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Drugs

, Volume 33, Supplement 2, pp 67–74 | Cite as

Cyclandelate as a Calcium Modulating Agent in Rat Cerebral Cortex

  • A. Bast
  • R. Leurs
  • H. Timmerman
Section 1: Pharmacological Studies: Modes and Mechanisms of Action

Summary

Cyclandelate is clinically effective in a variety of cerebrovascular indications, but its precise mode of action is unclear. Hence, this study investigated the interaction of cyclandelate, cyclandelate alcohol and cyclandelate acid with the binding sites for radioactively labelled 3H- nitrendipine, a Ca++entry blocker of the 1,4- dihydropyridine type, on rat cerebral cortex membranes. Cyclandelate showed a dissociation constant (Kd) of 7.1 ± 1.4 × 10− 5 mol/L (35% inhibition of 3H- nitrendipine binding at 2 × 10− 4 mol/L cyclandelate), cyclandelate alcohol had a Kd value of 1.7 ± 0.1 × 10− 4 mol/L (maximal 70% inhibition of 3H- nitrendipine binding) whereas cyclandelate acid was inactive. For comparison, nifedipine (Kd of 2.6 ± 0.3 × 10− 9 mol/L inhibition of 68% of 3H- nitrendipine binding), d- cis diltiazem (Kd of 1.1 ± 0.1 × 10−7mol/L enhancement of 39% of 3H nitrendipine binding) and ± -verapamil [Kd values of 1.4 ± 0.4 × 70−7mol/L (38% inhibition) and 5.3 ± 1.7 × 10− 4 mol/L (62% inhibition)] were used.

Thus, cyclandelate may exert its clinical activity in cerebral ischaemia or hypoxia at least in part through a calcium modulatory effect.

Keywords

Verapamil Nifedipine Diltiazem Nitrendipine Entry Blocker 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Résumé

En clinique, le cyclandélate est indiqué dans le traitement de nombreux troubles vasculaires cérébraux. Son mécanisme d’action précis n’est cependant pas clair. En conséquence, la présente étude a été consacrée à la recherche des éventuelles interactions du cyclandélate, du cyclandélate alcool et du cyclandélate acide avec les sites de liaison de la nitrendipine tritiée, un bloqueur de l’entrée de Ca2+ du type de la 1,4-dihydropyridine, dans les membranes du cortex cérébral du rat. La constante de dissociation (Kd) du cyclandélate a été de 7,1 ± 1,4 × 10−5 mol/l (35% d’inhibition de la liaison de la 3H-nitrendipine pour une concentration de cyclandélate de 2. 10−4 mol/l). Le Kd du cyclandélate alcool a été de 1,7 ± 0,1 × 10−4 mol/l, avec une inhibition maximale de 70% de la liaison de la 3H-nitrendipine, alors que le cyclandélate acide s’est montré inactif. Pour comparer ces valeurs à celles de produits connus, on a utilisé la nifédipine (Kd=2,6 ± 0,3 × 10−9 mol/l; inhibition de la liaison de la 3H-nitrendipine: 68%), le d-cis diltiazem (Kd=1,1 ± 0,1 x 10−7 mol/l; renforcement de la liaison de la 3H-nitrendipine: 39%) et le vérapamil racémique (Kd=1,4 ± 0,4 × 10−7 molli, inhibition: 38% et Kd=5,3 ± 1,7 × 10−4mol/l, inhibition: 62% pour les formes dextrogyre et lévogyre).

En conséquence, il semble que l’activité clinique du cyclandélate sur l’ischémie cérébrale et l’hypoxie passe, au moins en partie, par un blocage de l’entrée intra-cellulaire des ions calcium.

Riassunto

Il ciclandelato è clinicamente efficace in varie indicazioni cerebrovascolari, ma il suopreciso meccanismo d’azione non risulta chiaro. Questa ricerca ha esaminato, sulle membrane della corteccia cerebrale del ratto, I’interazione del ciclandelato, delValcool ciclandelico e dell’acido ciclandelico con i siti di legame della 3H-nitrendipina, radioattivamente marcata, un bloccante dell’ingresso del Ca2+ del tipo della 1,4-diidropiridina. Il ciclandelato ha dimostrato una costante di dissociazione (Kd × 7,1 ± 1,4 × 10−5 mol/l (35% di inibizione delia 3H-nitrendipina che si lega al ciclandelato a 2 × 10−4 mol/l). L’alcool ciclandelico aveva un valore della Kd di 1,7 ±0,1 × 10−4 mol/l (inibizione massima al 70% del legame con la 3H-nitrendipina) mentre l’acido ciclandelico era inattivo. Per il confronto furono impiegate lanifedipina (Kd2,6 ± 0,3 × 10−9mol/l, 68% di inibizione dellagame con la 3H-nitrendipina), il d-cisdiltiazem (Kd 1,1 ±0,1 × 10-7 mol/l, rafforzando del 39% il legame con la 3H-nitrendipina) e i valori ± del verapamil (Kd 1,4 ± 0,4 × 10−7 mol/l (38% di inibizione) e5,3 ±1,7 × 10−4 mol/l (62% di inibizione).

Il ciclandelato può esercitare la sua attività clinica nell’ischemia cerebrale o nell’ipossia almeno in parte tramite un effetto bloccante l’ingresso del calcio.

Samenvatting

Cyclandelaat is klinisch effectief bij een hele reeks cerebrovasculaire indicaties, maar de precieze werkingsrvijze van de stof is nog onduidelijk. Daarom werd in deze Studie de interactie nagegaan tussen cyclandelaat, cyclandelaatalcohol en cyclandelaatzuur en de bindingsplaatsen voor radioactief gemerkt 3H-nitrendipine, een Ca2+-entry blocker van het 1,4-dihydropyritinetype, op de hersenschorsmembranen van de rat. Cyclandelaat vertoonde een dissociatieconstante (Kd) van 7,1 ± 1,4 × 10−5 mol/l (35 % inhibitie van de 3H-nitrendi-pinebinding bij 2 × 10−4 molli cyclandelaat). Cyclandelaatalcohol had een Kd-waarde van 1,7 ± 0,1 × 10−4 mol/l (maximaal 70% inhibitie van de 3H-nitrendipinebinding), terwijl cyclandelaatzuur inactief was. Ter vergelijking namen we nifedipine (met een Kd-waarde van 2,6 ± 0,3 × 10−9 molli en een inhibitie van 68% van de 3H-nitrendipinebinding), d-cis diltiazem (Kd-waarde van 1,1 ± 0,1 × 10−7 mol/l en een verhoging met 39% van de 3H-nitredipinebinding) en ± -verapamil (Kd-waarden van 1,4 ± 0,4 × 10−7 mol/l (38% inhibitie) en 5,3 ± 1,7 × 10−4mol/l (62% inhibitie).

De klinische activiteit van cyclandelaat bij cerebrale ischemie of hypoxie kan bijgevolg ten minste gedeeltelijk toegeschreven worden aan zijn calciummodulerende effekt.

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References

  1. Bast A, Haenen GRMM. Cytochrome P-450 and glutathione: what is the significance of their interrelationship in lipid peroxidation. Trends in Biochemical Sciences 9: 510–513, 1984CrossRefGoogle Scholar
  2. Braughler JM, Duncan LA, Goodman T. Calcium enhances in vitro free radical-induced damage to brain synaptosomes, mitochondria, and cultured spinal cord neurons. Journal of Neurochemistry 45: 1288–1293, 1985PubMedCrossRefGoogle Scholar
  3. Glossmann H, Ferry DR, Goll A. Striessing J, Schober M. Calcium channels: basic properties as revealed by radioligand binding studies. Journal of Cardiovascular Research 7 (Suppl. 6): S20–S30, 1985Google Scholar
  4. Jain SK, Shohet SB. Calcium potentiates the peroxidation of erythrocyte membrane lipids. Biochimica et Biophysica Acta 642: 46–54, 1981PubMedCrossRefGoogle Scholar
  5. Meerson FZ, Kagan VE, Kozlov YP, Belkina LM, Arkhipenko YV. The role of lipid peroxidation in pathogenesis of ischémic damage and the antioxidant protection of the heart. Basic Research in Cardiology 77: 465–485, 1982PubMedCrossRefGoogle Scholar
  6. Milde LN, Milde JH, Michenfelder JD. Delayed treatment with nimodipine improves cerebral blood flow after complete cerebral ischaemia in the dog. Journal of Cerebral Blood Flow and Metabolism 6: 322–337, 1986Google Scholar
  7. Munson PJ, Rodbard D. LIGAND: a versatile computerized approach for characterization of ligand binding systems. Analytical Biochemistry 107: 220–239, 1980PubMedCrossRefGoogle Scholar
  8. Nayler WG, Dillon JG, Elz JS, McKelvie M. An effect of ischemia on myocardial dihydropyridine binding sites. European Journal of Pharmacology 115: 81–89, 1985PubMedCrossRefGoogle Scholar
  9. Orrenius S. Biochemical mechanisms of cytotoxicity. Trends in Pharmacological Sciences 6 (Suppl. Federation of European Societies of Toxicology): 15–20, 1985CrossRefGoogle Scholar
  10. Rehncrona S, Folbergrová J, Smith DS, Sresjö BK. Influence of complete and pronounced incomplete cerebral ischemia and subsequent recirculation on cortical concentrations of oxidized and reduced glutathione in the rat. Journal of Neurochemistry 34: 477–486, 1980PubMedCrossRefGoogle Scholar
  11. Spedding M, Cavero I. ‘Calcium antagonists’: a class of drugs with a bright future. Part II. Determination of basic pharmacological properties. Life Sciences 35: 575–587, 1984PubMedCrossRefGoogle Scholar
  12. Timmerman H. Modes and mechanisms of action of vasoactive drugs and especially of cyclandelate. British Journal of Clinical Practice 38 (Suppl.): 10–18, 1984Google Scholar
  13. Triggle DJ, Janis RA. Calcium channel antagonists: new perspectives from radioligand binding assay. In Spector et al. (Eds) Modern methods in pharmacology, Vol. 2, pp. 1–28, Alan R. Liss Inc., New York, 1984Google Scholar
  14. Trump BF, Berezesky IK. The role of calcium in cell injury and repair. Survey and Synthesis of Pathology Research 4: 248–256, 1985PubMedGoogle Scholar
  15. Van der Vusse GJ, Reneman RS. Pharmacological intervention in acute myocardial ischemia and reperfusion. Trends in Pharmacological Sciences 6: 76–79, 1985CrossRefGoogle Scholar
  16. Van Zwieten PA. Calciumantagonisten, calcium entry blockers en calcium overload blockers: nomenclatuur en indeling. Nederlands Tijdschrift voor Geneeskunde 129: 777–780, 1985PubMedGoogle Scholar

Copyright information

© ADIS Press Limited 1987

Authors and Affiliations

  • A. Bast
    • 1
  • R. Leurs
    • 1
  • H. Timmerman
    • 1
  1. 1.Department of Pharmacochemistry, Subfaculty of ChemistryVrije UniversiteitAmsterdamThe Netherlands

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