Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1989 Aug;84(2):493–498. doi: 10.1172/JCI114191

Relaxation of rat vascular muscle by peripheral benzodiazepine modulators.

P Erne 1, M Chiesi 1, S Longoni 1, J Fulbright 1, K Hermsmeyer 1
PMCID: PMC548908  PMID: 2569475

Abstract

Effects of peripheral benzodiazepine receptor modulating drugs, Ro 5-4864 and PK 11195, on tension induced by K+ and the calcium agonist SDZ 202 791 (S isomer), were studied in rat caudal arteries. A significant reduction of tonic phase tension occurred with 30 nM PK 11195 or 3 microM Ro 5-4864, but decreases of the initial (first 3 min), phasic contraction were detected only at the highest concentrations of Ro 5-4864 and PK 11195. Protoporphyrin IX, the putative endogenous ligand of the peripheral benzodiazepine receptor, (at 10-100 nM) markedly increased the effectiveness of Ro 5-4864 and PK 11195 in reducing phasic contraction. Intracellular calcium localization and distribution in fura-2 loaded single vascular cells were quantitated using a high sensitivity, two-stage microchannel plate, photon-counting (PMI-VIM) camera. Peripheral benzodiazepines reduced intracellular calcium release from centrally located calcium pools, and this decrease of calcium release was potentiated by protoporphyrin IX. The decrease in intracellular calcium activity, which was more pronounced in the central regions where sarcoplasmic reticular elements are numerous, was probably the major mechanism of these vasodilator properties. Measurements of soluble guanylate cyclase activity also supported the intracellular Ca2+ release mechanism. Under conditions where protoporphyrin IX did not significantly stimulate guanylate cyclase, Ro 5-4864 alone or more effectively in combination with protoporphyrin IX stimulated cGMP production and caused relaxation. Guanylate cyclase forms a possible target for these benzodiazepine modulators, a hypothesis that merits further investigation.

Full text

PDF
493

Selected References

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

  1. Anholt R. R., Aebi U., Pedersen P. L., Snyder S. H. Solubilization and reassembly of the mitochondrial benzodiazepine receptor. Biochemistry. 1986 Apr 22;25(8):2120–2125. doi: 10.1021/bi00356a041. [DOI] [PubMed] [Google Scholar]
  2. Anholt R. R., De Souza E. B., Oster-Granite M. L., Snyder S. H. Peripheral-type benzodiazepine receptors: autoradiographic localization in whole-body sections of neonatal rats. J Pharmacol Exp Ther. 1985 May;233(2):517–526. [PubMed] [Google Scholar]
  3. Anholt R. R., Pedersen P. L., De Souza E. B., Snyder S. H. The peripheral-type benzodiazepine receptor. Localization to the mitochondrial outer membrane. J Biol Chem. 1986 Jan 15;261(2):576–583. [PubMed] [Google Scholar]
  4. Aprigliano O., Rybarczyk K. E., Hermsmeyer K., Van Orden L. S. Adrenergic neuronal degeneration induced in portal vein and caudal artery by 6-hydroxydopamine in vitro. J Pharmacol Exp Ther. 1976 Sep;198(3):578–588. [PubMed] [Google Scholar]
  5. Doble A., Benavides J., Ferris O., Bertrand P., Menager J., Vaucher N., Burgevin M. C., Uzan A., Gueremy C., Le Fur G. Dihydropyridine and peripheral type benzodiazepine binding sites: subcellular distribution and molecular size determination. Eur J Pharmacol. 1985 Dec 17;119(3):153–167. doi: 10.1016/0014-2999(85)90291-2. [DOI] [PubMed] [Google Scholar]
  6. Erne P., Hermsmeyer K. Desensitization to norepinephrine includes refractoriness of calcium release in myocardial cells. Biochem Biophys Res Commun. 1988 Feb 29;151(1):333–338. doi: 10.1016/0006-291x(88)90598-0. [DOI] [PubMed] [Google Scholar]
  7. Grynkiewicz G., Poenie M., Tsien R. Y. A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem. 1985 Mar 25;260(6):3440–3450. [PubMed] [Google Scholar]
  8. Hermsmeyer K., Mason R. Norepinephrine sensitivity and desensitization of cultured single vascular muscle cells. Circ Res. 1982 May;50(5):627–632. doi: 10.1161/01.res.50.5.627. [DOI] [PubMed] [Google Scholar]
  9. Hermsmeyer K., Robinson R. B. High sensitivity of cultured cardiac muscle cells to autonomic agents. Am J Physiol. 1977 Nov;233(5):C172–C179. doi: 10.1152/ajpcell.1977.233.5.C172. [DOI] [PubMed] [Google Scholar]
  10. Hof R. P., Rüegg U. T., Hof A., Vogel A. Stereoselectivity at the calcium channel: opposite action of the enantiomers of a 1,4-dihydropyridine. J Cardiovasc Pharmacol. 1985 Jul-Aug;7(4):689–693. doi: 10.1097/00005344-198507000-00012. [DOI] [PubMed] [Google Scholar]
  11. Holck M., Osterrieder W. The peripheral, high affinity benzodiazepine binding site is not coupled to the cardiac Ca2+ channel. Eur J Pharmacol. 1985 Dec 3;118(3):293–301. doi: 10.1016/0014-2999(85)90140-2. [DOI] [PubMed] [Google Scholar]
  12. Hunkeler W., Möhler H., Pieri L., Polc P., Bonetti E. P., Cumin R., Schaffner R., Haefely W. Selective antagonists of benzodiazepines. Nature. 1981 Apr 9;290(5806):514–516. doi: 10.1038/290514a0. [DOI] [PubMed] [Google Scholar]
  13. Ignarro L. J., Degnan J. N., Baricos W. H., Kadowitz P. J., Wolin M. S. Activation of purified guanylate cyclase by nitric oxide requires heme. Comparison of heme-deficient, heme-reconstituted and heme-containing forms of soluble enzyme from bovine lung. Biochim Biophys Acta. 1982 Sep 17;718(1):49–59. doi: 10.1016/0304-4165(82)90008-3. [DOI] [PubMed] [Google Scholar]
  14. Ignarro L. J., Wood K. S., Wolin M. S. Activation of purified soluble guanylate cyclase by protoporphyrin IX. Proc Natl Acad Sci U S A. 1982 May;79(9):2870–2873. doi: 10.1073/pnas.79.9.2870. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lamon J. M. Clinical aspects of porphyrin measurement, other than lead poisoning. Clin Chem. 1977 Feb;23(2 Pt 1):260–263. [PubMed] [Google Scholar]
  16. Lincoln T. M. Effects of nitroprusside and 8-bromo-cyclic GMP on the contractile activity of the rat aorta. J Pharmacol Exp Ther. 1983 Jan;224(1):100–107. [PubMed] [Google Scholar]
  17. Marvin W. J., Jr, Robinson R. B., Hermsmeyer K. Correlation of function and morphology of neonatal rat and embryonic chick cultured cardiac and vascular muscle cells. Circ Res. 1979 Oct;45(4):528–540. doi: 10.1161/01.res.45.4.528. [DOI] [PubMed] [Google Scholar]
  18. Mestre M., Carriot T., Belin C., Uzan A., Renault C., Dubroeucq M. C., Guérémy C., Le Fur G. Electrophysiological and pharmacological characterization of peripheral benzodiazepine receptors in a guinea pig heart preparation. Life Sci. 1984 Aug 27;35(9):953–962. doi: 10.1016/0024-3205(84)90661-1. [DOI] [PubMed] [Google Scholar]
  19. Mestre M., Carriot T., Néliat G., Uzan A., Renault C., Dubroeucq M. C., Guérémy C., Doble A., Le Fur G. PK 11195, an antagonist of peripheral type benzodiazepine receptors, modulates Bay K8644 sensitive but not beta- or H2-receptor sensitive voltage operated calcium channels in the guinea pig heart. Life Sci. 1986 Jul 28;39(4):329–339. doi: 10.1016/0024-3205(86)90651-x. [DOI] [PubMed] [Google Scholar]
  20. Raeymaekers L., Hofmann F., Casteels R. Cyclic GMP-dependent protein kinase phosphorylates phospholamban in isolated sarcoplasmic reticulum from cardiac and smooth muscle. Biochem J. 1988 May 15;252(1):269–273. doi: 10.1042/bj2520269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Verma A., Nye J. S., Snyder S. H. Porphyrins are endogenous ligands for the mitochondrial (peripheral-type) benzodiazepine receptor. Proc Natl Acad Sci U S A. 1987 Apr;84(8):2256–2260. doi: 10.1073/pnas.84.8.2256. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Wang J. K., Morgan J. I., Spector S. Differentiation of Friend erythroleukemia cells induced by benzodiazepines. Proc Natl Acad Sci U S A. 1984 Jun;81(12):3770–3772. doi: 10.1073/pnas.81.12.3770. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. With T. K. Porphyrins in erythrocytes and blood plasma: preliminary studies with qualitative thin-layer chromatography. Clin Sci Mol Med. 1977 May;52(5):463–467. doi: 10.1042/cs0520463. [DOI] [PubMed] [Google Scholar]
  24. Wolin M. S., Wood K. S., Ignarro L. J. Guanylate cyclase from bovine lung. A kinetic analysis of the regulation of the purified soluble enzyme by protoporphyrin IX, heme, and nitrosyl-heme. J Biol Chem. 1982 Nov 25;257(22):13312–13320. [PubMed] [Google Scholar]
  25. Zavala F., Haumont J., Lenfant M. Interaction of benzodiazepines with mouse macrophages. Eur J Pharmacol. 1984 Nov 27;106(3):561–566. doi: 10.1016/0014-2999(84)90059-1. [DOI] [PubMed] [Google Scholar]
  26. van Gog H., Schothorst A. A. Determination of very small amounts of protoporphyrin in epidermis, plasma, and blister fluids. J Invest Dermatol. 1973 Jul;61(1):42–45. doi: 10.1111/1523-1747.ep12674138. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES