Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1989 Oct;84(4):1267–1275. doi: 10.1172/JCI114294

Decreased adrenergic neuronal uptake activity in experimental right heart failure. A chamber-specific contributor to beta-adrenoceptor downregulation.

C S Liang 1, T H Fan 1, J T Sullebarger 1, S Sakamoto 1
PMCID: PMC329787  PMID: 2551925

Abstract

The reduction of myocardial beta-adrenoceptor density in congestive heart failure has been thought to be caused by agonist-induced homologous desensitization. However, recent evidence suggests that excessive adrenergic stimulation may not produce myocardial beta-receptor downregulation unless there is an additional defect in the local norepinephrine (NE) uptake mechanism. To investigate the association between beta-adrenoceptor regulation and NE uptake activity, we carried out studies in 30 dogs with right heart failure (RHF) produced by tricuspid avulsion and progressive pulmonary artery constriction and 23 sham-operated control dogs. We determined NE uptake activity by measuring accumulation of [3H]NE in tissue slices, NE uptake-1 carrier density by [3H]mazindol binding and beta-adrenoceptor density by [3H]dihydroalprenolol binding. Compared with sham-operated dogs, RHF dogs showed a 26% decrease in beta-adrenoceptor density, a 51% reduction in NE uptake activity, and a 57% decrease in NE uptake-1 carrier density in their right ventricles. In addition, right ventricle beta-receptor density correlated significantly with NE uptake activity and NE uptake-1 carrier density. In contrast, neither NE uptake activity nor beta-receptor density in the left ventricle and renal cortex was affected by RHF. Thus, the failing myocardium is associated with an organ- and chamber-specific subnormal neuronal NE uptake. This chamber-specific loss of NE uptake-1 carrier could effectively reduce local NE clearance, and represent a local factor that predisposes the failing ventricle to beta-adrenoceptor downregulation.

Full text

PDF
1267

Selected References

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

  1. BARGER A. C., ROE B. B., RICHARDSON G. S. Relation of valvular lesions and of exercise to auricular pressure, work tolerance, and to development of chronic, congestive failure in dogs. Am J Physiol. 1952 May;169(2):384–399. doi: 10.1152/ajplegacy.1952.169.2.384. [DOI] [PubMed] [Google Scholar]
  2. Bristow M. R., Ginsburg R., Minobe W., Cubicciotti R. S., Sageman W. S., Lurie K., Billingham M. E., Harrison D. C., Stinson E. B. Decreased catecholamine sensitivity and beta-adrenergic-receptor density in failing human hearts. N Engl J Med. 1982 Jul 22;307(4):205–211. doi: 10.1056/NEJM198207223070401. [DOI] [PubMed] [Google Scholar]
  3. Bristow M. R., Ginsburg R., Umans V., Fowler M., Minobe W., Rasmussen R., Zera P., Menlove R., Shah P., Jamieson S. Beta 1- and beta 2-adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective beta 1-receptor down-regulation in heart failure. Circ Res. 1986 Sep;59(3):297–309. doi: 10.1161/01.res.59.3.297. [DOI] [PubMed] [Google Scholar]
  4. CHIDSEY C. A., BRAUNWALD E., MORROW A. G. CATECHOLAMINE EXCRETION AND CARDIAC STORES OF NOREPINEPHRINE IN CONGESTIVE HEART FAILURE. Am J Med. 1965 Sep;39:442–451. doi: 10.1016/0002-9343(65)90211-1. [DOI] [PubMed] [Google Scholar]
  5. CHIDSEY C. A., KAISER G. A., SONNENBLICK E. H., SPANN J. F., BRAUNWALD E. CARDIAC NOREPHINEPHRINE STORES IN EXPERIMENTAL HEART FAILURE IN THE DOG. J Clin Invest. 1964 Dec;43:2386–2393. doi: 10.1172/JCI105113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Colucci W. S., Alexander R. W., Williams G. H., Rude R. E., Holman B. L., Konstam M. A., Wynne J., Mudge G. H., Jr, Braunwald E. Decreased lymphocyte beta-adrenergic-receptor density in patients with heart failure and tolerance to the beta-adrenergic agonist pirbuterol. N Engl J Med. 1981 Jul 23;305(4):185–190. doi: 10.1056/NEJM198107233050402. [DOI] [PubMed] [Google Scholar]
  7. Currie P. J., Kelly M. J., McKenzie A., Harper R. W., Lim Y. L., Federman J., Anderson S. T., Pitt A. Oral beta-adrenergic blockade with metoprolol in chronic severe dilated cardiomyopathy. J Am Coll Cardiol. 1984 Jan;3(1):203–209. doi: 10.1016/s0735-1097(84)80449-0. [DOI] [PubMed] [Google Scholar]
  8. Davidson D. M., Covell J. W., Malloch C. I., Ross J., Jr Factors influencing indices of left ventricle contractility in the conscious dog. Cardiovasc Res. 1974 May;8(3):299–312. doi: 10.1093/cvr/8.3.299. [DOI] [PubMed] [Google Scholar]
  9. Denniss A. R., Marsh J. D., Quigg R. J., Gordon J. B., Colucci W. S. Beta-adrenergic receptor number and adenylate cyclase function in denervated transplanted and cardiomyopathic human hearts. Circulation. 1989 May;79(5):1028–1034. doi: 10.1161/01.cir.79.5.1028. [DOI] [PubMed] [Google Scholar]
  10. Fan T. H., Liang C. S., Kawashima S., Banerjee S. P. Alterations in cardiac beta-adrenoceptor responsiveness and adenylate cyclase system by congestive heart failure in dogs. Eur J Pharmacol. 1987 Aug 11;140(2):123–132. doi: 10.1016/0014-2999(87)90798-9. [DOI] [PubMed] [Google Scholar]
  11. Fowler M. B., Laser J. A., Hopkins G. L., Minobe W., Bristow M. R. Assessment of the beta-adrenergic receptor pathway in the intact failing human heart: progressive receptor down-regulation and subsensitivity to agonist response. Circulation. 1986 Dec;74(6):1290–1302. doi: 10.1161/01.cir.74.6.1290. [DOI] [PubMed] [Google Scholar]
  12. Francis G. S., Goldsmith S. R., Cohn J. N. Relationship of exercise capacity to resting left ventricular performance and basal plasma norepinephrine levels in patients with congestive heart failure. Am Heart J. 1982 Oct;104(4 Pt 1):725–731. doi: 10.1016/0002-8703(82)90003-5. [DOI] [PubMed] [Google Scholar]
  13. Glaubiger G., Tsai B. S., Lefkowitz R. J., Weiss B., Johnson E. M., Jr Chronic guanethidine treatment increases cardiac beta-adrenergic receptors. Nature. 1978 May 18;273(5659):240–242. doi: 10.1038/273240a0. [DOI] [PubMed] [Google Scholar]
  14. Greenberg T. T., Richmond W. H., Stocking R. A., Gupta P. D., Meehan J. P., Henry J. P. Impaired atrial receptor responses in dogs with heart failure due to tricuspid insufficiency and pulmonary artery stenosis. Circ Res. 1973 Apr;32(4):424–433. doi: 10.1161/01.res.32.4.424. [DOI] [PubMed] [Google Scholar]
  15. Harden T. K. Agonist-induced desensitization of the beta-adrenergic receptor-linked adenylate cyclase. Pharmacol Rev. 1983 Mar;35(1):5–32. [PubMed] [Google Scholar]
  16. Heilbrunn S. M., Shah P., Bristow M. R., Valantine H. A., Ginsburg R., Fowler M. B. Increased beta-receptor density and improved hemodynamic response to catecholamine stimulation during long-term metoprolol therapy in heart failure from dilated cardiomyopathy. Circulation. 1989 Mar;79(3):483–490. doi: 10.1161/01.cir.79.3.483. [DOI] [PubMed] [Google Scholar]
  17. Higgins C. B., Vatner S. F., Eckberg D. L., Braunwald E. Alterations in the baroreceptor reflex in conscious dogs with heart failure. J Clin Invest. 1972 Apr;51(4):715–724. doi: 10.1172/JCI106865. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Insel P. A., Mahan L. C., Motulsky H. J., Stoolman L. M., Koachman A. M. Time-dependent decreases in binding affinity of agonists for beta-adrenergic receptors of intact S49 lymphoma cells. A mechanism of desensitization. J Biol Chem. 1983 Nov 25;258(22):13597–13605. [PubMed] [Google Scholar]
  19. Javitch J. A., Blaustein R. O., Snyder S. H. [3H]mazindol binding associated with neuronal dopamine and norepinephrine uptake sites. Mol Pharmacol. 1984 Jul;26(1):35–44. [PubMed] [Google Scholar]
  20. Krall J. F., Connelly M., Tuck M. L. Acute regulation of beta adrenergic catecholamine sensitivity in human lymphocytes. J Pharmacol Exp Ther. 1980 Sep;214(3):554–560. [PubMed] [Google Scholar]
  21. 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]
  22. Lefkowitz R. J., Caron M. G., Stiles G. L. Mechanisms of membrane-receptor regulation. Biochemical, physiological, and clinical insights derived from studies of the adrenergic receptors. N Engl J Med. 1984 Jun 14;310(24):1570–1579. doi: 10.1056/NEJM198406143102406. [DOI] [PubMed] [Google Scholar]
  23. Liang C. S., Imai N., Stone C. K., Woolf P. D., Kawashima S., Tuttle R. R. The role of endogenous opioids in congestive heart failure: effects of nalmefene on systemic and regional hemodynamics in dogs. Circulation. 1987 Feb;75(2):443–451. doi: 10.1161/01.cir.75.2.443. [DOI] [PubMed] [Google Scholar]
  24. Longabaugh J. P., Vatner D. E., Vatner S. F., Homcy C. J. Decreased stimulatory guanosine triphosphate binding protein in dogs with pressure-overload left ventricular failure. J Clin Invest. 1988 Feb;81(2):420–424. doi: 10.1172/JCI113335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. McPherson G. A. Analysis of radioligand binding experiments. A collection of computer programs for the IBM PC. J Pharmacol Methods. 1985 Nov;14(3):213–228. doi: 10.1016/0160-5402(85)90034-8. [DOI] [PubMed] [Google Scholar]
  26. POTTER L. T., COOPER T., WILLMAN V. L., WOLFE D. E. SYNTHESIS, BINDING, RELEASE, AND METABOLISM OF NOREPINEPHRINE IN NORMAL AND TRANSPLANTED DOG HEARTS. Circ Res. 1965 May;16:468–481. doi: 10.1161/01.res.16.5.468. [DOI] [PubMed] [Google Scholar]
  27. Petch M. C., Nayler W. G. Uptake of catecholamines by human cardiac muscle in vitro. Br Heart J. 1979 Mar;41(3):336–339. doi: 10.1136/hrt.41.3.336. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Peuler J. D., Johnson G. A. Simultaneous single isotope radioenzymatic assay of plasma norepinephrine, epinephrine and dopamine. Life Sci. 1977 Sep 1;21(5):625–636. doi: 10.1016/0024-3205(77)90070-4. [DOI] [PubMed] [Google Scholar]
  29. Pool P. E., Covell J. W., Levitt M., Gibb J., Braunwald E. Reduction of cardiac tyrosine hydroxylase activity in experimental congestive heart failure. Its role in the depletion of cardiac norepinephrine stores. Circ Res. 1967 Mar;20(3):349–353. doi: 10.1161/01.res.20.3.349. [DOI] [PubMed] [Google Scholar]
  30. Raum W. J., Laks M. M., Garner D., Ikuhara M. H., Swerdloff R. S. Norepinephrine increases beta-receptors and adenylate cyclase in canine myocardium. Am J Physiol. 1984 Jan;246(1 Pt 2):H31–H36. doi: 10.1152/ajpheart.1984.246.1.H31. [DOI] [PubMed] [Google Scholar]
  31. Rose C. P., Burgess J. H., Cousineau D. Reduced aortocoronary sinus extraction of epinephrine in patients with left ventricular failure secondary to long-term pressure or volume overload. Circulation. 1983 Aug;68(2):241–244. doi: 10.1161/01.cir.68.2.241. [DOI] [PubMed] [Google Scholar]
  32. Rose C. P., Burgess J. H., Cousineau D. Tracer norepinephrine kinetics in coronary circulation of patients with heart failure secondary to chronic pressure and volume overload. J Clin Invest. 1985 Nov;76(5):1740–1747. doi: 10.1172/JCI112164. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Sachs C. Noradrenaline uptake mechanisms in the mouse atrium. A biochemical and histochemical study. Acta Physiol Scand Suppl. 1970;341:1–66. [PubMed] [Google Scholar]
  34. Sassa H. Mechanism of myocardial catecholamine depletion in cardiac hypertrophy and failure in rabbits. Jpn Circ J. 1971 Apr;35(4):391–403. doi: 10.1253/jcj.35.391. [DOI] [PubMed] [Google Scholar]
  35. Shanes J. G. Beta-blockade--rational or irrational therapy for congestive heart failure? Circulation. 1987 Nov;76(5):971–973. doi: 10.1161/01.cir.76.5.971. [DOI] [PubMed] [Google Scholar]
  36. Sharma V. K., Banerjee S. P. Inhibition of [3H]norepinephrine uptake in peripheral organs of some mammalian species by ouabain. Eur J Pharmacol. 1977 Feb 21;41(4):417–429. doi: 10.1016/0014-2999(77)90262-x. [DOI] [PubMed] [Google Scholar]
  37. Sibley D. R., Lefkowitz R. J. Molecular mechanisms of receptor desensitization using the beta-adrenergic receptor-coupled adenylate cyclase system as a model. Nature. 1985 Sep 12;317(6033):124–129. doi: 10.1038/317124a0. [DOI] [PubMed] [Google Scholar]
  38. Sole M. J., Kamble A. B., Hussain M. N. A possible change in the rate-limiting step for cardiac norepinephrine synthesis in the cardiomyopathic Syrian hamster. Circ Res. 1977 Dec;41(6):814–817. doi: 10.1161/01.res.41.6.814. [DOI] [PubMed] [Google Scholar]
  39. Spann J. F., Jr, Chidsey C. A., Pool P. E., Braunwald E. Mechanism of norepinephrine depletion in experimental heart failure produced by aortic constriction in the guinea pig. Circ Res. 1965 Oct;17(4):312–321. doi: 10.1161/01.res.17.4.312. [DOI] [PubMed] [Google Scholar]
  40. Stone C. K., Liang C. S., Imai N., Sakamoto S., Sladek C. D., Hood W. B., Jr Short-term hemodynamic effects of vasopressin V1-receptor inhibition in chronic right-sided congestive heart failure. Circulation. 1988 Nov;78(5 Pt 1):1251–1259. doi: 10.1161/01.cir.78.5.1251. [DOI] [PubMed] [Google Scholar]
  41. Sundaresan P. R., Sharma V. K., Gingold S. I., Banerjee S. P. Decreased beta-adrenergic receptors in rat heart in streptozotocin-induced diabetes: role of thyroid hormones. Endocrinology. 1984 Apr;114(4):1358–1363. doi: 10.1210/endo-114-4-1358. [DOI] [PubMed] [Google Scholar]
  42. Thomas J. A., Marks B. H. Plasma norepinephrine in congestive heart failure. Am J Cardiol. 1978 Feb;41(2):233–243. doi: 10.1016/0002-9149(78)90162-5. [DOI] [PubMed] [Google Scholar]
  43. Vatner D. E., Lavallee M., Amano J., Finizola A., Homcy C. J., Vatner S. F. Mechanisms of supersensitivity to sympathomimetic amines in the chronically denervated heart of the conscious dog. Circ Res. 1985 Jul;57(1):55–64. doi: 10.1161/01.res.57.1.55. [DOI] [PubMed] [Google Scholar]
  44. Vatner D. E., Vatner S. F., Fujii A. M., Homcy C. J. Loss of high affinity cardiac beta adrenergic receptors in dogs with heart failure. J Clin Invest. 1985 Dec;76(6):2259–2264. doi: 10.1172/JCI112235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Wahr D. W., Swedberg K., Rabbino M., Hoyle M. J., Curran D., Parmley W. W., Chatterjee K. Intravenous and oral prenalterol in congestive heart failure. Effects on systemic and coronary hemodynamics and myocardial catecholamine balance. Am J Med. 1984 Jun;76(6):999–1005. doi: 10.1016/0002-9343(84)90848-9. [DOI] [PubMed] [Google Scholar]

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

RESOURCES