Abstract
Calcium subserves a ubiquitous role in the organisation of cell function. Ca2+ channels which control influx may be modified in disease states. Animal models of cerebral ischaemia do present some problems when investigating potential therapies involving Ca2+ channels. However, it is important not to be too rigid in searching for models which exactly mimic the human disease state, when even the best experimental approaches fall short of such an ideal. There are differences between different classes of calcium entry blocking drugs with regard to their activity on Ca2+ channels and transmembrane Ca2+ movement. Some calcium antagonists may also affect ion channels other than Ca2+, and this potential is exemplified by the novel ion channel modulator RS-87476, which affords experimental neurocytoprotection. Limitation of intracellular Na+ influx during ischaemia-induced depolarization may be useful.
Full text
PDF![199](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cded/1381389/830b55e31160/brjclinpharm00042-0017.png)
![200](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cded/1381389/48349672a038/brjclinpharm00042-0018.png)
![201](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cded/1381389/8b2f88055b0b/brjclinpharm00042-0019.png)
![202](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cded/1381389/1e0a7258a1f5/brjclinpharm00042-0020.png)
![203](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cded/1381389/95f07b17af6f/brjclinpharm00042-0021.png)
![204](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cded/1381389/b2f4d54d1f71/brjclinpharm00042-0022.png)
![205](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cded/1381389/be458e29b913/brjclinpharm00042-0023.png)
![206](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cded/1381389/64267d5cc31b/brjclinpharm00042-0024.png)
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Alps B. J., Calder C., Hass W. K., Wilson A. D. Comparative protective effects of nicardipine, flunarizine, lidoflazine and nimodipine against ischaemic injury in the hippocampus of the Mongolian gerbil. Br J Pharmacol. 1988 Apr;93(4):877–883. doi: 10.1111/j.1476-5381.1988.tb11475.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Alps B. J., Hass W. K. The potential beneficial effect of nicardipine in a rat model of transient forebrain ischemia. Neurology. 1987 May;37(5):809–814. doi: 10.1212/wnl.37.5.809. [DOI] [PubMed] [Google Scholar]
- Bean B. P., Sturek M., Puga A., Hermsmeyer K. Calcium channels in muscle cells isolated from rat mesenteric arteries: modulation by dihydropyridine drugs. Circ Res. 1986 Aug;59(2):229–235. doi: 10.1161/01.res.59.2.229. [DOI] [PubMed] [Google Scholar]
- Bogousslavsky J., Regli F., Zumstein V., Köbberling W. Double-blind study of nimodipine in non-severe stroke. Eur Neurol. 1990;30(1):23–26. doi: 10.1159/000116620. [DOI] [PubMed] [Google Scholar]
- Bolger G. T., Gengo P., Klockowski R., Luchowski E., Siegel H., Janis R. A., Triggle A. M., Triggle D. J. Characterization of binding of the Ca++ channel antagonist, [3H]nitrendipine, to guinea-pig ileal smooth muscle. J Pharmacol Exp Ther. 1983 May;225(2):291–309. [PubMed] [Google Scholar]
- Boll W., Lux H. D. Action of organic antagonists on neuronal calcium currents. Neurosci Lett. 1985 May 23;56(3):335–339. doi: 10.1016/0304-3940(85)90265-4. [DOI] [PubMed] [Google Scholar]
- Bou J., Llenas J., Massingham R. Calcium entry blocking drugs, 'calcium antagonists' and vascular smooth muscle function. J Auton Pharmacol. 1983 Sep;3(3):219–232. doi: 10.1111/j.1474-8673.1983.tb00538.x. [DOI] [PubMed] [Google Scholar]
- Clifton G. L., Taft W. C., Blair R. E., Choi S. C., DeLorenzo R. J. Conditions for pharmacologic evaluation in the gerbil model of forebrain ischemia. Stroke. 1989 Nov;20(11):1545–1552. doi: 10.1161/01.str.20.11.1545. [DOI] [PubMed] [Google Scholar]
- Fedulova S. A., Kostyuk P. G., Veselovsky N. S. Two types of calcium channels in the somatic membrane of new-born rat dorsal root ganglion neurones. J Physiol. 1985 Feb;359:431–446. doi: 10.1113/jphysiol.1985.sp015594. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fleckenstein A. Historical overview. The calcium channel of the heart. Ann N Y Acad Sci. 1988;522:1–15. doi: 10.1111/j.1749-6632.1988.tb33337.x. [DOI] [PubMed] [Google Scholar]
- Forsman M., Olsnes B. T., Semb G., Steen P. A. Effects of nimodipine on cerebral blood flow and neuropsychological outcome after cardiac surgery. Br J Anaesth. 1990 Oct;65(4):514–520. doi: 10.1093/bja/65.4.514. [DOI] [PubMed] [Google Scholar]
- Fox A. P., Nowycky M. C., Tsien R. W. Kinetic and pharmacological properties distinguishing three types of calcium currents in chick sensory neurones. J Physiol. 1987 Dec;394:149–172. doi: 10.1113/jphysiol.1987.sp016864. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Friedman M. E., Suarez-Kurtz G., Kaczorowski G. J., Katz G. M., Reuben J. P. Two calcium currents in a smooth muscle cell line. Am J Physiol. 1986 Apr;250(4 Pt 2):H699–H703. doi: 10.1152/ajpheart.1986.250.4.H699. [DOI] [PubMed] [Google Scholar]
- Gelmers H. J., Gorter K., de Weerdt C. J., Wiezer H. J. A controlled trial of nimodipine in acute ischemic stroke. N Engl J Med. 1988 Jan 28;318(4):203–207. doi: 10.1056/NEJM198801283180402. [DOI] [PubMed] [Google Scholar]
- Gill R., Foster A. C., Woodruff G. N. Systemic administration of MK-801 protects against ischemia-induced hippocampal neurodegeneration in the gerbil. J Neurosci. 1987 Oct;7(10):3343–3349. doi: 10.1523/JNEUROSCI.07-10-03343.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Harris R. J., Symon L., Branston N. M., Bayhan M. Changes in extracellular calcium activity in cerebral ischaemia. J Cereb Blood Flow Metab. 1981;1(2):203–209. doi: 10.1038/jcbfm.1981.21. [DOI] [PubMed] [Google Scholar]
- Heffez D. S., Nowak T. S., Jr, Passonneau J. V. Nimodipine levels in gerbil brain following parenteral drug administration. J Neurosurg. 1985 Oct;63(4):589–592. doi: 10.3171/jns.1985.63.4.0589. [DOI] [PubMed] [Google Scholar]
- Kirino T. Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Res. 1982 May 6;239(1):57–69. doi: 10.1016/0006-8993(82)90833-2. [DOI] [PubMed] [Google Scholar]
- Kucharczyk J., Mintorovitch J., Moseley M. E., Asgari H. S., Sevick R. J., Derugin N., Norman D. Ischemic brain damage: reduction by sodium-calcium ion channel modulator RS-87476. Radiology. 1991 Apr;179(1):221–227. doi: 10.1148/radiology.179.1.2006281. [DOI] [PubMed] [Google Scholar]
- Kuroiwa T., Bonnekoh P., Hossmann K. A. Prevention of postischemic hyperthermia prevents ischemic injury of CA1 neurons in gerbils. J Cereb Blood Flow Metab. 1990 Jul;10(4):550–556. doi: 10.1038/jcbfm.1990.97. [DOI] [PubMed] [Google Scholar]
- Loirand G., Pacaud P., Mironneau C., Mironneau J. Evidence for two distinct calcium channels in rat vascular smooth muscle cells in short-term primary culture. Pflugers Arch. 1986 Nov;407(5):566–568. doi: 10.1007/BF00657519. [DOI] [PubMed] [Google Scholar]
- Magnoni M. S., Govoni S., Battaini F., Trabucchi M. L-type calcium channels are modified in rat hippocampus by short-term experimental ischemia. J Cereb Blood Flow Metab. 1988 Feb;8(1):96–99. doi: 10.1038/jcbfm.1988.12. [DOI] [PubMed] [Google Scholar]
- Martínez-Vila E., Guillén F., Villanueva J. A., Matías-Guiu J., Bigorra J., Gil P., Carbonell A., Martínez-Lage J. M. Placebo-controlled trial of nimodipine in the treatment of acute ischemic cerebral infarction. Stroke. 1990 Jul;21(7):1023–1028. doi: 10.1161/01.str.21.7.1023. [DOI] [PubMed] [Google Scholar]
- Middlemiss D. N., Spedding M. A functional correlate for the dihydropyridine binding site in rat brain. Nature. 1985 Mar 7;314(6006):94–96. doi: 10.1038/314094a0. [DOI] [PubMed] [Google Scholar]
- Nilius B., Hess P., Lansman J. B., Tsien R. W. A novel type of cardiac calcium channel in ventricular cells. Nature. 1985 Aug 1;316(6027):443–446. doi: 10.1038/316443a0. [DOI] [PubMed] [Google Scholar]
- Paci A., Ottaviano P., Trenta A., Iannone G., De Santis L., Lancia G., Moschini E., Carosi M., Amigoni S., Caresia L. Nimodipine in acute ischemic stroke: a double-blind controlled study. Acta Neurol Scand. 1989 Oct;80(4):282–286. doi: 10.1111/j.1600-0404.1989.tb03879.x. [DOI] [PubMed] [Google Scholar]
- Patmore L., Duncan G. P., Spedding M. Interaction of palmitoyl carnitine with calcium antagonists in myocytes. Br J Pharmacol. 1989 Jun;97(2):443–450. doi: 10.1111/j.1476-5381.1989.tb11971.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Patmore L., Duncan G. P., Spedding M. The effects of calcium antagonists on calcium overload contractures in embryonic chick myocytes induced by ouabain and veratrine. Br J Pharmacol. 1989 May;97(1):83–94. doi: 10.1111/j.1476-5381.1989.tb11927.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Poignet H., Beaughard M., Lecoin G., Massingham R. Functional, behavioral, and histological changes induced by transient global cerebral ischemia in rats: effects of cinnarizine and flunarizine. J Cereb Blood Flow Metab. 1989 Oct;9(5):646–654. doi: 10.1038/jcbfm.1989.92. [DOI] [PubMed] [Google Scholar]
- Pulsinelli W. A., Brierley J. B. A new model of bilateral hemispheric ischemia in the unanesthetized rat. Stroke. 1979 May-Jun;10(3):267–272. doi: 10.1161/01.str.10.3.267. [DOI] [PubMed] [Google Scholar]
- Pulsinelli W. A., Waldman S., Rawlinson D., Plum F. Moderate hyperglycemia augments ischemic brain damage: a neuropathologic study in the rat. Neurology. 1982 Nov;32(11):1239–1246. doi: 10.1212/wnl.32.11.1239. [DOI] [PubMed] [Google Scholar]
- Sanguinetti M. C., Krafte D. S., Kass R. S. Voltage-dependent modulation of Ca channel current in heart cells by Bay K8644. J Gen Physiol. 1986 Sep;88(3):369–392. doi: 10.1085/jgp.88.3.369. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Siesjö B. K. Cell damage in the brain: a speculative synthesis. J Cereb Blood Flow Metab. 1981;1(2):155–185. doi: 10.1038/jcbfm.1981.18. [DOI] [PubMed] [Google Scholar]
- Spedding M. Activators and inactivators of Ca++ channels: new perspectives. J Pharmacol. 1985 Oct-Dec;16(4):319–343. [PubMed] [Google Scholar]
- Spedding M. Assessment of "Ca2+ -antagonist" effects of drugs in K+ -depolarized smooth muscle. Differentiation of antagonist subgroups. Naunyn Schmiedebergs Arch Pharmacol. 1982 Feb;318(3):234–240. doi: 10.1007/BF00500485. [DOI] [PubMed] [Google Scholar]
- Spedding M., Berg C. Antagonism of Ca2+-induced contractions of K+-depolarized smooth muscle by local anaesthetics. Eur J Pharmacol. 1985 Jan 22;108(2):143–150. doi: 10.1016/0014-2999(85)90718-6. [DOI] [PubMed] [Google Scholar]
- Spedding M. Changing surface charge with salicylate differentiates between subgroups of calcium-antagonists. Br J Pharmacol. 1984 Sep;83(1):211–220. doi: 10.1111/j.1476-5381.1984.tb10137.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Spedding M., Kilpatrick A. T., Alps B. J., Speddings M. Activators and inactivators of calcium channels: effects in the central nervous system. Fundam Clin Pharmacol. 1989;3 (Suppl):3s–29s. doi: 10.1111/j.1472-8206.1989.tb00472.x. [DOI] [PubMed] [Google Scholar]
- Takahashi K., Akaike N. Calcium antagonist effects on low-threshold (T-type) calcium current in rat isolated hippocampal CA1 pyramidal neurons. J Pharmacol Exp Ther. 1991 Jan;256(1):169–175. [PubMed] [Google Scholar]
- Tsien R. W., Lipscombe D., Madison D. V., Bley K. R., Fox A. P. Multiple types of neuronal calcium channels and their selective modulation. Trends Neurosci. 1988 Oct;11(10):431–438. doi: 10.1016/0166-2236(88)90194-4. [DOI] [PubMed] [Google Scholar]
- Uematsu D., Araki N., Greenberg J. H., Sladky J., Reivich M. Combined therapy with MK-801 and nimodipine for protection of ischemic brain damage. Neurology. 1991 Jan;41(1):88–94. doi: 10.1212/wnl.41.1.88. [DOI] [PubMed] [Google Scholar]
- Welsh F. A., Harris V. A. Postischemic hypothermia fails to reduce ischemic injury in gerbil hippocampus. J Cereb Blood Flow Metab. 1991 Jul;11(4):617–620. doi: 10.1038/jcbfm.1991.112. [DOI] [PubMed] [Google Scholar]
- Welsh F. A., Sims R. E., Harris V. A. Mild hypothermia prevents ischemic injury in gerbil hippocampus. J Cereb Blood Flow Metab. 1990 Jul;10(4):557–563. doi: 10.1038/jcbfm.1990.98. [DOI] [PubMed] [Google Scholar]
- Yatani A., Seidel C. L., Allen J., Brown A. M. Whole-cell and single-channel calcium currents of isolated smooth muscle cells from saphenous vein. Circ Res. 1987 Apr;60(4):523–533. doi: 10.1161/01.res.60.4.523. [DOI] [PubMed] [Google Scholar]