Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1984 Mar;81(5):1549–1552. doi: 10.1073/pnas.81.5.1549

Interaction of calcium channel blockers with non-neuronal benzodiazepine binding sites.

E H Cantor, A Kenessey, G Semenuk, S Spector
PMCID: PMC344874  PMID: 6324202

Abstract

The ability of calcium channel blockers to displace the binding of benzodiazepine ligands was investigated in rat heart, kidney, and brain. The dihydropyridine calcium channel blockers nifedipine and nitrendipine displaced the binding of the non-neuronal-site ligand [3H]Ro5-4864, but not that of the neuronal-site ligands [3H]flurazepam or [3H]clonazepam. The inhibition was competitive, with Ki values in the micromolar range. Other calcium channel blockers--i.e., verapamil and diltiazem--were inactive at both sites. Thus, non-neuronal benzodiazepines bind to a class of sites that also binds dihydropyridines. This implies a role for benzodiazepines in the mediation of calcium-dependent phenomena.

Full text

PDF
1551

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abel R. M., Reis R. L., Staroscik R. N. Corory vasodilatation following diazepam (Valium). Br J Pharmacol. 1970 May;38(3):620–631. doi: 10.1111/j.1476-5381.1970.tb10604.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Abel R. M., Staroscik R. N., Reis R. L. The effects of diazepam (Valium) on left ventricular function and systemic vascular resistance. J Pharmacol Exp Ther. 1970 Jun;173(2):364–370. [PubMed] [Google Scholar]
  3. 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]
  4. Bowling A. C., DeLorenzo R. J. Micromolar affinity benzodiazepine receptors: identification and characterization in central nervous system. Science. 1982 Jun 11;216(4551):1247–1250. doi: 10.1126/science.6281893. [DOI] [PubMed] [Google Scholar]
  5. Braestrup C., Squires R. F. Specific benzodiazepine receptors in rat brain characterized by high-affinity (3H)diazepam binding. Proc Natl Acad Sci U S A. 1977 Sep;74(9):3805–3809. doi: 10.1073/pnas.74.9.3805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chai C. Y., Wang S. C. Cardiovascular actions of diazepam in the cat. J Pharmacol Exp Ther. 1966 Nov;154(2):271–280. [PubMed] [Google Scholar]
  7. Cheng Y., Prusoff W. H. Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol. 1973 Dec 1;22(23):3099–3108. doi: 10.1016/0006-2952(73)90196-2. [DOI] [PubMed] [Google Scholar]
  8. Daniell H. B. Cardiovascular effects of diazepam and chlordiazepoxide. Eur J Pharmacol. 1975 May;32(1):58–65. doi: 10.1016/0014-2999(75)90323-4. [DOI] [PubMed] [Google Scholar]
  9. Davies L. P., Huston V. Peripheral benzodiazepine binding sites in heart and their interaction with dipyridamole. Eur J Pharmacol. 1981 Jul 17;73(2-3):209–211. doi: 10.1016/0014-2999(81)90092-3. [DOI] [PubMed] [Google Scholar]
  10. DeLorenzo R. J., Burdette S., Holderness J. Benzodiazepine inhibition of the calcium-calmodulin protein kinase system in brain membrane. Science. 1981 Jul 31;213(4507):546–549. doi: 10.1126/science.6264605. [DOI] [PubMed] [Google Scholar]
  11. DePover A., Matlib M. A., Lee S. W., Dubé G. P., Grupp I. L., Grupp G., Schwartz A. Specific binding of [3H]nitrendipine to membranes from coronary arteries and heart in relation to pharmacological effects. Paradoxical stimulation by diltiazem. Biochem Biophys Res Commun. 1982 Sep 16;108(1):110–117. doi: 10.1016/0006-291x(82)91838-1. [DOI] [PubMed] [Google Scholar]
  12. Del Zompo M., Post R. M., Tallman J. F. Properties of two benzodiazepine binding sites in spinal cord. Neuropharmacology. 1983 Jan;22(1):115–118. doi: 10.1016/0028-3908(83)90269-1. [DOI] [PubMed] [Google Scholar]
  13. Ehlert F. J., Itoga E., Roeske W. R., Yamamura H. I. The interaction of [3H]nitrendipine with receptors for calcium antagonists in the cerebral cortex and heart of rats. Biochem Biophys Res Commun. 1982 Feb 11;104(3):937–943. doi: 10.1016/0006-291x(82)91339-0. [DOI] [PubMed] [Google Scholar]
  14. Fleckenstein A. Specific pharmacology of calcium in myocardium, cardiac pacemakers, and vascular smooth muscle. Annu Rev Pharmacol Toxicol. 1977;17:149–166. doi: 10.1146/annurev.pa.17.040177.001053. [DOI] [PubMed] [Google Scholar]
  15. Gallager D. W. Benzodiazepines: potentiation of a GABA inhibitory response in the dorsal raphe nucleus. Eur J Pharmacol. 1978 May 15;49(2):133–143. doi: 10.1016/0014-2999(78)90069-9. [DOI] [PubMed] [Google Scholar]
  16. Gallager D. W., Mallorga P., Oertel W., Henneberry R., Tallman J. [3H]Diazepam binding in mammalian central nervous system: a pharmacological characterization. J Neurosci. 1981 Feb;1(2):218–225. doi: 10.1523/JNEUROSCI.01-02-00218.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Glossmann H., Ferry D. R., Lübbecke F., Mewes R., Hofmann F. Identification of voltage operated calcium channels by binding studies: differentiation of subclasses of calcium antagonist drugs with 3H-nimodipine radioligand binding. J Recept Res. 1983;3(1-2):177–190. doi: 10.3109/10799898309041932. [DOI] [PubMed] [Google Scholar]
  18. Hescheler J., Pelzer D., Trube G., Trautwein W. Does the organic calcium channel blocker D600 act from inside or outside on the cardiac cell membrane? Pflugers Arch. 1982 Jun;393(4):287–291. doi: 10.1007/BF00581411. [DOI] [PubMed] [Google Scholar]
  19. Hullihan J. P., Spector S., Taniguchi T., Wang J. K. The binding of [3H]-diazepam to guinea-pig ileal longitudinal muscle and the in vitro inhibition of contraction by benzodiazepines. Br J Pharmacol. 1983 Feb;78(2):321–327. doi: 10.1111/j.1476-5381.1983.tb09397.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  21. Marangos P. J., Martino A. M. Studies on the relationship of gamma-aminobutyric acid-stimulated diazepam binding and the gamma-aminobutyric acid receptor. Mol Pharmacol. 1981 Jul;20(1):16–21. [PubMed] [Google Scholar]
  22. Marangos P. J., Patel J., Boulenger J. P., Clark-Rosenberg R. Characterization of peripheral-type benzodiazepine binding sites in brain using [3H]Ro 5-4864. Mol Pharmacol. 1982 Jul;22(1):26–32. [PubMed] [Google Scholar]
  23. Marangos P. J., Patel J., Miller C., Martino A. M. Specific calcium antagonist binding sites in brain. Life Sci. 1982 Oct 11;31(15):1575–1585. doi: 10.1016/0024-3205(82)90049-2. [DOI] [PubMed] [Google Scholar]
  24. Morgan J. I., Perris A. D. The influence of sex steroids on calcium- and magnesium-induced mitogenesis in isolated rat thymic lymphocytes. J Cell Physiol. 1974 Apr;83(2):287–296. doi: 10.1002/jcp.1040830216. [DOI] [PubMed] [Google Scholar]
  25. Paul S. M., Marangos P. J., Skolnick P. The benzodiazepine--GABA--chloride ionophore receptor complex: common site of minor tranquilizer action. Biol Psychiatry. 1981 Mar;16(3):213–229. [PubMed] [Google Scholar]
  26. Schoemaker H., Bliss M., Yamamura H. I. Specific high-affinity saturable binding of [3H] R05-4864 to benzodiazepine binding sites in the rat cerebral cortex. Eur J Pharmacol. 1981 Apr 24;71(1):173–175. doi: 10.1016/0014-2999(81)90405-2. [DOI] [PubMed] [Google Scholar]
  27. Syapin P. J., Skolnick P. Characterization of benzodiazepine binding sites in cultured cells of neural origin. J Neurochem. 1979 Mar;32(3):1047–1051. doi: 10.1111/j.1471-4159.1979.tb04592.x. [DOI] [PubMed] [Google Scholar]
  28. Tallman J. F., Thomas J. W., Gallager D. W. GABAergic modulation of benzodiazepine binding site sensitivity. Nature. 1978 Jul 27;274(5669):383–385. doi: 10.1038/274383a0. [DOI] [PubMed] [Google Scholar]
  29. Taniguchi T., Wang J. K., Spector S. Properties of [3H] diazepam binding to rat peritoneal mast cells. Life Sci. 1980 Jul 14;27(2):171–178. doi: 10.1016/0024-3205(80)90460-9. [DOI] [PubMed] [Google Scholar]
  30. Wang J. K., Taniguchi T., Spector S. Properties of [3H]diazepam binding sites on rat blood platelets. Life Sci. 1980 Nov 17;27(20):1881–1888. doi: 10.1016/0024-3205(80)90434-8. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES