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British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1990 Feb;99(2):237–242. doi: 10.1111/j.1476-5381.1990.tb14687.x

Phorbol esters inhibit smooth muscle contractions through activation of Na(+)-K(+)-ATPase.

T Sasaguri 1, S P Watson 1
PMCID: PMC1917384  PMID: 1691673

Abstract

1. The role of protein kinase C (PKC) in agonist-induced contractions of guinea-pig ileum longitudinal smooth muscle has been investigated. 2. The phorbol esters, phorbol 12,13-dibutyrate (PDBu), phorbol 12,13-diacetate (PDA) and phorbol 12-myristate 13-acetate (PMA), relaxed tissues precontracted by submaximal concentrations of carbachol, histamine or substance P. 3. This inhibitory action of the phorbol esters was reversed following the application of ouabain, a specific inhibitor of Na(+)-K(+)-ATPase. Similarly, pretreatment with ouabain inhibited the ability of phorbol esters to relax tissues precontracted by the above agonists. 4. The slow relaxation of the tonic component of contraction induced by submaximal concentrations of carbachol and histamine, and all concentrations of substance P, was abolished in the presence of ouabain. 5. In Na(+)-loaded tissues, PDBu and carbachol caused a concentration-dependent increase of Na(+)-K(+)-ATPase activity, assessed by ouabain-sensitive 86Rb(+)-uptake. Extrusion of Na+, assessed by the cellular content of the ion, was also stimulated by PDBu (the effect of carbachol was not investigated). 6. We conclude that phorbol esters inhibit the tonic component of contractions induced by submaximal concentrations of these agonists through activation of Na(+)-K(+)-ATPase. We suggest that PKC may exert feedback control over the tonic component of agonist contractions through stimulation of the pump.

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Selected References

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  1. Baraban J. M., Gould R. J., Peroutka S. J., Snyder S. H. Phorbol ester effects on neurotransmission: interaction with neurotransmitters and calcium in smooth muscle. Proc Natl Acad Sci U S A. 1985 Jan;82(2):604–607. doi: 10.1073/pnas.82.2.604. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Berridge M. J. Inositol trisphosphate and diacylglycerol: two interacting second messengers. Annu Rev Biochem. 1987;56:159–193. doi: 10.1146/annurev.bi.56.070187.001111. [DOI] [PubMed] [Google Scholar]
  3. Bill D. J., Hughes I. E., Stephens R. J. The thermogenic actions of alpha 2-adrenoceptor agonists in reserpinized mice are mediated via a central postsynaptic alpha 2-adrenoceptor mechanism. Br J Pharmacol. 1989 Jan;96(1):133–143. doi: 10.1111/j.1476-5381.1989.tb11793.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bolton T. B. Effects of electrogenic sodium pumping on the membrane potential of longitudinal smooth muscle from terminal ileum of guinea-pig. J Physiol. 1973 Feb;228(3):693–712. doi: 10.1113/jphysiol.1973.sp010107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bolton T. B. The role of electrogenic sodium pumping in the response of smooth muscle to acetylcholine. J Physiol. 1973 Feb;228(3):713–731. doi: 10.1113/jphysiol.1973.sp010108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Brading A. F. Sodium/sodium exchange in the smooth muscle of the guinea-pig taenia coli. J Physiol. 1975 Sep;251(1):79–105. doi: 10.1113/jphysiol.1975.sp011082. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Brading A. F., Widdicombe J. H. An estimate of sodium-potassium pump activity and the number of pump sites in the smooth muscle of the guinea-pig taenia coli, using (3H)ouabain. J Physiol. 1974 Apr;238(2):235–249. doi: 10.1113/jphysiol.1974.sp010521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Castagna M., Takai Y., Kaibuchi K., Sano K., Kikkawa U., Nishizuka Y. Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters. J Biol Chem. 1982 Jul 10;257(13):7847–7851. [PubMed] [Google Scholar]
  9. Glynn I. M., Karlish S. J. The sodium pump. Annu Rev Physiol. 1975;37:13–55. doi: 10.1146/annurev.ph.37.030175.000305. [DOI] [PubMed] [Google Scholar]
  10. Greene D. A., Lattimer S. A. Protein kinase C agonists acutely normalize decreased ouabain-inhibitable respiration in diabetic rabbit nerve. Implications for (Na,K)-ATPase regulation and diabetic complications. Diabetes. 1986 Feb;35(2):242–245. doi: 10.2337/diab.35.2.242. [DOI] [PubMed] [Google Scholar]
  11. Hashimoto T., Hirata M., Itoh T., Kanmura Y., Kuriyama H. Inositol 1,4,5-trisphosphate activates pharmacomechanical coupling in smooth muscle of the rabbit mesenteric artery. J Physiol. 1986 Jan;370:605–618. doi: 10.1113/jphysiol.1986.sp015953. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Holzer P., Lembeck F. Neurally mediated contraction of ileal longitudinal muscle by substance P. Neurosci Lett. 1980 Apr;17(1-2):101–105. doi: 10.1016/0304-3940(80)90069-5. [DOI] [PubMed] [Google Scholar]
  13. Hootman S. R., Brown M. E., Williams J. A. Phorbol esters and A23187 regulate Na+-K+-pump activity in pancreatic acinar cells. Am J Physiol. 1987 Apr;252(4 Pt 1):G499–G505. doi: 10.1152/ajpgi.1987.252.4.G499. [DOI] [PubMed] [Google Scholar]
  14. Jørgensen P. L. Mechanism of the Na+, K+ pump. Protein structure and conformations of the pure (Na+ +K+)-ATPase. Biochim Biophys Acta. 1982 Aug 11;694(1):27–68. doi: 10.1016/0304-4157(82)90013-2. [DOI] [PubMed] [Google Scholar]
  15. Kaplan J. H. Ion movements through the sodium pump. Annu Rev Physiol. 1985;47:535–544. doi: 10.1146/annurev.ph.47.030185.002535. [DOI] [PubMed] [Google Scholar]
  16. Lynch C. J., Wilson P. B., Blackmore P. F., Exton J. H. The hormone-sensitive hepatic Na+-pump. Evidence for regulation by diacylglycerol and tumor promoters. J Biol Chem. 1986 Nov 5;261(31):14551–14556. [PubMed] [Google Scholar]
  17. Menkes H., Baraban J. M., Snyder S. H. Protein kinase C regulates smooth muscle tension in guinea-pig trachea and ileum. Eur J Pharmacol. 1986 Mar 11;122(1):19–27. doi: 10.1016/0014-2999(86)90153-6. [DOI] [PubMed] [Google Scholar]
  18. Nishizuka Y. Studies and perspectives of protein kinase C. Science. 1986 Jul 18;233(4761):305–312. doi: 10.1126/science.3014651. [DOI] [PubMed] [Google Scholar]
  19. Nishizuka Y. The role of protein kinase C in cell surface signal transduction and tumour promotion. Nature. 1984 Apr 19;308(5961):693–698. doi: 10.1038/308693a0. [DOI] [PubMed] [Google Scholar]
  20. Sasaguri T., Watson S. P. Lowering of the extracellular Na+ concentration enhances high-K+-induced formation of inositol phosphates in the guinea-pig ileum. Biochem J. 1988 Jun 15;252(3):883–888. doi: 10.1042/bj2520883. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Sasaguri T., Watson S. P. Protein kinase C regulates the tonic but not the phasic component of contraction in guinea-pig ileum. Br J Pharmacol. 1989 Nov;98(3):791–798. doi: 10.1111/j.1476-5381.1989.tb14607.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Watson S. P., Godfrey P. P. The role of receptor-stimulated inositol phospholipid hydrolysis in the autonomic nervous system. Pharmacol Ther. 1988;38(3):387–417. doi: 10.1016/0163-7258(88)90011-3. [DOI] [PubMed] [Google Scholar]
  23. Watson S. P., Stanley A. F., Sasaguri T. Does the hydrolysis of inositol phospholipids lead to the opening of voltage operated Ca2+ channels in guinea-pig ileum? Studies with fluoride ions and caffeine. Biochem Biophys Res Commun. 1988 May 31;153(1):14–20. doi: 10.1016/s0006-291x(88)81183-5. [DOI] [PubMed] [Google Scholar]
  24. Yingst D. R. Modulation of the Na,K-ATPase by Ca and intracellular proteins. Annu Rev Physiol. 1988;50:291–303. doi: 10.1146/annurev.ph.50.030188.001451. [DOI] [PubMed] [Google Scholar]

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