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. 1996 Dec;119(7):1355–1360. doi: 10.1111/j.1476-5381.1996.tb16046.x

Influence of adrenodemedullation on beta 2- and beta 3-adrenoceptors mediating relaxation of oesophageal smooth muscle of spontaneously hypertensive rats.

R E de Boer 1, M R Steegstra 1, P A Kroezen 1, J Smit 1, J Zaagsma 1
PMCID: PMC1915822  PMID: 8968543

Abstract

1. In oesophageal smooth muscle strips from spontaneously hypertensive rats (SHR) of 8-10 and 22-24 weeks of age, respectively, beta-adrenoceptor-mediated relaxation was investigated, by use of the beta-agonists, (-)-isoprenaline and fenoterol (both in the absence and presence of the beta 2-selective antagonist ICI 118,551) and the selective beta 3-agonist, BRL 37,344. 2. In preparations from 8-10 week SHR, (-)-isoprenaline- and fenoterol-induced concentration-response curves (CRCs) were hardly antagonized by ICI 118,551 at concentrations up to 1 microM, indicating only a minor contribution of beta 2-adrenoceptors. pA2-values for ICI 118,551 of 5.30 ((-)-isoprenaline as agonist) and 5.46 (fenoterol as agonist), estimated from the shifts at the highest (10-100 microM) antagonist concentrations, are consistent with affinity at a beta 3-adrenoceptor, similar to that in Wistar rat oesophageal smooth muscle. 3. In 8-10 week SHR, adrenodemedullated at 4 weeks of age (SHR-ADM4) the potency of fenoterol was markedly increased and CRCs were shallow. In addition, ICI 118,551 (0.1 microM) now produced a clear rightward shift accompanied by a steepening of the CRC. A marked further shift was observed only at 100 microM of the antagonist. The data are compatible with the involvement of both beta 2- and beta 3-adrenoceptors. 4. In 22-24 week animals, the same differences between SHR and SHR-ADM4 were observed with fenoterol as in 8-10 week animals, though beta-adrenoceptor responsiveness was slightly decreased. The potency of ICI 118,551 at beta 3-adrenoceptors (pA2 = 5.11) was significantly different from the pA2 value of 5.46 obtained with the younger animals. 5. Responses to the beta 3-adrenoceptor agonist, BRL 37,344, were similar in Wistar rat and SHR preparations. In 8-10 week SHR, a small decrease in the maximal response was observed, which in animals of 22-24 weeks of age was accompanied by a small decrease in the pEC50 value as well. 6. The results clearly indicate that beta 2-adrenoceptors in SHR oesophageal muscularis mucosae are desensitized, whereas beta 3-adrenoceptor-mediated responses are unaffected and similar to the responses observed in the Wistar rat oesophagus. The functional presence of beta 2-adrenoceptor-responses in SHR-ADM4 suggests a major role for adrenal-derived adrenaline in the desensitization of the beta 2-adrenoceptor-population.

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Selected References

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  1. ARUNLAKSHANA O., SCHILD H. O. Some quantitative uses of drug antagonists. Br J Pharmacol Chemother. 1959 Mar;14(1):48–58. doi: 10.1111/j.1476-5381.1959.tb00928.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bond R. A., Clarke D. E. Agonist and antagonist characterization of a putative adrenoceptor with distinct pharmacological properties from the alpha- and beta-subtypes. Br J Pharmacol. 1988 Nov;95(3):723–734. doi: 10.1111/j.1476-5381.1988.tb11698.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Borkowski K. R. Effect of adrenal demedullation and adrenaline on hypertension development and vascular reactivity in young spontaneously hypertensive rats. J Auton Pharmacol. 1991 Feb;11(1):1–14. doi: 10.1111/j.1474-8673.1991.tb00239.x. [DOI] [PubMed] [Google Scholar]
  4. Borkowski K. R., Gros R., Schneider H. Vascular beta-adrenoceptor-mediated responses in hypertension and ageing in rats. J Auton Pharmacol. 1992 Dec;12(6):389–401. doi: 10.1111/j.1474-8673.1992.tb00387.x. [DOI] [PubMed] [Google Scholar]
  5. Borkowski K. R., Porter M. An altered beta-adrenoreceptor-mediated modulation of noradrenaline-induced vasoconstriction in spontaneously hypertensive rat mesenteric arteries. J Auton Pharmacol. 1984 Mar;4(1):27–31. doi: 10.1111/j.1474-8673.1984.tb00430.x. [DOI] [PubMed] [Google Scholar]
  6. Borkowski K. R., Quinn P. Adrenaline and the development of spontaneous hypertension in rats. J Auton Pharmacol. 1985 Jun;5(2):89–100. doi: 10.1111/j.1474-8673.1985.tb00109.x. [DOI] [PubMed] [Google Scholar]
  7. Borkowski K. R., Quinn P. The effect of bilateral adrenal demedullation on vascular reactivity and blood pressure in spontaneously hypertensive rats. Br J Pharmacol. 1983 Nov;80(3):429–437. doi: 10.1111/j.1476-5381.1983.tb10712.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Böhm M., Castellano M., Paul M., Erdmann E. Cardiac norepinephrine, beta-adrenoceptors, and Gi alpha-proteins in prehypertensive and hypertensive spontaneously hypertensive rats. J Cardiovasc Pharmacol. 1994 Jun;23(6):980–987. doi: 10.1097/00005344-199406000-00017. [DOI] [PubMed] [Google Scholar]
  9. Carpéné C., Galitzky J., Collon P., Esclapez F., Dauzats M., Lafontan M. Desensitization of beta-1 and beta-2, but not beta-3, adrenoceptor-mediated lipolytic responses of adipocytes after long-term norepinephrine infusion. J Pharmacol Exp Ther. 1993 Apr;265(1):237–247. [PubMed] [Google Scholar]
  10. Cases A., Bono M., Gaya J., Jimenez W., Calls J., Esforzado N., Rivera F., Revert L. Reversible decrease of surface beta 2-adrenoceptor number and response in lymphocytes of patients with pheochromocytoma. Clin Exp Hypertens. 1995 Apr;17(3):537–549. doi: 10.3109/10641969509037423. [DOI] [PubMed] [Google Scholar]
  11. Cohen M. L., Berkowitz B. A. Decreased vascular relaxation in hypertension. J Pharmacol Exp Ther. 1976 Feb;196(2):396–406. [PubMed] [Google Scholar]
  12. Coppes R. P., Brouwer F., Freie I., Smit J., Zaagsma J. Sustained prejunctional facilitation of noradrenergic neurotransmission by adrenaline as a co-transmitter in the portal vein of freely moving rats. Br J Pharmacol. 1994 Oct;113(2):342–344. doi: 10.1111/j.1476-5381.1994.tb16992.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. DOYLE A. E., FRASER J. R. Vascular reactivity in hypertension. Circ Res. 1961 May;9:755–761. doi: 10.1161/01.res.9.3.755. [DOI] [PubMed] [Google Scholar]
  14. Deisher T. A., Mankani S., Hoffman B. B. Role of cyclic AMP-dependent protein kinase in the diminished beta adrenergic responsiveness of vascular smooth muscle with increasing age. J Pharmacol Exp Ther. 1989 Jun;249(3):812–819. [PubMed] [Google Scholar]
  15. Ekas R. D., Jr, Lokhandwala M. F. Sympathetic nerve function and vascular reactivity in spontaneously hypertensive rats. Am J Physiol. 1981 Nov;241(5):R379–R384. doi: 10.1152/ajpregu.1981.241.5.R379. [DOI] [PubMed] [Google Scholar]
  16. Emorine L. J., Feve B., Pairault J., Briend-Sutren M. M., Marullo S., Delavier-Klutchko C., Strosberg D. A. Structural basis for functional diversity of beta 1-, beta 2- and beta 3-adrenergic receptors. 1991 Mar 15-Apr 1Biochem Pharmacol. 41(6-7):853–859. doi: 10.1016/0006-2952(91)90188-b. [DOI] [PubMed] [Google Scholar]
  17. Feldman R. D. Beta-adrenergic receptor alterations in hypertension--physiological and molecular correlates. Can J Physiol Pharmacol. 1987 Aug;65(8):1666–1672. doi: 10.1139/y87-261. [DOI] [PubMed] [Google Scholar]
  18. Granneman J. G. Effects of agonist exposure on the coupling of beta 1 and beta 3 adrenergic receptors to adenylyl cyclase in isolated adipocytes. J Pharmacol Exp Ther. 1992 May;261(2):638–642. [PubMed] [Google Scholar]
  19. Granneman J. G., Lahners K. N. Differential adrenergic regulation of beta 1- and beta 3-adrenoreceptor messenger ribonucleic acids in adipose tissues. Endocrinology. 1992 Jan;130(1):109–114. doi: 10.1210/endo.130.1.1309320. [DOI] [PubMed] [Google Scholar]
  20. Grobecker G., Roizen M. F., Weise V., Saavedra J. M., Kopin I. J. Letter: Sympathoadrenal medullary activity in young, spontaneously hypertensive rats. Nature. 1975 Nov 20;258(5532):267–268. doi: 10.1038/258267a0. [DOI] [PubMed] [Google Scholar]
  21. Hano T., Rho J. Norepinephrine overflow in perfused mesenteric arteries of spontaneously hypertensive rats. Hypertension. 1989 Jul;14(1):44–53. doi: 10.1161/01.hyp.14.1.44. [DOI] [PubMed] [Google Scholar]
  22. Liggett S. B., Freedman N. J., Schwinn D. A., Lefkowitz R. J. Structural basis for receptor subtype-specific regulation revealed by a chimeric beta 3/beta 2-adrenergic receptor. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3665–3669. doi: 10.1073/pnas.90.8.3665. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Limas C. J., Limas C. Decreased number of beta-adrenergic receptors in hypertensive vessels. Biochim Biophys Acta. 1979 Feb 1;582(3):533–536. doi: 10.1016/0304-4165(79)90144-2. [DOI] [PubMed] [Google Scholar]
  24. MacKay D. How should values of pA2 and affinity constants for pharmacological competitive antagonists be estimated? J Pharm Pharmacol. 1978 May;30(5):312–313. doi: 10.1111/j.2042-7158.1978.tb13237.x. [DOI] [PubMed] [Google Scholar]
  25. Mendlowitz M. Vascular reactivity in systemic arterial hypertension. Am Heart J. 1973 Feb;85(2):252–259. doi: 10.1016/0002-8703(73)90467-5. [DOI] [PubMed] [Google Scholar]
  26. Michel M. C., Brodde O. E., Insel P. A. Peripheral adrenergic receptors in hypertension. Hypertension. 1990 Aug;16(2):107–120. doi: 10.1161/01.hyp.16.2.107. [DOI] [PubMed] [Google Scholar]
  27. Michel M. C., Siepmann F., Büscher R., Philipp T., Brodde O. E. Ontogenesis of sympathetic responsiveness in spontaneously hypertensive rats. I. Renal alpha 1-, alpha 2-, and beta-adrenergic receptors and their signaling. Hypertension. 1993 Aug;22(2):169–177. doi: 10.1161/01.hyp.22.2.169. [DOI] [PubMed] [Google Scholar]
  28. Michel M. C., Wang X. L., Schlicker E., Göthert M., Beckeringh J. J., Brodde O. E. Increased beta 2-adrenoreceptor density in heart, kidney and lung of spontaneously hypertensive rats. J Auton Pharmacol. 1987 Mar;7(1):41–51. doi: 10.1111/j.1474-8673.1987.tb00132.x. [DOI] [PubMed] [Google Scholar]
  29. Nantel F., Bonin H., Emorine L. J., Zilberfarb V., Strosberg A. D., Bouvier M., Marullo S. The human beta 3-adrenergic receptor is resistant to short term agonist-promoted desensitization. Mol Pharmacol. 1993 Apr;43(4):548–555. [PubMed] [Google Scholar]
  30. OKAMOTO K., AOKI K. Development of a strain of spontaneously hypertensive rats. Jpn Circ J. 1963 Mar;27:282–293. doi: 10.1253/jcj.27.282. [DOI] [PubMed] [Google Scholar]
  31. Remie R., Van Rossum J. X., Coppes R. P., Zaagsma J. Dysfunctional presynaptic alpha 2-adrenoceptors expose facilitatory beta 2-adrenoceptors in the vasculature of spontaneously hypertensive rats. Eur J Pharmacol. 1992 Feb 11;211(2):257–261. doi: 10.1016/0014-2999(92)90537-e. [DOI] [PubMed] [Google Scholar]
  32. Struyker-Boudier H. A., Vervoort-Peters L. H., Rousch M. J., Smits J. F., Thijssen H. H. Beta-adrenoceptors in kidney tubules of spontaneously hypertensive and normotensive rats. Life Sci. 1986 Jan 13;38(2):137–145. doi: 10.1016/0024-3205(86)90005-6. [DOI] [PubMed] [Google Scholar]
  33. Thomas R. F., Holt B. D., Schwinn D. A., Liggett S. B. Long-term agonist exposure induces upregulation of beta 3-adrenergic receptor expression via multiple cAMP response elements. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4490–4494. doi: 10.1073/pnas.89.10.4490. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Toal C. B., Leenen F. H. Blood pressure responsiveness to isoproterenol during the development of hypertension in conscious, spontaneously hypertensive rats. Blood Vessels. 1984;21(5):252–256. doi: 10.1159/000158518. [DOI] [PubMed] [Google Scholar]
  35. Tsujimoto G., Lee C. H., Hoffman B. B. Age-related decrease in beta adrenergic receptor-mediated vascular smooth muscle relaxation. J Pharmacol Exp Ther. 1986 Nov;239(2):411–415. [PubMed] [Google Scholar]
  36. de Boer R. E., Brouwer F., Zaagsma J. Noradrenaline-induced relaxation of rat oesophageal muscularis mucosae: mediation solely by innervated beta 3-adrenoceptors. Br J Pharmacol. 1995 Oct;116(3):1945–1947. doi: 10.1111/j.1476-5381.1995.tb16396.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. de Boer R. E., Brouwer F., Zaagsma J. The beta-adrenoceptors mediating relaxation of rat oesophageal muscularis mucosae are predominantly of the beta 3-, but also of the beta 2-subtype. Br J Pharmacol. 1993 Sep;110(1):442–446. doi: 10.1111/j.1476-5381.1993.tb13830.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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