dihydropyridines and Ischemic-Attack--Transient

CV-159, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic++ + acid methyl 6-(5-phenyl-3-pyrazolyloxy)hexyl ester, is a dihydropyridine derivative that blocks the L-type Ca2+ channel and inhibits the calmodulin (CaM)-dependent pathway. In this study, we examined the effects of CV-159 on rat ischemic brain injury. CV-159 (5 and 10 mg/kg, p.o.) gave significant protection against delayed neuronal death in the hippocampal CA1 region after 15-min transient forebrain ischemia. In contrast, the Ca2+ antagonists nicardipine (1 and 10 mg/kg, p.o.) and nifedipine (1 mg/kg, i.p.) and the CaM antagonist N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7, 500 ng, i.c.v.) had no effect on this hippocampal neuronal death. CV-159 also diminished the size of the brain infarct after permanent middle cerebral artery (MCA) occlusion, although physiological variables, including regional cerebral blood flow, were not affected. The increase in the water content of the infarcted cortex induced by MCA occlusion was significantly reduced by CV-159. On the other hand, neither nicardipine nor nifedipine affected the brain infarct size, volume or increased water content induced by MCA occlusion, as previously reported (A. Sauter and M. Rudin, Am. J. Hypertens. 4 121S-127S, 1991). These findings indicate that Ca2+ antagonists, such as nicardipine and nifedipine, and W-7 have no effect on rat ischemic brain injury. The results suggest that CV-159 protects against ischemic brain injury. This might be mediated by both blocking the L-type Ca2+ channel and inhibiting CaM-dependent function via Ca2+/CaM binding at a different binding site from that of W-7 to CaM (H. Umekawa, K. Yamakawa, K. Nunoki, N. Taira, T. Tanaka, and H. Hidaka, Biochem. Pharmacol. 37 3377-3381, 1988).

Topics: Animals; Body Temperature; Brain Edema; Calcium Channel Blockers; Calcium-Calmodulin-Dependent Protein Kinases; Cell Death; Cerebral Infarction; Dihydropyridines; Hemodynamics; Hippocampus; Ischemic Attack, Transient; Male; Neurons; Neuroprotective Agents; Nicardipine; Nifedipine; Rats; Rats, Sprague-Dawley; Sulfonamides; Time Factors; Water

We investigated the effects of lacidipine on focal cerebral ischemia in rats, and these effects were compared with those of nicardipine. Drugs were administered orally 5 min after middle cerebral artery occlusion (MCAO). Neurological scores as described by Bederson et al. (Stroke 17, 472-476, 1986) and cerebral infarct size (CIS) determined by the 2,3,5-triphenyltetrazolium chloride staining method were measured 24 hr after MCAO. Cerebral blood flow (CBF) and energy metabolites were determined by the hydrogen clearance method and an enzymatic method, respectively. In the drug-untreated group, we observed low-CBF of approximate 13 ml/100 g/min during 0.5-6 hr of occlusion and extensive cerebral infarction associated with severe neurologic deficits (ND). Lacidipine at 1 and 3 mg/kg, although it lowered blood pressure, improved low-CBF to approximate 20 ml/100 g/min during 1.5-6 hr of occlusion and increased tissue levels of ATP 6 hr after MCAO in a dose-dependent manner. Nicardipine at 30 mg/kg also improved low-CBF and increased tissue levels of ATP significantly. However, the improvement of low-CBF by nicardipine was transient. Lacidipine at 3 mg/kg reduced CIS and ameliorated ND significantly. In contrast, nicardipine at 30 mg/kg could not ameliorate ND in spite of a significant reduction of CIS similar to that of lacidipine (3 mg/kg). These results suggest that the improvement of focal cerebral ischemia by lacidipine may be partly due to long-lasting improvement of collateral blood supply to the ischemic area.

Topics: Adenosine Triphosphate; Animals; Brain; Calcium Channel Blockers; Cerebral Arterial Diseases; Cerebral Infarction; Cerebrovascular Circulation; Dihydropyridines; Disease Models, Animal; Dose-Response Relationship, Drug; Energy Metabolism; Ischemic Attack, Transient; Male; Neurologic Examination; Nicardipine; Rats; Rats, Sprague-Dawley

During cerebral ischemia, both promoting and limiting factors are present for activation of the N-methyl-D-aspartate (NMDA) receptor ion channel and the dihydropyridine (DHP)-sensitive Ca2+ channels. We investigated the activity of these channels during ischemia and reperfusion in the rat hippocampus in situ.. Reversible ischemia was induced by bilateral carotid artery ligation. NMDA and BAY K8644 were applied by iontophoresis or pneumatic ejection, and extracellular field potential and resistance changes were recorded from the CA1 region of the rat hippocampus. Resting membrane potentials of the CA1 neurons were also recorded.. DC potential shifts produced by NMDA and BAY K8644 were reduced when ischemia depressed the evoked activity more than 50%. They disappeared on total failure of synaptic transmission and recovered during reperfusion. When the evoked activity was depressed less than 50%, DC shifts were greater than their preischemic values; however, BAY K8644-induced potentiation did not reach statistical significance. CA1 neurons were depolarized during ischemia.. These data suggest that ischemia severe enough to cause transmission failure inactivates NMDA and DHP-sensitive Ca2+ currents. During less intense ischemia and reperfusion, NMDA and DHP-sensitive Ca2+ channels are functional, and their overactivation may lead to neurotoxicity.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Calcium Channel Agonists; Calcium Channel Blockers; Calcium Channels; Dihydropyridines; Electric Impedance; Electrophysiology; Evoked Potentials; Excitatory Amino Acid Agonists; Hippocampus; Ion Channels; Iontophoresis; Ischemic Attack, Transient; Male; Membrane Potentials; N-Methylaspartate; Neurons; Rats; Receptors, N-Methyl-D-Aspartate; Reperfusion

We examined the cerebral protective effects of lacidipine (L) using three different types of cerebral ischemia models, and the effects were compared with those of nicardipine (N). (1) In the transient forebrain ischemia model of the rat, oral administration of L (0.3 and 1 mg/kg) before ischemia significantly decreased the number of acidophilic neurons in CA1 regions of the hippocampus 7 days after ischemia. N (3 mg/kg, p.o.) before ischemia also produced a significant reduction in the number of acidophilic neurons, and it's effectiveness was almost the same as that of L (1 mg/kg). (2) In the focal cerebral ischemia model of the rat, oral administration of L (1 and 3 mg/kg) before of after left middle cerebral artery occlusion (MCAO) significantly reduced infarct size at 24 hr after MCAO. Such an ameliorative effect was also observed when N was administered orally. However, the effect of N at 30 mg/kg was less than that of L at 1 mg/kg. (3) In the delayed cerebral vasospasm model of the dog after subarachnoid hemorrhage (SAH), intravertebral artery injection of L (10 micrograms/kg) or N (10 micrograms/kg) dilated the contracted basilar artery 3 days after SAH to the level before SAH. Finally, while both L and N increased cerebral blood flow (CBF) in a dose-dependent manner in conscious normal rat, the increment of CBF induced by L at a given level of reduced-blood pressure was greater than that induced by N. These results indicate that lacidipine may be a potential therapeutic agent that exerts a protective effect against brain damage after cerebral ischemia.

Topics: Animals; Blood Pressure; Calcium Channel Blockers; Cerebrovascular Circulation; Dihydropyridines; Disease Models, Animal; Dogs; Ischemic Attack, Transient; Male; Nicardipine; Rats; Rats, Sprague-Dawley

We investigated the effects of calcium antagonists against ischemic injury in vivo and against excitotoxic damage in vitro. In vivo nimodipine protected significantly the CA1 hippocampal neurons from neurodegeneration after transient global ischemia in rats without changing the local cerebral blood flow. Furnidipine reduced the area of ischemia after permanent MCA-occlusion in mice. The results in vitro using the Ca(2+)-sensitive dye fura-2 showed that nimodipine reduced in a dose-dependent manner the elevation of [Ca2+]i in hippocampal neurons induced by K(+)-stimulation. The present in vitro and in vivo data show that calcium antagonists are potent agents in protecting neurons against the deleterious consequences of an excitotoxic or ischemic insult.

Topics: Animals; Calcium Channel Blockers; Dihydropyridines; Dose-Response Relationship, Drug; Electroencephalography; Hippocampus; Ischemic Attack, Transient; Mice; Nerve Degeneration; Nimodipine; Rats; Time Factors

Acute cerebral ischemia in cats (both carotid arteries occlusion during 30 min after permanent occlusion of both vertebral arteries) was accompanied by postischemic hypoperfusion and hypo-oxygenation of the cerebral tissue. Intravenous infusion of cerebrocrast (1 micrograms.kg-1.min-1 during 60 min) prevented manifestation of the postischemic phenomena. Antihypoxic effect of cerebrocrast involved the cerebral blood flow increase, brain oxygen consumption lowering and Hb-O2-affinity decrease.

Topics: Acute Disease; Animals; Brain; Calcium Channel Blockers; Cats; Dihydropyridines; Drug Evaluation, Preclinical; Female; Hemodynamics; Ischemic Attack, Transient; Male; Oxygen Consumption; Time Factors; Vasodilator Agents

We performed receptor autoradiography to determine sequential alterations in the binding of muscarinic cholinergic and adenosine A1 receptors and of a voltage dependent L-type calcium channel blocker 1 h-1 month after transient cerebral ischemia in the gerbil brain. [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. Transient ischemia was induced for 10 min. [3H]QNB and [3H]CHA binding showed no significant alteration in selectively vulnerable areas at an early stage (1-24 h) of recirculation. However, the dentate molecular layer which was resistant to ischemia revealed a significant decrease in the [3H]CHA binding sites 24 h after ischemia. Thereafter, the [3H]QNB and [3H]CHA binding showed significant reduction in most of selectively vulnerable areas. Marked reduction was especially found in the dorsolateral part of striatum and the hippocampal CA1 sector which was the most vulnerable to ischemia. In contrast, [3H]PN200-110 binding showed a transient elevation in the hippocampal CA1 sector, the dentate molecular layer and the thalamus 1 h of recirculation. However, the striatum and neocortex revealed no alteration in the [3H]PN200-110 binding. Thereafter, the reduction in the [3H]PN200-110 binding was seen only in the dorsolateral part of the striatum and the hippocampal CA1 sector. The results suggest that transient cerebral ischemia can cause the alterations in the binding of muscarinic cholinergic and adenosine A1 receptors and of L-type calcium channel blocker in most of selectively vulnerable areas.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine; Animals; Autoradiography; Brain; Calcium Channel Blockers; Calcium Channels; Dihydropyridines; Gerbillinae; Ischemic Attack, Transient; Isradipine; Male; Organ Specificity; Quinuclidinyl Benzilate; Receptors, Muscarinic; Receptors, Nicotinic; Receptors, Purinergic; Time Factors; Tritium

AE0047, a novel calcium antagonist, has mild and long-acting hypotensive effects. This drug also has more selective dilating action on cerebral arteries than on other systemic ones. We studied the cerebral vasodilatative effects of AE0047 by means of vertebral angiography in anesthetized dogs. Vertebral blood flow (VBF) was significantly increased by 91, 139 and 132% in 10, 30 and 60 min after intravenous administration of AE0047 at 30 micrograms/kg, respectively. No difference in vasodilating action was observed among basilar, posterior communicating, middle cerebral and internal carotid arteries. In basilar artery, the dilatative rate was about 30% between 10 and 60 min after injection of AE0047. Following intravertebral administration of endothelin at 100 pmol/kg, small vessels of the cerebral artery were constricted, and VBF was gradually decreased. AE0047 eliminated the vasoconstriction and increased VBF. Moreover, the vasoconstrictive effect of endothelin was prevented by pre-treatment of AE0047. These results indicate that AE0047 has potent vasodilating and spasmolytic actions on cerebral arteries.

Topics: Animals; Calcium Channel Blockers; Cerebral Arteries; Cerebrovascular Circulation; Dihydropyridines; Dogs; Endothelins; Female; Ischemic Attack, Transient; Male; Peptides; Vasoconstriction; Vasodilator Agents