Lymphocyte Beta-Adrenoreceptor Function in Congestive Heart Failure: Modulation by Dopamine-beta-Hydroxylase
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.
KeywordsAdenylate Cyclase Coronary Sinus Systolic Time Interval cAMP Generation Sympathetic Nerve Terminal
Unable to display preview. Download preview PDF.
- 3.Delaunois AL (1973) Biostatistics in pharmacology. Pergamon, OxfordGoogle Scholar
- 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
- 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
- 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
- 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
- 13.Katz AM (1977) Physiology of the heart. Raven, New YorkGoogle Scholar
- 20.Silverberg AB, Shah SD, Haymond MW, Cryer PE (1978) Norepinephrine: hormone and neurotransmitter in man. Am J Physiol 243: E252–E256Google Scholar
- 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
- 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
- 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.Weinshilboum RM (1979) Serum dopamine-beta-hydroxylase. Pharm Rev 30: 133–166Google Scholar
- 28.Weissler AM, Harris WS, Schoenfeld CD (1968) Systolic time intervals in heart failure in man. Circulation 37: 140–159Google Scholar