Lymphocyte Beta-Adrenoreceptor Function in Congestive Heart Failure: Modulation by Dopamine-beta-Hydroxylase

  • J. A. Thomas
  • D. V. Unverferth
  • B. H. Marks
Conference paper


Congestive heart failure (CHF) is clinically characterized by a reduction in exercise capacity, which, in the presence of severe ventricular impairment, forces the patient to remain at complete bed rest. We have previously reported that biochemically, CHF is characterized by elevated levels of plasma norepinephrine (NE). The greater the degree of left ventricular dysfunction, the higher the plasma NE level. Peripheral blood lymphocytes from these patients with the highest NE levels and the greatest degree of cardiac decompensation failed to generate normal amounts of cyclic-3′,5′-adenosine monophosphate (cAMP) following stimulation with a beta adrenoreceptor (BAR) agonist.

Patients with the severest cardiac decompensation also demonstrated a reduction in plasma dopamine-beta-hydroxylase (DBH) enzymatic activity in conjunction with the high NE. When the ratios of NE/DBH in heart failure patients were compared to controls, they were significantly greater in the patients with the most severe heart failure. Pre-incubation of lymphocytes with purified human DBH prior to incubation with isoproterenol (ISO) produced a significant increase in the amount of cAMP generated. The ability of DBH to enhance ISO stimulated cAMP production was dependent upon the integrity of the amino acid sequence of DBH. DBH did not significantly increase cAMP in the absence of ISO.

We have concluded from our data that low DBH enzyme activity in patients with CHF may reflect the failure of the sympathetic nerve terminals to secrete physiologic amounts of DBH into the synaptic cleft, and that such a failure of secretion of this neurosecretory protein may result from prolonged hyperfunction of the sympathetic system. We further propose that this “neuronal DBH deficiency response” may function to uncouple the catecholamine overload generated by the stress, from the intracellular structures which amplify and transmit this stress to the effector units within the cell. In this instance, the DBH deficiency may promote the downregulation of BAR.


Adenylate Cyclase Coronary Sinus Systolic Time Interval cAMP Generation Sympathetic Nerve Terminal 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Boyum A (1968) Isolation of mononuclear cells and granulocytes from human blood. Scand J Clin Lab Invest 21: 77–89CrossRefGoogle Scholar
  2. 2.
    Covell JW, Chidsey CA, Braunwald E (1962) Reduction of the cardiac response to post-ganglionic sympathetic nerve stimulation in experimental heart failure. N Engl J Med 267: 650–654CrossRefGoogle Scholar
  3. 3.
    Delaunois AL (1973) Biostatistics in pharmacology. Pergamon, OxfordGoogle Scholar
  4. 4.
    Goldstein M, Lauber E, McKereghan M (1965) Studies on the purification and characterization of 3,4-dihydroxy-phenylethylamine-beta-hydroxylase. J Biol Chem 240: 2077–2072Google Scholar
  5. 5.
    Haneda T, Miura Y, Arai T et al. (1980) Norepinephrine levels in the coronary sinus in patients with cardiovascular diseases at rest and during isometric handgrip exercise. Am Heart J 100: 465–472PubMedCrossRefGoogle Scholar
  6. 6.
    Haneda T, Miura Y, Miyazawa K et al. (1978) Plasma norepinephrine concentrations in the coronary sinus in cardiomyopathies. Cathet Cardiovasc Diagn 4: 399–405PubMedCrossRefGoogle Scholar
  7. 7.
    Hansen JF, Christensen NJ, Hesse B (1978) Determinants of coronary sinus noradrenaline in patients with ischaemic heart disease: coronary sinus catecholamine concentration in relation to arterial catecholamine concentration, pulmonary artery oxygen saturation and left ventricular end-diastolic pressure. Cardiovasc Res 12: 415–421PubMedCrossRefGoogle Scholar
  8. 8.
    Henry DP, Starman BJ, Johnson DG (1975) A sensitive radioenzymatic assay for norepinephrine in tissues and plasma. Life Sci 16: 375–384PubMedCrossRefGoogle Scholar
  9. 9.
    Hoffman BB, Lefkowitz RJ (1980) Radioligand binding studies of adrenergic receptors: New insights into molecular and physiological regulation. Ann Rev Pharmacol Toxicol 20: 581–608Google Scholar
  10. 10.
    Hortnagl H, Stadler-Wolffersgrun R, Brucke T, Hammerle AF, Hackl JM (1978) Changes of dopamine-beta-hydroxylase activity in human plasma during prolonged overactivity of the sympathetic nervous system in various diseases. Naunyn-Schmiedebergs Arch Pharmacol 303: 235–242PubMedGoogle Scholar
  11. 11.
    Horwitz LD, Travis VL (1978) Low serum dopamine-beta-hydroxylase activity: A marker of congestive heart failure. J Clin Invest 62: 899–906Google Scholar
  12. 12.
    Karliner JS, Barnes P, Brown M, Dollery CT (1980) Chronic heart failure in the guinea pig increases cardiac alpha-1 and beta-adrenoreceptors. Eur J Pharmacol 67: 115–118PubMedCrossRefGoogle Scholar
  13. 13.
    Katz AM (1977) Physiology of the heart. Raven, New YorkGoogle Scholar
  14. 14.
    Mukherjee C, Caron MC, Lefkowitz RJ (1975) Catecholamine-induced subsensitivity of adenylate cyclase associated with loss of beta–adrenergic binding sites. Proc Natl Acad Sci USA 72: 1945–1949PubMedCrossRefGoogle Scholar
  15. 15.
    Marsh JD, Barry WH, Neer EJ, Alexander RW, Smith TW (1980) Desensitization of chick embryo ventricle to the physiological and biochemical effects of isoproterenol. Circ Res 47: 493–501PubMedGoogle Scholar
  16. 16.
    Newman WH (1977) A depressed response of ventricular contractile force to isoproterenol and norepinephrine in dogs with congestive heart failure. Am Heart J 93: 216–221PubMedCrossRefGoogle Scholar
  17. 17.
    Penttila O, Merikallio E, Pispa J, Klinge E, Siltanen P, Kyosola K (1978) Auricular tyrosine hydroxylase and dopamine-beta-hydroxylase activities and noradrenaline content in ischaemic heart disease. Acta Med Scand 203: 161–166PubMedCrossRefGoogle Scholar
  18. 18.
    Parker CW, Smith JW (1973) Alterations in cyclic adenosine monophosphate metabolism in human bronchial asthma: leukocyte responsiveness to beta adrenergic agents. J Clin Invest 52: 48–59PubMedCrossRefGoogle Scholar
  19. 19.
    Rutenberg HL, Spann JF (1973) Alterations of cardiac sympathetic neurotransmitter activity in congestive heart failure. Am J Cardiol 32: 472–480PubMedCrossRefGoogle Scholar
  20. 20.
    Silverberg AB, Shah SD, Haymond MW, Cryer PE (1978) Norepinephrine: hormone and neurotransmitter in man. Am J Physiol 243: E252–E256Google Scholar
  21. 21.
    Steiner AL, Wehmann RE, Parker CW et al. Radioimmunoassay for the measurement of cyclic nucleotides. Adv Cycl Nucl Res (1972), Vol 2, pp 51–62Google Scholar
  22. 22.
    Thomas JA, Marks BH (1978) Plasma norepinephrine in congestive heart failure. Am J Cardiol 41: 233–243PubMedCrossRefGoogle Scholar
  23. 23.
    Thomas JA, Sakai KK, Hoick MI, Marks BH (1980) Dopamine-beta-hydroxylase: A modulator of beta adrenergic receptor activity. Res Comm Chem Pathol Pharmacol 29: 3–14Google Scholar
  24. 24.
    Tse J, Powell JR, Baste CA, Priest RE, Kuo JF (1979) Isoproterenol: induced cardiac hypertrophy: modifications in characteristics of beta-adrenergic receptor, adenylate cyclase, and ventricular contraction. Endocrinology 105: 246–255PubMedCrossRefGoogle Scholar
  25. 25.
    Unverferth DV, Miller M, Thomas JA etal. (submitted) The evolution of beta adrenergic dysfunction during the induction of heart failure in dogsGoogle Scholar
  26. 26.
    Weinshilboum RM (1979) Serum dopamine-beta-hydroxylase. Pharm Rev 30: 133–166Google Scholar
  27. 27.
    Weinshilboum RM, Axelrod J (1971) Serum dopamine–beta–hydroxylase activity. Circ Res 28: 307–315PubMedGoogle Scholar
  28. 28.
    Weissler AM, Harris WS, Schoenfeld CD (1968) Systolic time intervals in heart failure in man. Circulation 37: 140–159Google Scholar

Copyright information

© Springer-Verlag, Berlin, Heidelberg 1981

Authors and Affiliations

  • J. A. Thomas
  • D. V. Unverferth
  • B. H. Marks

There are no affiliations available

Personalised recommendations