Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1996 Sep;119(2):239–244. doi: 10.1111/j.1476-5381.1996.tb15977.x

Renal effects of TAPP, a highly selective mu-opioid agonist.

J Gutkowska 1, P W Schiller 1
PMCID: PMC1915876  PMID: 8886404

Abstract

1. The effect of i.v. administration of TAPP, a highly selective and exclusively peripherally-acting mu-opioid receptor agonist, on urine output, urinary sodium, potassium and cyclic GMP, and on plasma immunoreactive atrial natriuretic factor (IR-ANF) levels was studied in conscious normally hydrated female rats (200-250 g). 2. TAPP treatment produced a significant dose-dependent increase of urine output and urinary sodium, potassium and cyclic GMP excretion during the first hour. The highest TAPP dose used (2.5 mg kg-1. body weight) elicited a 10 fold elevation of urine output from 0.23 +/- 0.06 ml h-1 to 2.5 +/- 0.3 ml h-1 (n = 18) accompanied by augmented sodium [from 17.0 +/- 4.7 mu Eq h-1 to 79 +/- 12.7 mu Eq h-1, n = 18 (P < 0.001)], potassium [from 9.5 +/- 2.5 mu Eq h-1 to 39.4 +/- 6.6 mu Eq h-1, n = 18 (P < 0.005)], and cyclic GMP excretion [from 191 +/- 21 pmol h-1 to 1340 +/- 322 pmol h-1, n = 18 (P < 0.001)]. Plasma IR-ANF rose from 22 +/- 4 pg ml-1 to 508 +/- 22 pg ml-1 (n = 18) (P < 0.001) 5 min after administration of TAPP (2500 micrograms kg-1). 3. TAPP lowered systemic blood pressure, also in a dose-related manner, 1-5 min after injection. This decrease in blood pressure was transient and did not last more than 10 min. 4. Pretreatment with the opioid antagonist naloxone (0.8 mg per rat) abolished the diuretic, natriuretic and kaliuretic effect of TAPP (250 micrograms kg-1); urine output dropped from 1.16 +/- 0.15 ml h-1, n = 12, to the control value of 0.15 +/- 0.06 ml h-1, n = 12 (P < 0.001), sodium excretion fell from 57.5 +/- 11 mu Eq h-1, to 21.3 +/- 8.5 mu Eq h-1, n = 12 (P < 0.001), and potassium excretion decreased from 45.4 +/- 9.7 mu Eq h-1, n = 12, to 16.1 +/- 7.0 mu Eq h-1, (P < 0.001). 5. Pretreatment with anti-ANF serum (0.4 ml) abolished the diuretic effect of TAPP: urine output diminished significantly from 1.93 +/- 0.28 to 0.88 +/- 0.29 ml h-1 (P < 0.01) (n = 6). The TAPP-induced diuretic action, increased sodium/potassium excretion and elevated urinary cyclic GMP levels were also reversed by anti-ANF antibodies. 6. Since TAPP is totally unable to cross the blood-brain barrier, the ensemble of these observations led to the conclusion that the diuretic, natriuretic, kaliuretic and hypotensive effects produced by this mu-opioid agonist through interaction with peripheral mu-opioid receptors occur via ANF release.

Full text

PDF
239

Selected References

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

  1. Ationu A., Hassall C., Moules E., Patton M., Singer D. R., Burnstock G., Carter N. D. Secretion of atrial and brain natriuretic peptides from human cardiac atrial explants in culture: effect of dynorphin. Cardioscience. 1994 Jun;5(2):81–85. [PubMed] [Google Scholar]
  2. Atweh S. F., Kuhar M. J. Autoradiographic localization of opiate receptors in rat brain. II. The brain stem. Brain Res. 1977 Jun 24;129(1):1–12. doi: 10.1016/0006-8993(77)90965-9. [DOI] [PubMed] [Google Scholar]
  3. Ballerman B. J., Brenner B. M. Biologically active atrial peptides. J Clin Invest. 1985 Dec;76(6):2041–2048. doi: 10.1172/JCI112206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Borges F., Anderson J. V., Volta C., Perry L., Drury P. L., Bloom S. R., Besser G. M., Grossman A. Opioid peptides do not modulate atrial natriuretic peptide or aldosterone release under basal conditions in man. J Endocrinol. 1988 Feb;116(2):313–317. doi: 10.1677/joe.0.1160313. [DOI] [PubMed] [Google Scholar]
  5. Chavkin C., Goldstein A. Specific receptor for the opioid peptide dynorphin: structure--activity relationships. Proc Natl Acad Sci U S A. 1981 Oct;78(10):6543–6547. doi: 10.1073/pnas.78.10.6543. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chen M., Lee J., Huang B. S., Grekin R. J., Malvin R. L. Clonidine and morphine increase atrial natriuretic peptide secretion in anesthetized rats. Proc Soc Exp Biol Med. 1989 Jul;191(3):299–303. doi: 10.3181/00379727-191-42924. [DOI] [PubMed] [Google Scholar]
  7. Crum R. L., Brown M. R. Effects of morphine and opioid peptides on plasma levels of atrial natriuretic peptide. Life Sci. 1988;43(10):851–858. doi: 10.1016/0024-3205(88)90512-7. [DOI] [PubMed] [Google Scholar]
  8. Faden A. I., Feuerstein G. Hypothalamic regulation of the cardiovascular and respiratory systems: role of specific opiate receptors. Br J Pharmacol. 1983 Aug;79(4):997–1002. doi: 10.1111/j.1476-5381.1983.tb10547.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Ferrari R., Agnoletti G. Atrial natriuretic peptide: its mechanism of release from the atrium. Int J Cardiol. 1989 Aug;24(2):137–149. doi: 10.1016/0167-5273(89)90297-0. [DOI] [PubMed] [Google Scholar]
  10. Feuerstein G., Faden A. I. Differential cardiovascular effects of mu, delta and kappa opiate agonists at discrete hypothalamic sites in the anesthetized rat. Life Sci. 1982 Nov 15;31(20-21):2197–2200. doi: 10.1016/0024-3205(82)90117-5. [DOI] [PubMed] [Google Scholar]
  11. Fontana F., Bernardi P., Merlo Pich E., Boschi S., De Iasio R., Capelli M., Carboni L., Spampinato S. Endogenous opioid system and atrial natriuretic factor in normotensive offspring of hypertensive parents at rest and during exercise test. J Hypertens. 1994 Nov;12(11):1285–1290. [PubMed] [Google Scholar]
  12. Fontana F., Bernardi P., Pich E. M., Capelli M., Bortoluzzi L., Spampinato S., Canossa M. Relationship between plasma atrial natriuretic factor and opioid peptide levels in healthy subjects and in patients with acute congestive heart failure. Eur Heart J. 1993 Feb;14(2):219–225. doi: 10.1093/eurheartj/14.2.219. [DOI] [PubMed] [Google Scholar]
  13. Garcia R., Lachance D., Thibault G., Cantin M., Gutkowska J. Mechanisms of release of atrial natriuretic factor. II. Effect of chronic administration of alpha- and beta-adrenergic and cholinergic agonists on plasma and atrial ANF in the rat. Biochem Biophys Res Commun. 1986 Apr 29;136(2):510–520. doi: 10.1016/0006-291x(86)90470-5. [DOI] [PubMed] [Google Scholar]
  14. Gutkowska J., Nemer M. Structure, expression, and function of atrial natriuretic factor in extraatrial tissues. Endocr Rev. 1989 Nov;10(4):519–536. doi: 10.1210/edrv-10-4-519. [DOI] [PubMed] [Google Scholar]
  15. Gutkowska J., Racz K., Garcia R., Thibault G., Kuchel O., Genest J., Cantin M. The morphine effect on plasma ANF. Eur J Pharmacol. 1986 Nov 12;131(1):91–94. doi: 10.1016/0014-2999(86)90519-4. [DOI] [PubMed] [Google Scholar]
  16. Gutkowska J. Radioimmunoassay for atrial natriuretic factor. Int J Rad Appl Instrum B. 1987;14(4):323–331. doi: 10.1016/0883-2897(87)90009-2. [DOI] [PubMed] [Google Scholar]
  17. Gutkowska J., Strick D. M., Pan L., McCann S. M. Effect of morphine on urine output: possible role of atrial natriuretic factor. Eur J Pharmacol. 1993 Sep 21;242(1):7–13. doi: 10.1016/0014-2999(93)90003-z. [DOI] [PubMed] [Google Scholar]
  18. Hamet P., Pang S. C., Tremblay J. Atrial natriuretic factor-induced egression of cyclic guanosine 3':5'-monophosphate in cultured vascular smooth muscle and endothelial cells. J Biol Chem. 1989 Jul 25;264(21):12364–12369. [PubMed] [Google Scholar]
  19. Hassen A. H., Feuerstein G., Faden A. I. mu Receptors and opioid cardiovascular effects in the NTS of rat. Peptides. 1982 Nov-Dec;3(6):1031–1037. doi: 10.1016/0196-9781(82)90074-2. [DOI] [PubMed] [Google Scholar]
  20. Hassen A. H., Feuerstein G., Pfeiffer A., Faden A. I. Delta versus mu receptors: cardiovascular and respiratory effects of opiate agonists microinjected into nucleus tractus solitarius of cats. Regul Pept. 1982 Nov;4(6):299–309. doi: 10.1016/0167-0115(82)90140-9. [DOI] [PubMed] [Google Scholar]
  21. Holaday J. W. Cardiovascular effects of endogenous opiate systems. Annu Rev Pharmacol Toxicol. 1983;23:541–594. doi: 10.1146/annurev.pa.23.040183.002545. [DOI] [PubMed] [Google Scholar]
  22. Horký K., Gutkowska J., Garcia R., Thibault G., Genest J., Cantin M. Effect of different anesthetics on immunoreactive atrial natriuretic factor concentrations in rat plasma. Biochem Biophys Res Commun. 1985 Jun 28;129(3):651–657. doi: 10.1016/0006-291x(85)91941-2. [DOI] [PubMed] [Google Scholar]
  23. Hughes J., Smith T. W., Kosterlitz H. W., Fothergill L. A., Morgan B. A., Morris H. R. Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature. 1975 Dec 18;258(5536):577–580. doi: 10.1038/258577a0. [DOI] [PubMed] [Google Scholar]
  24. JOHANNESSON T., WOODS L. A. ANALGESIC ACTION AND BRAIN AND PLASMA LEVELS OF MORPHINE AND CODEINE IN MORPHINE TOLERANT, CODEINE TOLERANT AND NON-TOLERANT RATS. Acta Pharmacol Toxicol (Copenh) 1964;21:381–396. doi: 10.1111/j.1600-0773.1964.tb01803.x. [DOI] [PubMed] [Google Scholar]
  25. Katsube N., Schwartz D., Needleman P. Release of atriopeptin in the rat by vasoconstrictors or water immersion correlates with changes in right atrial pressure. Biochem Biophys Res Commun. 1985 Dec 31;133(3):937–944. doi: 10.1016/0006-291x(85)91226-4. [DOI] [PubMed] [Google Scholar]
  26. Kidd J. E., Gilchrist N. L., Utley R. J., Nicholls M. G., Espiner E. A., Yandle T. G. Effect of opiate, general anaesthesia and surgery on plasma atrial natriuretic peptide levels in man. Clin Exp Pharmacol Physiol. 1987 Oct;14(10):755–760. doi: 10.1111/j.1440-1681.1987.tb01866.x. [DOI] [PubMed] [Google Scholar]
  27. Kunos G., Farsang C., Ramirez-Gonzales M. D. beta-Endorphin: possible involvement in the antihypertensive effect of central alpha-receptor activation. Science. 1981 Jan 2;211(4477):82–84. doi: 10.1126/science.6108611. [DOI] [PubMed] [Google Scholar]
  28. Louisy F., Guezennec C. Y., Lartigue M., Aldigier J. C., Galen F. X. Influence of endogenous opioids on atrial natriuretic factor release during exercise in man. Eur J Appl Physiol Occup Physiol. 1989;59(1-2):34–38. doi: 10.1007/BF02396577. [DOI] [PubMed] [Google Scholar]
  29. MILLER J. W., ELLIOTT H. W. Rat tissue levels of carbon-14 labeled analgetics as related to pharmacological activity. J Pharmacol Exp Ther. 1955 Mar;113(3):283–291. [PubMed] [Google Scholar]
  30. Maack T., Camargo M. J., Kleinert H. D., Laragh J. H., Atlas S. A. Atrial natriuretic factor: structure and functional properties. Kidney Int. 1985 Apr;27(4):607–615. doi: 10.1038/ki.1985.54. [DOI] [PubMed] [Google Scholar]
  31. Manning P. T., Schwartz D., Katsube N. C., Holmberg S. W., Needleman P. Vasopressin-stimulated release of atriopeptin: endocrine antagonists in fluid homeostasis. Science. 1985 Jul 26;229(4711):395–397. doi: 10.1126/science.2990050. [DOI] [PubMed] [Google Scholar]
  32. McCormack T., Martin T., Smallwood R. H., Robinson P., Walton L., Johnson A. G. Doppler ultrasound probe for assessment of blood-flow in oesophageal varices. Lancet. 1983 Mar 26;1(8326 Pt 1):677–678. doi: 10.1016/s0140-6736(83)91971-2. [DOI] [PubMed] [Google Scholar]
  33. Oğtman C., Ozben T., Sadan G., Trakya A., Isbir M. Morphine increases plasma immunoreactive atrial natriuretic peptide levels in humans. Ann Clin Biochem. 1990 Jan;27(Pt 1):21–24. doi: 10.1177/000456329002700105. [DOI] [PubMed] [Google Scholar]
  34. Pan L., Gutkowska J. Is clonidine-induced diuresis mediated by atrial natriuretic factor? Endocrinology. 1988 Sep;123(3):1259–1263. doi: 10.1210/endo-123-3-1259. [DOI] [PubMed] [Google Scholar]
  35. Pesonen A., Leppäluoto J., Ruskoaho H. Mechanism of opioid-induced atrial natriuretic peptide release in conscious rats. J Pharmacol Exp Ther. 1990 Aug;254(2):690–695. [PubMed] [Google Scholar]
  36. Ruskoaho H. Atrial natriuretic peptide: synthesis, release, and metabolism. Pharmacol Rev. 1992 Dec;44(4):479–602. [PubMed] [Google Scholar]
  37. Schiller P. W., Nguyen T. M., Chung N. N., Lemieux C. Dermorphin analogues carrying an increased positive net charge in their "message" domain display extremely high mu opioid receptor selectivity. J Med Chem. 1989 Mar;32(3):698–703. doi: 10.1021/jm00123a035. [DOI] [PubMed] [Google Scholar]
  38. Simantov R., Kuhar M. J., Uhl G. R., Snyder S. H. Opioid peptide enkephalin: immunohistochemical mapping in rat central nervous system. Proc Natl Acad Sci U S A. 1977 May;74(5):2167–2171. doi: 10.1073/pnas.74.5.2167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Stasch J. P., Grote H., Kazda S., Hirth C. Dynorphin stimulates the release of ANP from isolated rat atria. Eur J Pharmacol. 1989 Jan 2;159(1):101–102. doi: 10.1016/0014-2999(89)90050-2. [DOI] [PubMed] [Google Scholar]
  40. Tang J., Xie C. W., Xie X. Z., Gao X. M., Chang J. K. Dynorphin A-(1-10) amide stimulates the release of atrial natriuretic polypeptide (ANP) from rat atrium. Eur J Pharmacol. 1987 Apr 29;136(3):449–450. doi: 10.1016/0014-2999(87)90325-6. [DOI] [PubMed] [Google Scholar]
  41. Vollmar A. M., Arendt R. M., Schulz R. The effect of opioids on rat plasma atrial natriuretic peptide. Eur J Pharmacol. 1987 Nov 17;143(3):315–321. doi: 10.1016/0014-2999(87)90455-9. [DOI] [PubMed] [Google Scholar]
  42. Xie C. W., Yin L. Y., Xie X. Z., Gao X. M., Xia Z. Q., Chang J. K., Tang J. A dynorphin peptide induces hypotension by stimulating the release of atrial natriuretic peptide from rat atrium. Life Sci. 1988;42(11):1117–1122. doi: 10.1016/0024-3205(88)90605-4. [DOI] [PubMed] [Google Scholar]
  43. Yamada K., Yoshida S., Shimada Y. Atrial natriuretic polypeptide secretion via selective activation of kappa-opioid receptor: role of dynorphin. Am J Physiol. 1991 Sep;261(3 Pt 1):E293–E297. doi: 10.1152/ajpendo.1991.261.3.E293. [DOI] [PubMed] [Google Scholar]
  44. de Bold A. J., Borenstein H. B., Veress A. T., Sonnenberg H. A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats. Life Sci. 1981 Jan 5;28(1):89–94. doi: 10.1016/0024-3205(81)90370-2. [DOI] [PubMed] [Google Scholar]
  45. de Wardener H. E., MacGregor G. A. Dahl's hypothesis that a saluretic substance may be responsible for a sustained rise in arterial pressure: its possible role in essential hypertension. Kidney Int. 1980 Jul;18(1):1–9. doi: 10.1038/ki.1980.104. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES