L unlabeled nitrendipine to determine total and nonspecific binding.. Infant cortex maximal binding (Bmax) increased to 176% of control after 5 minutes of global cerebral ischemia and remained significantly elevated (172% of control) after 10 minutes before falling to near control levels by 20 minutes. Adolescent cortex Bmax increased to 157% of control levels after 5 minutes but did not remain elevated, falling to 131% of control by 10 minutes and near control by 20 minutes. Infant caudate and hippocampus binding were significantly elevated after 10 (124% and 149% of control, respectively) and 20 (115% and 120% of control, respectively) minutes of ischemia. Adolescent caudate and hippocampus binding was either not significantly different from control levels (hippocampus at 10 minutes) or less than control after 10 and 20 minutes of global cerebral ischemia. The decrease in binding following the initial upregulation, which appeared earlier in the adolescent than the infant pigs, may indicate decreased tolerance to ischemia in the adolescent.. The binding of 3HPN200-110 in brain is altered during 20 minutes of global cerebral ischemia, and these changes are region- and age-dependent.

Topics: Aging; Animals; Blood Pressure; Brain Ischemia; Calcium Channels; Caudate Nucleus; Cerebral Cortex; Dihydropyridines; Hippocampus; Isradipine; Ligands; Membrane Proteins; Nitrendipine; Protein Binding; Swine; Synaptosomes; Time Factors

The effect of benidipine on experimental cerebral ischemia was investigated in rats subjected to occlusion of the bilateral common carotid arteries. Benidipine (30 micrograms/kg, i.p.) improved neurological symptoms such as ataxia, convulsion and loss of righting reflex, and prolonged survival time after occlusion of the bilateral common carotid arteries. In the nicardipine (100 micrograms/kg, i.p.)-treated group, a similar effect was observed, whereas nifedipine (100, 300 micrograms/kg, i.p.) and verapamil (300 micrograms/kg, i.p.) did not show any beneficial effect in this model. Furthermore, pretreatment with benidipine (30 micrograms/kg, i.p.) suppressed the increase in cerebral water content 3 h after the occlusion. Nicardipine (100 micrograms/kg, i.p.) showed a tendency to reduce the increase in cerebral water content, though the effect was not statistically significant. Nifedipine (100 micrograms/kg, i.p.) produced no improvement. After occlusion of the bilateral common carotid arteries, depletion of adenosine triphosphate (ATP) and phosphocreatine (CP) and an accumulation of lactate occurred in a time-dependent manner. Prophylactic administration of benidipine (30 micrograms/kg, i.p.), 20 min before occlusion, attenuated the depletion of ATP and CP and the accumulation of lactate 3h after the occlusion. Furthermore, post-treatment with benidipine 30 min after occlusion also suppressed these metabolic disorders. In conclusion, the beneficial effects of benidipine in this severe cerebral ischemia model show that the compound has advantages over nicardipine, nifedipine and verapamil. Thus, these results suggest that benidipine may be useful in the treatment of acute ischemic cerebral damage.

Topics: Adenosine Triphosphate; Animals; Behavior, Animal; Brain; Brain Chemistry; Brain Ischemia; Calcium Channel Blockers; Carotid Artery, Common; Dihydropyridines; Lactates; Lactic Acid; Male; Nicardipine; Nifedipine; Phosphocreatine; Potassium; Rats; Rats, Wistar; Sodium; Verapamil

The effects of a novel dihydrothienopyridine Ca antagonist S-(+)-methyl-4,7-dihydro-3-isobutyl-6-methyl-4-(3-nitrophenyl)-thieno [2,3-b]pyridine-5-carboxylate (S-312-d), on the amount of amino acid release during cerebral ischemia and delayed neuronal death in the hippocampal CA1 region of stroke-prone spontaneously hypertensive rats were studied and compared with those of nimodipine. The released amino acids were measured by high-performance liquid chromatography after microdialysis. Cerebral ischemia was produced by occlusion of the bilateral common carotid arteries for 20 min. Intraduodenal administration of 0.3 mg/kg of S-312-d at 60 min before the carotid occlusion significantly decreased the ischemic release of glutamate and taurine, but did not influence their basal release. However, nimodipine did not inhibit the ischemic glutamate release even at a dose of 10 mg/kg. Similar peripheral hemodynamic effects were observed before and during bilateral carotid occlusion in groups treated with S-312-d or nimodipine. During the carotid occlusion, almost no cerebral blood flow was observed in either group. Therefore, the inhibitory effect of S-312-d on ischemic amino acid release probably arises from its potent direct action on neuronal cells. The neuronal cell densities of the CA1 subfield at 7 days after 20-min bilateral carotid occlusion significantly decreased in the vehicle-control group compared with the sham-operated group. Intraperitoneal administration of 0.1 mg/kg of S-312-d at 60 min before ischemia prevented the decrease of neuronal cell density compared with the vehicle control. These results show that S-312-d can offer marked neuronal protective effects against ischemic injury.

Topics: Amino Acids; Animals; Antihypertensive Agents; Brain Ischemia; Calcium Channel Blockers; Cell Death; Dihydropyridines; Hemodynamics; Male; Neurons; Nimodipine; Rats; Rats, Inbred SHR

Elevated intracellular calcium (iCa2+) plays an important role in the pathophysiology of ischemic brain damage. The mechanisms by which iCa2+ increases are uncertain. Recent evidence implicates the voltage-dependent calcium channel (VDCC) as a likely site for the alteration in Ca2+ homeostasis during ischemia. The purpose of this study was to determine whether VDCCs are altered by global ischemia and reperfusion in a canine cardiac arrest, resuscitation model. We employed the radioligand, [3H]PN200-110, to quantitate the equilibrium binding characteristics of the VDCCs in the cerebral cortex. Twenty-five adult beagles were separated into four experimental groups: (a) nonischemic controls, (b) those undergoing 10-min ventricular fibrillation and apnea, (c) those undergoing 10-min ventricular fibrillation and apnea followed by spontaneous circulation and controlled respiration for 2 and (d) 24 h. Brain cortex samples were taken prior to killing of the animal, frozen immediately in liquid nitrogen, and crude synaptosomal membranes isolated by differential centrifugation/filtration. After 10 min of ischemia the maximal binding (Bmax) of [3H]PN200-110 increased to greater than 250% of control values (control Bmax 11.16 +/- 0.98; ischemic 28.35 +/- 2.78 fmol/mg protein; p less than 0.05). Bmax returned to near control values after 2 h of reperfusion but remained significantly greater than the control at 24 h. Although the affinity constant (Kd) (control = 0.12 +/- 0.03 nM) appeared to increase with ischemia and normalize with reperfusion, the changes were not statistically significant. We conclude that the binding of [3H]PN200-110 to L-type VDCCs is increased after 10 min of global ischemia/anoxia produced by ventricular fibrillation and apnea in the dog.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Binding Sites; Brain Ischemia; Calcium Channel Blockers; Calcium Channels; Cerebral Cortex; Dihydropyridines; Dogs; Female; Isradipine; Nitrendipine; Reperfusion; Synaptosomes

Acute cerebral ischemia was produced in rats by injection of arachidonic acid (AA) into the internal carotid artery. Evans blue (EB) was intravenously injected and its extravasation into the brain was determined as an indicator of disturbances in the blood-brain barrier and endothelial cells. Control animals showed severe cerebral edema and marked blue staining of the brain. Benidipine (30 micrograms/kg, i.p.) suppressed the increase in cerebral water content and the extravasation of EB. Similarly nicardipine (100 micrograms/kg, i.p.) suppressed the elevation of water content and the extravasation of EB. Furthermore, both benidipine (30 micrograms/kg, i.p.) and nicardipine (100 micrograms/kg, i.p.) improved the neuronal injuries following AA-injection. An antiplatelet agent, ticlopidine (100 mg/kg, i.p.), and a thromboxane A2 synthetase inhibitor, OKY-1581 (3 mg/kg, i.p.), also suppressed the elevation of cerebral water content. A lipoxygenase inhibitor, AA-561 (200 mg/kg, p.o.), and a cyclooxygenase inhibitor, indomethacin (10 mg/kg, i.p.), did not prevent the increase in cerebral water content. Neither benidipine (3-30 micrograms/kg, i.v.) nor nicardipine (100 micrograms/kg, i.v.) inhibited the AgNO3-induced thrombus formation of the abdominal aorta, whereas ticlopidine (100 mg/kg, p.o.) and OKY-1581 (3 mg/kg, i.v.) prevented the thrombus formation. From the present results, it is suggested that benidipine, as well as nicardipine, may protect against AA-induced acute cerebral infarction via a mechanism independent of antithrombotic action.

Topics: Animals; Arachidonic Acid; Benzoquinones; Blood-Brain Barrier; Brain Edema; Brain Ischemia; Calcium Channel Blockers; Cerebral Infarction; Dihydropyridines; Evans Blue; Lipoxygenase Inhibitors; Male; Methacrylates; Nicardipine; Rats; Rats, Inbred Strains; Thromboxane-A Synthase; Ticlopidine

With an in-vivo autoradiographic method the binding of 3H-nimodipine (CAS 66085-59-4) and cerebral blood flow (14C-iodoantipyrine method) were measured in rat brain after occlusion of the middle cerebral and common carotid arteries. The dependence of the binding to neuronal cellular membranes on the duration of ischemia can be interpreted as indicator of the tissue's functional state or its responsiveness to therapy with calcium entry blockers. In the two analyzed structures, dorsolateral caudate and overlying sensorimotor cortex, the appearance of infarction is preceded by an activation of the nimodipine binding sites followed by persistent decline of the binding intensity. Binding to nimodipine may therefore be a useful marker of ischemic but salvageable brain tissue.

Topics: Animals; Brain Ischemia; Calcium Channels; Carotid Arteries; Cerebral Arteries; Dihydropyridines; Male; Nimodipine; Rats; Rats, Inbred Strains

We performed quantitative autoradiography to determine sequential alterations in the binding of muscarinic cholinergic and adenosine A1 receptors and of an L-type calcium channel blocker in the gerbil hippocampus following repeated brief ischemic insults. [3H]Quinuclidinyl benzilate (QNB). [3H]cyclohexyladenosine (CHA) and [3H]PN200-110 were used to label muscarinic and adenosine A1 receptors and L-type calcium channels, respectively. Changes at 1 h, 6 h, 1 day, 4 days and 1 month after three 2-min ischemic insults were compared with changes after single 2- or 6-min ischemia. Two-minute ischemia, which causes no histopathological neuronal damage, produced no persistent alterations in binding sites. We observed a transient and mild increase in binding activities, especially in [3H]CHA binding, at 1 h of recirculation. Following 6-min ischemia and three 2-min ischemic insults. [3H]QNB and [3H]PN200-110 binding decreased by more than 50% in the CA1 subfield by 1 month, but [3H]CHA binding decreased transiently by 20-30% at 4 days when delayed neuronal death of hippocampal CA1 pyramidal cells took place. Reductions in binding, especially in [3H]QNB binding, following three 2-min ischemic insults were greater and appeared earlier than those after 6-min ischemia. Furthermore, alterations extended to the CA3 subfield and the dentate gyrus following repeated insults. Thus, alterations in receptor binding after repeated ischemic insults were greater than those after equivalent single period of ischemia.

Topics: Adenosine; Animals; Autoradiography; Brain Ischemia; Calcium Channel Blockers; Calcium Channels; Dihydropyridines; Gerbillinae; Hippocampus; Isradipine; Male; Quinuclidinyl Benzilate; Receptors, Muscarinic; Receptors, Nicotinic; Receptors, Purinergic

The effect of NB-818, a new dihydropyridine calcium entry blocker, on delayed neuronal death (DND) in the hippocampal CA1 subfield of gerbils after 5 minutes of forebrain ischemia induced by bilateral carotid artery occlusion was examined. Gerbils were treated intraperitoneally with NB-818 (0.1-3 mg/kg) just after release of the occlusion. Four days after the ischemia, they were fixed by perfusing 10% buffered-formalin, and the neuronal cell density (NCD, cell/mm) in the CA1 subfield was estimated under microscopy. The average NCD in the ischemic control group was 43 +/- 10.8 cells/mm, whereas NB-818 (3 mg/kg) significantly ameliorated DND with an average NCD of 143 +/- 24.2 cells/mm (P less than 0.01). In addition, NB-818 (3 mg/kg) significantly inhibited DND at 1, 2 and 4 weeks after transient ischemia: the average NCD of the NB-818 and ischemic control groups were 80 +/- 9.4 (P less than 0.01) and 43 +/- 7.7 cells/mm, 92 +/- 13.7 (P less than 0.05) and 52 +/- 9.3 cells/mm, and 57 +/- 5.0 (P less than 0.01) and 43 +/- 12.4 cells/mm, respectively. In this experiment, NB-818 exhibited a protective effect on DND in the hippocampal CA1 subfield after transient forebrain ischemia, and its effect persisted for up to 4 weeks. These findings suggest that NB-818 may be useful for clinical treatment of neurological deficit after an ischemic insult.

Topics: Animals; Brain Ischemia; Calcium Channel Blockers; Cell Survival; Dihydropyridines; Dizocilpine Maleate; Gerbillinae; Hippocampus; Histocytochemistry; Injections, Intraperitoneal; Male; Neurons

The effect of NB-818 on regional cerebral cortical blood flow (rCBF) during normal and ischemic periods was studied in Mongolian gerbils by means of hydrogen clearance methods, and that effect was compared with that of nimodipine. In normal animals, the rCBF increased dose-dependently, when NB-818 was tested. The increased rCBF showed a slow onset and long duration of action. When comparing the potency of increase in rCBF, the action of NB-818 (0.01-0.1 mg/kg i.p.) was more potent and longer lasting than that of nimodipine (0.01-0.1 mg/kg i.p.). Thus, the cerebral ischemia, produced by unilateral common carotid artery (CCA) occlusion, was studied. Before the unilateral CCA occlusion, the rCBF value was 41.4 +/- 0.27 ml/100 g of brain per min. The rCBF after unilateral CCA occlusion in gerbils was divided into three types as follows: rCBF values of above 30 ml/100 g of brain per min (type I), between 20 to 29 ml/100 g of brain per min (type II) and below 19 ml/100 g of brain per min (type III). In type I and II, NB-818 (0.01-0.1 mg/kg i.p.) significantly improved the reduced rCBF after the occlusion, and its effects continued throughout the experiments. In type II and III, supratentorial brain edema was observed 4.5 hr after the occlusion. The brain edema was significantly inhibited by NB-818 in the type II but not in the type III because the increased rCBF in type III with NB-818 was slight.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Pressure; Brain Ischemia; Calcium Channel Blockers; Cerebrovascular Circulation; Dihydropyridines; Female; Gerbillinae; Injections, Intraperitoneal; Male; Nifedipine; Nimodipine