Effect of dihydropyridines and diphenylalkylamines on pentylenetetrazol-induced seizures and cerebral blood flow in cats

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✓ Nimodipine, a dihydropyridine that interacts with a Ca++ channel-associated binding site, when delivered (30 to 150 µg/kg) intra-arterially (ia) to enflurane-anesthetized cats, produced a dose-dependent suppression of seizures evoked by pentylenetetrazol. A comparable suppression was produced by clonazepam (1 to 30 µg/kg, ia). Phenytoin was maximally effective only at nearly lethal doses (90 mg/kg, ia). Verapamil, a diphenyl-alkylamine that interacts with a separate Ca++ channel-associated site, at the maximum nonlethal dose (6 mg/kg, ia) resulted in a mild facilitation of seizure activity. The drug vehicle used in these studies (50% polyethylene glycol-400) had no effect when given alone. Regional cerebral blood flow (rCBF) as measured by the clearance of xenon-133 was markedly elevated immediately after the onset of seizure activity (89 ± 3 to 168 ± 4 ml/100 gm/min). Concurrent with their resolution of the seizure activity, both nimodipine and clonazepam reduced rCBF to near preseizure levels and preserved the rCBF response to hypercarbia which would otherwise have been abolished following prolonged seizure activity. Moreover, the effect of nimodipine on rCBF and seizures occurred without any prominent alterations in mean arterial blood pressure as compared to preseizure levels. These data support the proposition that a dihydropyridine Ca++ channel binding site may play a role in modulating paroxysmal neuronal activity, and suggest that this class of agents may reflect a novel group of antiepileptic drugs.

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Address reprint requests to: Tony L. Yaksh, Ph.D., Departments of Neurologic Surgery and Pharmacology, Mayo Clinic, Rochester, Minnesota 55905.

© AANS, except where prohibited by US copyright law.

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Figures

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    Electroencephalographic (EEG) tracings in cats after induction of seizures with intravenous Metrazol (PTZ), 200 mg. BP = blood pressure. Upper: Tracings depicting continuing epileptiform activity despite intra-arterial treatment with vehicle (polyethylene glycol-400) 10 minutes after PTZ infusion began. Lower: Tracings showing effective abolition of seizures and return to a normal EEG tracing after intra-arterial treatment with nimodipine, 150 µg/kg. Temporal sequence of each tracing is presented with the numbers below.

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    Burst duration on electroencephalograms, expressed as percentage control at the time of drug administration and plotted as a function of time after drug treatment.

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    Total cumulative bursts recorded on electroencephalograms (summated over 50 minutes). Data are plotted versus log dose (µg/kg) of drug administered intra-arterially: clonazepam to 11 cats; nimodipine to 17 cats; verapamil to five cats; and phenytoin to 11 cats. The effects of saline and vehicle (VEH, polyethylene glycol-400) are shown at left (eight cats in each group).

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    Burst duration on electroencephalograms, expressed as percentage control at the time of drug administration and plotted as a function of time after intra-arterial drug treatment. Verapamil, 6 mg/kg, was given to five cats; phenytoin, 30 mg/kg, to five cats; and clonazepam, 30 µg/kg, to three cats.

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    Cerebral blood flow measured by the xenon-133 method (CBF-Xe133, upper) and mean arterial blood pressure (MABP, lower) at intervals before, during, and after the intravenous administration of Metrazol (PTZ), 200 mg. Eight cats received saline (control); eight received vehicle (PEG-400); eight received nimodipine, 150 µg/kg; three received clonazepam, 30 µg/kg; five received verapamil, 6 mg/kg; and five received phenytoin, 30 mg/kg.

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    Cerebral blood flow (CBF)-PaCO2 response slopes measured at 70 minutes after induction of seizures. The slopes are plotted against the total cumulative bursting recorded 50 minutes following drug treatment. For statistics of slopes see text. Group 1 = no seizure; Group 2 = saline treatment; Group 3 = vehicle (polyethylene glycol-400) treatment; Group 4 = clonazepam, 30 µg/kg; Group 5 = clonazepam, 10 µg/kg; Group 6 = clonazepam, 1 µg/kg; Group 7 = nimodipine, 150 µg/kg; Group 8 = nimodipine, 50 µg/kg; Group 9 = phenytoin, 30 mg/kg; and Group 10 = verapamil, 6 mg/kg.

References

  • 1.

    Alger BENicoll RA: Epileptiform burst afterhyperpolarization: calcium-dependent potassium potential in hippocampal CA1 pyramidal cells. Science 210:112211241980Alger BE Nicoll RA: Epileptiform burst afterhyperpolarization: calcium-dependent potassium potential in hippocampal CA1 pyramidal cells. Science 210:1122–1124 1980

  • 2.

    Alvarez-Leefmans FJMiledi R: Voltage sensitive calcium entry in frog motoneurones. J Physiol (Lond) 308):2412571980Alvarez-Leefmans FJ Miledi R: Voltage sensitive calcium entry in frog motoneurones. J Physiol (Lond) 308):241–257 1980

  • 3.

    Bingmann DSpeckmann EJ: Actions of pentylenetetrazol (PTZ) on CA3 neurons in hippocampal slices of guinea pigs. Exp Brain Res 64:941041986Bingmann D Speckmann EJ: Actions of pentylenetetrazol (PTZ) on CA3 neurons in hippocampal slices of guinea pigs. Exp Brain Res 64:94–104 1986

  • 4.

    Connors BWGutnick MJPrince DA: Electrophysiological properties of neocortical neurons in vitro. J Neurophysiol 48:130213201982Connors BW Gutnick MJ Prince DA: Electrophysiological properties of neocortical neurons in vitro. J Neurophysiol 48:1302–1320 1982

  • 5.

    Daniell CBarr EMLeslie SW: 45Ca2+ uptake into rat whole brain synaptosomes unaltered by dihydropyridine calcium antagonists. J Neurochem 41:145514591983Daniell C Barr EM Leslie SW: 45Ca2+ uptake into rat whole brain synaptosomes unaltered by dihydropyridine calcium antagonists. J Neurochem 41:1455–1459 1983

  • 6.

    Dichter MSpencer WA: Penicillin-induced interictal discharges from the cat hippocampus. II. Mechanisms underlying origin and restriction. J Neurophysiol 32:6636871969Dichter M Spencer WA: Penicillin-induced interictal discharges from the cat hippocampus. II. Mechanisms underlying origin and restriction. J Neurophysiol 32:663–687 1969

  • 7.

    Duncan DB: Multiple range and multiple F tests. Biostatistics 11:1421955Duncan DB: Multiple range and multiple F tests. Biostatistics 11:1–42 1955

  • 8.

    Gorman ALFHermann AThomas MV: Intracellular calcium and the control of neuronal pacemaker activity. Fed Proc 40:223322391981Gorman ALF Hermann A Thomas MV: Intracellular calcium and the control of neuronal pacemaker activity. Fed Proc 40:2233–2239 1981

  • 9.

    Heinemann UPumain R: Extracellular calcium activity changes in cat sensorimotor cortex induced by iontophoretic application of aminoacids. Exp Brain Res 40:2472501980Heinemann U Pumain R: Extracellular calcium activity changes in cat sensorimotor cortex induced by iontophoretic application of aminoacids. Exp Brain Res 40:247–250 1980

  • 10.

    Hotson JRPrince DA: A calcium-activated hyperpolarization follows repetitive firing in hippocampal neurons. J Neurophysiol 43:4094191980Hotson JR Prince DA: A calcium-activated hyperpolarization follows repetitive firing in hippocampal neurons. J Neurophysiol 43:409–419 1980

  • 11.

    Johnston DHablitz JJWilson WA: Voltage clamp discloses slow inward current in hippocampal burst-firing neurones. Nature 286:3913931980Johnston D Hablitz JJ Wilson WA: Voltage clamp discloses slow inward current in hippocampal burst-firing neurones. Nature 286:391–393 1980

  • 12.

    Kandel ERSpencer WA: Electrophysiology of hippocampal neurons. II. After-potentials and repetitive firing. J Neurophysiol 24:2432591961Kandel ER Spencer WA: Electrophysiology of hippocampal neurons. II. After-potentials and repetitive firing. J Neurophysiol 24:243–259 1961

  • 13.

    Llinás RYarom Y: Properties and distribution of ionic conductances generating electroresponsiveness of mammalian inferior olivary neurones in vitro. J Physiol (Lond) 315:5695841981Llinás R Yarom Y: Properties and distribution of ionic conductances generating electroresponsiveness of mammalian inferior olivary neurones in vitro. J Physiol (Lond) 315:569–584 1981

  • 14.

    Lothman WESomjen GG: Functions of primary afferents and responses of extracellular K+ during spinal epileptiform seizures. Electroencephalogr Clin Neurophysiol 41:2532671976Lothman WE Somjen GG: Functions of primary afferents and responses of extracellular K+ during spinal epileptiform seizures. Electroencephalogr Clin Neurophysiol 41:253–267 1976

  • 15.

    Lothman WESomjen GG: Reflex effects and postsynaptic membrane potential changes during epileptiform activity induced by penicillin in decapitate spinal cords. Electroencephalogr Clin Neurophysiol 41:3373471976Lothman WE Somjen GG: Reflex effects and postsynaptic membrane potential changes during epileptiform activity induced by penicillin in decapitate spinal cords. Electroencephalogr Clin Neurophysiol 41:337–347 1976

  • 16.

    Meldrum BSNilsson B: Cerebral blood flow and metabolic rate early and late in prolonged epileptic seizures induced in rats by bicuculline. Brain 99:5235421976Meldrum BS Nilsson B: Cerebral blood flow and metabolic rate early and late in prolonged epileptic seizures induced in rats by bicuculline. Brain 99:523–542 1976

  • 17.

    Meyer FBAnderson RESundt TM Jret al: Selective central nervous system calcium channel blockers — a new class of anticonvulsant agents. Mayo Clin Proc 61:2392471986Meyer FB Anderson RE Sundt TM Jr et al: Selective central nervous system calcium channel blockers — a new class of anticonvulsant agents. Mayo Clin Proc 61:239–2471986

  • 18.

    Meyer FBTally PAnderson REet al: Inhibition of electrically induced seizures by a dihydropyridine calcium channel blocker. Brain Res 384:1801831986Meyer FB Tally P Anderson RE et al: Inhibition of electrically induced seizures by a dihydropyridine calcium channel blocker. Brain Res 384:180–183 1986

  • 19.

    Morocutti CPierelli FSanarelli Let al: Antiepileptic effects of a calcium antagonist (nimodipine) on cefazolininduced epileptogenic foci in rabbits. Epilepsia 27:4985031986Morocutti C Pierelli F Sanarelli L et al: Antiepileptic effects of a calcium antagonist (nimodipine) on cefazolininduced epileptogenic foci in rabbits. Epilepsia 27:498–5031986

  • 20.

    Murphy KMMGould RJLargent BLet al: A unitary mechanism of calcium antagonist drug action. Proc Natl Acad Sci USA 80:8608641983Murphy KMM Gould RJ Largent BL et al: A unitary mechanism of calcium antagonist drug action. Proc Natl Acad Sci USA 80:860–864 1983

  • 21.

    Nowycky MCFox APTsien RW: Three types of neuronal calcium channel with different calcium agonist sensitivity. Nature 316:4404431985Nowycky MC Fox AP Tsien RW: Three types of neuronal calcium channel with different calcium agonist sensitivity. Nature 316:440–443 1985

  • 22.

    Ogura ATakahashi M: Differential effect of a dihydropyridine derivative to Ca2+ entry pathways in neuronal preparations. Brain Res 301:3233301984Ogura A Takahashi M: Differential effect of a dihydropyridine derivative to Ca2+ entry pathways in neuronal preparations. Brain Res 301:323–330 1984

  • 23.

    Porter IDGardiner IMde Belleroche J: Nimodipine has an inhibitory action on neurotransmitter release from human cerebral arteries. J Cereb Blood Flow Metab 5:3383421985Porter ID Gardiner IM de Belleroche J: Nimodipine has an inhibitory action on neurotransmitter release from human cerebral arteries. J Cereb Blood Flow Metab 5:338–3421985

  • 24.

    Prince DA: Epileptogenesis in hippocampal and neocortical neurons in Klee MRLux HDSpeckman EJ (eds): Physiology and Pharmacology of Epileptogenic Phenomena. New York: Raven Press1982 pp 151162Prince DA: Epileptogenesis in hippocampal and neocortical neurons in Klee MR Lux HD Speckman EJ (eds): Physiology and Pharmacology of Epileptogenic Phenomena. New York: Raven Press 1982 pp 151–162

  • 25.

    Shalaby IAKongsamut SFreedman SBet al: The effects of dihydropyridines on neurotransmitter release from cultured neuronal cells. Life Sci 35:128912951984Shalaby IA Kongsamut S Freedman SB et al: The effects of dihydropyridines on neurotransmitter release from cultured neuronal cells. Life Sci 35:1289–1295 1984

  • 26.

    Snead OC III: On the sacred disease: the neurochemistry of epilepsy. Int Rev Neurobiol 24:931801983Snead OC III: On the sacred disease: the neurochemistry of epilepsy. Int Rev Neurobiol 24:93–180 1983

  • 27.

    Snyder SH: Drug and neurotransmitter receptors in the brain. Science 224:22311984Snyder SH: Drug and neurotransmitter receptors in the brain. Science 224:22–31 1984

  • 28.

    Sokoloff L: Relationships among local functional activity, energy metabolism, and blood flow in the central nervous system. Fed Proc 40:231123161981Sokoloff L: Relationships among local functional activity energy metabolism and blood flow in the central nervous system. Fed Proc 40:2311–2316 1981

  • 29.

    Somjen GG: Stimulus-evoked and seizure-related responses of extracellular calcium activity in spinal cord compared to those in cerebral cortex. J Neurophysiol 44:6176321980Somjen GG: Stimulus-evoked and seizure-related responses of extracellular calcium activity in spinal cord compared to those in cerebral cortex. J Neurophysiol 44:617–632 1980

  • 30.

    Somjen GGConnors BKinnes C: Calcium activity and seizure mechanisms in the spinal cord of cats in Klee MRLux HDSpeckman EJ (eds): Physiology and Pharmacology of Epileptogenic Phenomena. New York: Raven Press1982 pp 309318Somjen GG Connors B Kinnes C: Calcium activity and seizure mechanisms in the spinal cord of cats in Klee MR Lux HD Speckman EJ (eds): Physiology and Pharmacology of Epileptogenic Phenomena. New York: Raven Press 1982 pp 309–318

  • 31.

    Somjen GGLothman EDunn Pet al: Microphysiology of spinal seizures in Chalazonitis NBorsson M (eds): Abnormal Neuronal Discharges. New York: Raven Press1978 pp 1328Somjen GG Lothman E Dunn P et al: Microphysiology of spinal seizures in Chalazonitis N Borsson M (eds): Abnormal Neuronal Discharges. New York: Raven Press 1978 pp 13–28

  • 32.

    Tallarida RJMurray RB: Pharmacologic Calculation System. New York: Springer-Verlag1981Tallarida RJ Murray RB: Pharmacologic Calculation System. New York: Springer-Verlag 1981

  • 33.

    Traub RDLlinás R: Hippocampal pyramidal cells: significance of dendritic ionic conductances for neuronal function and epileptogenesis. J Neurophysiol 42:4764961979Traub RD Llinás R: Hippocampal pyramidal cells: significance of dendritic ionic conductances for neuronal function and epileptogenesis. J Neurophysiol 42:476–496 1979

  • 34.

    Turner TJGoldin SM: Calcium channels in rat brain synaptosomes: identification and pharmacological characterization. High affinity blockade by organic Ca2+ channel blockers. J Neurosci 5:8418491985Turner TJ Goldin SM: Calcium channels in rat brain synaptosomes: identification and pharmacological characterization. High affinity blockade by organic Ca2+ channel blockers. J Neurosci 5:841–849 1985

  • 35.

    Walden JSpeckmann EJWitte OW: Suppression of focal epileptiform discharges by intraventricular perfusion of a calcium antagonist. Electroencephalogr Clin Neurophysiol 61:2993091985Walden J Speckmann EJ Witte OW: Suppression of focal epileptiform discharges by intraventricular perfusion of a calcium antagonist. Electroencephalogr Clin Neurophysiol 61:299–309 1985

  • 36.

    Waltz AGWanek ARAnderson RE: Comparison of analytic methods for calculations of cerebral blood flow after intracarotid injection of 133Xe. J Neurol Med 13:66721972Waltz AG Wanek AR Anderson RE: Comparison of analytic methods for calculations of cerebral blood flow after intracarotid injection of 133Xe. J Neurol Med 13:66–72 1972

  • 37.

    Wauquier AAshton DClincke Get al: “Calcium entry blockers” as cerebral protecting agents: comparative activity in tests of hypoxia and hyperexcitability. Jpn J Pharmacol 38:171985Wauquier A Ashton D Clincke G et al: “Calcium entry blockers” as cerebral protecting agents: comparative activity in tests of hypoxia and hyperexcitability. Jpn J Pharmacol 38:1–7 1985

  • 38.

    Wong RKS: Postsynaptic potentiation mechanism in the hippocampal pyramidal cells in Klee MRLux HDSpeckman EJ (eds): Physiology and Pharmacology of Epileptogenic Phenomena. New York: Raven Press1982 pp 163173Wong RKS: Postsynaptic potentiation mechanism in the hippocampal pyramidal cells in Klee MR Lux HD Speckman EJ (eds): Physiology and Pharmacology of Epileptogenic Phenomena. New York: Raven Press 1982 pp 163–173

  • 39.

    Wong RKSPrince DA: Afterpotential generation in hippocampal pyramidal cells. J Neurophysiol 45:86971981Wong RKS Prince DA: Afterpotential generation in hippocampal pyramidal cells. J Neurophysiol 45:86–97 1981

  • 40.

    Wong RKSPrince DA: Dendritic mechanisms underlying penicillin-induced epileptiform activity. Science 204:122812311979Wong RKS Prince DA: Dendritic mechanisms underlying penicillin-induced epileptiform activity. Science 204:1228–1231 1979

  • 41.

    Wong RKSPrince DA: Participation of calcium spikes during intrinsic burst firing in hippocampal neurons. Brain Res 159:3853901978Wong RKS Prince DA: Participation of calcium spikes during intrinsic burst firing in hippocampal neurons. Brain Res 159:385–390 1978

  • 42.

    Woodbury PMPerry JKPippinger CEet al (eds): Antiepileptic Drugsed 2. New York: Raven Press1982 pp 167175Woodbury PM Perry JK Pippinger CE et al (eds): Antiepileptic Drugs ed 2. New York: Raven Press 1982 pp 167–175

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