Summary
Sympathetic regulation of myocardial performance has been shown to be altered in congestive heart failure. Right atrial tissue of children with severe acyanotic and cyanotic congenital heart disease (CHD) showed a significantly lowerΒ-receptor density than that of children with less severe defects. Since mononuclear leukocytes (MNL) contain a homogeneous population ofΒ 2-adrenoceptors which have similar properties to those of cardiacΒ 2-adrenoceptors, they are frequently used for studying theΒ-adrenergic system. In a group of 37 children with CHD of different types and severity who underwent cardiac surgery, we compared the MNLΒ-adrenoceptor density to the type and severity of CHD and looked for a possible relationship to plasma catecholamine levels and to the right atrialΒ-adrenoceptor density. Membranes of MNL and myocardial cells were radiolabeled with (−)3-[125I]Iodocyanopindolol ([125I]ICYP). A significantly higherΒ-adrenoceptor density on MNL was found in patients with moderate acyanotic CHD (group I) than in those with severe acyanotic (group II) and cyanotic CHD (group III). Patients of group I showed approximatively 50% higher myocardialΒ-receptor density than those of groups II and III. ICI 118.551-[125I]ICYP competition studies revealed that in groups II and III significantly lower proportions and densities ofΒ 1-receptors were found compared to group I. Noradrenaline (NA) plasma levels in group II and group III were significantly higher than those in group I. The adrenaline plasma levels were found to be very high in all children with CHD. A significant negative correlation between NA levels and myocardial total andΒ 1-adrenoceptor density, but no correlation between plasma catecholamines and MNLΒ-adrenoceptor density, was calculated. We conclude that modulation of MNLΒ-adrenoceptors is not simply controlled by circulating catecholamine levels. CardiacΒ 2-adrenoceptor density remained unaltered, but theΒ 1-density was significantly lowered.Β 2-adrenoceptors on MNL showed a slight but significant decrease. However, cardiacΒ 2-adrenoceptor density cannot be predicted by measuring theΒ-adrenoceptor density on MNL.
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Abbreviations
- CHD:
-
Congenital heart disease
- MNL:
-
mononuclear leukocytes
- NA:
-
noradrenaline
- PPA/PAO :
-
Ratio between pulmonary and aortic pressure
- Qp/Qs:
-
Ratio between pulmonary and systemic blood flow
- HPLC-ED:
-
High performance liquid chromatography with electrochemical detector
References
Bernstein D, Voss E, Huang S, Doshi R, Crane C (1990) Differential regulation of right and left ventricularΒ-adrenergic receptors in newborn lambs with experimental cyanotic heart disease. J Clin Invest 85:68–74
Bishopric NH, Cohen HJ, Lefkowitz RJ (1980) Beta adrenergic receptors in lymphocyte subpopulations. J Allergy Clin Immunol 65:29–33
Böyum A (1968) A one-stage procedure for isolation of granulocytes and lymphocytes from human blood. Scand J Clin Lab Invest 97 (Suppl):51–89
Bristow MR, Ginsburg R, Minobe W, Cubicciotti RS, Sageman WS, Lurie K, Billingham ME, Harrison DC, Stinson EB (1982) Decreased catecholamine sensitivity andΒ-adrenergic-receptor density in failing human hearts. N Engl J Med 307:205–211
Bristow MR, Ginsburg R, Umans V, Fowler M, Minobe W, Rasmussen R, Zera P, Menlove R, Shah P, Jamieson S, Stinson EB (1986)Β 1- andΒ 2-adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selectiveΒ 1-receptor down-regulation in heart failure. Circ Res 59:297–309
Bristow MR, Hershberger RE, Port JD, Minobe W, Rasmussen R (1989)Β 1- andΒ 2-adrenergic receptor-mediated adenylate cyclase stimulation in nonfailing and failing human ventricular myocardium. Mol Pharmacol 35:295–303
Bristow MR, Hershberger RE, Port JD, Gilbert EM, Sandoval A, Rasmussen R, Cates AE, Feldman AM (1990)Β-adrenergic pathways in nonfailing and failing human ventricular myocardium. Circulation 82 [Suppl I]:12–25
Brodde O-E, O'Hara N, Zerkowski HR, Rohm N (1984) Human cardiacΒ-adrenoceptors: bothΒ 1- andΒ 2-adrenoceptors are functionally coupled to the adenylate cyclase in right atrium. J Cardiovasc Pharmacol 6:1184–1191
Brodde O-E, Kreisch R, Ikezono K, Zerkowski H-R, Reidemeister JC (1986) HumanΒ-adrenoceptors: relation of myocardial and lymphocyteΒ-adrenoceptor density. Science 231:1584–1585
Brodde O-E (1987) Cardiac beta-adrenergic receptors. ISI atlas of science: Pharmacology. Vol 1, pp 107–112
Brodde O-E, Michel MC, Gordon EP, Sandoval A, Gilbert EM, Bristow MR (1989a)Β-adrenoceptor regulation in the human heart: can it be monitored in circulating lymphocytes? Eur Heart J 10 [Suppl B]:2–10
Brodde O-E, Zerkowski HR, Doetsch N, Motomura S, Khamssi M, Michel MC (1989b) Myocardial beta-adrenoceptor changes in heart failure: concomitant reduction in beta1- and beta2-adrenoceptor function related to the degree of heart failure in patients with mitral valve disease. J Am Coll Cardiol 14:323–331
Brodde O-E, Zerkowski HR, Borst HG, Maier W, Michel MC (1989c) Drug- and disease-induced changes of human cardiacΒ 1- andΒ 2-adrenoceptors. Eur Heart J 10 [Suppl B]:38–44
Cohn JN, Levine B, Olivari MT, Garberg V, Lura D, Francis GS, Simon AB, Rector T (1984) Plasma norepinephrine as a guide to prognosis in patients with chronic congestive cardiac failure. N Engl J Med 311:819–823
Colucci WS, Alexander RW, Williams GH, Rude RE, Holman BL, Konstam MA, Wynne J, Mudge GH, Braunwald E (1981) Decreased lymphocyte beta-adrenergic-receptor density in patients with heart failure and tolerance to the beta-adrenergic agonist pirbuterol. N Engl J Med 305:185–195
DeBlasi A, Maisel AS, Feldman RD, Ziegler MG, Fratelli M, DiLallo M, Smith DA, Lai C-YC, Motulsky HJ (1986) In vivo regulation ofΒ-adrenergic receptors on human mononuclear leukocytes: assessment of receptor number, location, and function after posture change, exercise, and isoproterenol infusion. J Clin Endocrinol 63:847–853
Dimsdale JE, Moss J (1980) Plasma catecholamines in stress and exercise. JAMA 243:340–342
Feldman AM, Cates AE, Veazey WB, Hershberger RE, Bristow MR, Baughman KL, Baumgartner WA, van Dop C (1988) Increase of the 40,000-mol wt pertussis toxin substrate (G protein) in the failing human heart. J Clin Invest 82:189–197
Hasking GJ, Esler MD, Jennings GL, Burton D, Johns JA, Korner PI (1986) Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardial sympathetic nervous activity. Circulation 73:615–621
Horn EM, Bilezikian JP (1990) Mechanisms of abnormal transmembrane signaling of theΒ-adrenergic receptor in congestive heart failure. Circulation 82 [Suppl I]:26–34
Kaumann AJ, Lemoine H (1987)Β 2-adrenoceptor-mediated positive inotropic effect of adrenaline in human ventricular myocardium. Quantitative discrepancies with binding and adenylate cyclase stimulation. Naunym-Schmiedebergs Arch Pharmacol 335:403–411
Kaumann AJ, Hall JA, Murray KJ, Wells FC, Brown MJ (1989) A comparison of the effects of adrenaline and noradrenaline on the human heart: the role ofΒ 1- andΒ 2-adrenoceptors in the stimulation of adenylate cyclase and contractile force. Eur Heart J 10 [Suppl B]:29–37
Kozlik R, Kramer HH, Wicht H, Krian A, Ostermeyer J, Reinhardt D (1991) MyocardialΒ-adrenoceptor density and the distribution ofΒ 1- andΒ 2-adrenoceptor subpopulations in children with congenital heart disease. Eur J Pediatr 150:388–394
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193:265–275
Maisel AS, Ziegler MG, Carter S, Insel Paul A, Motulsky HJ (1988) In vivo regulation ofΒ-adrenergic receptors on mononuclear leukocytes and heart. Assessment of receptor compartmentation after agonist infusion and acute aortic constriction in guinea pigs. J Clin Invest 82:2038–2044
Maisel AS, Michel MC (1989)Β-adrenergic receptors in congestive heart failure: present knowledge and future directions. Cardiology 76:338–346
Maisel AS, Harris T, Rearden A, Michel MC (1990)Β-adrenergic receptors in lymphocyte subsets after exercise: alterations in normal individuals and patients with congestive heart failure. Circulation 82:2003–2010
Maisel AS, Michel MC, Insel PA, Ennis C, Ziegler MG, Phillips C (1990) Pertussis toxin treatment of whole blood. A novel approach to assess G protein function in congestive heart failure. Circulation 81:1198–1204
Mancini DM, Frey MJ, Fischberg D, Molinoff PB, Wilson JR (1989) Characterization of lymphocyte beta-adrenergic receptors at rest and during exercise in ambulatory patients with chronic congestive heart failure. Am J Cardiol 63:307–312
McDevitt DG (1989) In vivo studies on the function of cardiacΒ-adrenoceptors in man. Eur Heart J 10 [Suppl B]:22–28
McPherson GA (1985) Analysis of radioligand binding experiments: a collection of computer programs for the IBM-PC. J Pharmacol Methods 14:213–228
Minami M, Yasuda H, Yamazaki N, Kohma S, Nishijima H, Matsumura N, Togashi H, Koike Y, Saito H (1983) Plasma norepinephrine concentration and plasma dopamine-beta-hydroxylase activity in patients with congestive heart failure. Circulation 67:1324–1329
Motomura S, Zerkowski H-R, Daul A, Brodde O-E (1990) On the physiologic role of beta-2 adrenoceptors in the human heart: in vitro and in vivo studies. Am Heart J 119:608–619
Motulsky HJ, Insel PA (1982) Adrenergic receptors in man: direct identification, physiologic regulation and clinical alterations. N Engl J Med 307:18–29
Pela G, Missale C, Raddino R, Condrelli E, Spano PF, Visioli O (1990)Β 1 andΒ 2-receptors are differentially desensitized in an experimental model of heart failure. J Cardiovasc Pharmacol 16:839–846
Reinhardt D, Zehmisch T, Becker B, Nagel-Hiemke M (1984) Age-dependency of alpha- and beta-adrenoceptors on thrombocytes and lymphocytes of asthmatic and nonasthmatic children. Eur J Pediatr 142:111–116
Scatchard G (1949) The attraction of proteins for small molecules and ions. Ann NY Acad Sci 51:660–672
Schwinger RG, Böhm M, Erdmann E (1990) Evidence against spare or uncoupledΒ-adrenoceptors in the human heart. Am Heart J 119:899–904
Williams LT, Snyderman R, Lefkowitz RJ (1976) Identification of beta-adrenergic receptors in human lymphocytes by (−)-3H-alprenolol binding. J Clin Invest 57:149–155
Zerkowski H-R, Ikezono K, Rohm N, Reidemeister JC, Brodde O-E (1986) Human myocardialΒ-adrenoceptors: demonstration of bothΒ 1- andΒ 2-adrenoceptors mediating contractile responses toΒ-agonists on the isolated human right atrium. Naunym-Schmiedebergs Arch Pharmacol 332:142–147
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Kozlik, R., Kramer, H.H., Wicht, H. et al. Β-Adrenoceptor density on mononuclear leukocytes and right atrial myocardium in infants and children with congenital heart disease. Klin Wochenschr 69, 910–916 (1991). https://doi.org/10.1007/BF01798537
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DOI: https://doi.org/10.1007/BF01798537