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. 1992 Mar;89(3):803–815. doi: 10.1172/JCI115659

Beta-adrenergic neuroeffector abnormalities in the failing human heart are produced by local rather than systemic mechanisms.

M R Bristow 1, W Minobe 1, R Rasmussen 1, P Larrabee 1, L Skerl 1, J W Klein 1, F L Anderson 1, J Murray 1, L Mestroni 1, S V Karwande 1, et al.
PMCID: PMC442925  PMID: 1311717

Abstract

In order to investigate the general cause of beta-adrenergic receptor neuroeffector abnormalities in the failing human heart, we measured ventricular myocardial adrenergic receptors, adrenergic neurotransmitters, and beta-adrenergic receptor-effector responses in nonfailing and failing hearts taken from nonfailing organ donors, subjects with endstage biventricular failure due to idiopathic dilated cardiomyopathy (IDC), and subjects with primary pulmonary hypertension (PPH) who exhibited isolated right ventricular failure. Relative to nonfailing PPH left ventricles, failing PPH right ventricles exhibited (a) markedly decreased beta 1-adrenergic receptor density, (b) marked depletion of tissue norepinephrine and neuropeptide Y, (c) decreased adenylate cyclase stimulation in response to the beta agonists isoproterenol and zinterol, and (d) decreased adenylate cyclase stimulation in response to Gpp(NH)p and forskolin. These abnormalities were directionally similar to, but generally more pronounced than, corresponding findings in failing IDC right ventricles, whereas values for these parameters in nonfailing left ventricles of PPH subjects were similar to values in the nonfailing left ventricles of organ donors. Additionally, relative to paired nonfailing PPH left ventricles and nonfailing right ventricles from organ donors, failing right ventricles from PPH subjects exhibited decreased adenylate cyclase stimulation by MnCl2. These data indicate that: (a) Adrenergic neuroeffector abnormalities present in the failing human heart are due to local mechanisms; systemic processes do not produce beta-adrenergic neuroeffector abnormalities. (b) Pressure-overloaded failing right ventricles of PPH subjects exhibit decreased activity of the catalytic subunit of adenylate cyclase, an abnormality not previously described in the failing human heart.

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Selected References

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  1. Bristow M. R., Anderson F. L., Port J. D., Skerl L., Hershberger R. E., Larrabee P., O'Connell J. B., Renlund D. G., Volkman K., Murray J. Differences in beta-adrenergic neuroeffector mechanisms in ischemic versus idiopathic dilated cardiomyopathy. Circulation. 1991 Sep;84(3):1024–1039. doi: 10.1161/01.cir.84.3.1024. [DOI] [PubMed] [Google Scholar]
  2. Bristow M. R., Cubicciotti R., Ginsburg R., Stinson E. B., Johnson C. Histamine-mediated adenylate cyclase stimulation in human myocardium. Mol Pharmacol. 1982 May;21(3):671–679. [PubMed] [Google Scholar]
  3. 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]
  4. Bristow M. R., Ginsburg R., Strosberg A., Montgomery W., Minobe W. Pharmacology and inotropic potential of forskolin in the human heart. J Clin Invest. 1984 Jul;74(1):212–223. doi: 10.1172/JCI111404. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. 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]
  6. Bristow M. R., Hershberger R. E., Port J. D., Minobe W., Rasmussen R. Beta 1- and beta 2-adrenergic receptor-mediated adenylate cyclase stimulation in nonfailing and failing human ventricular myocardium. Mol Pharmacol. 1989 Mar;35(3):295–303. [PubMed] [Google Scholar]
  7. Bristow M. R., Minobe W., Rasmussen R., Hershberger R. E., Hoffman B. B. Alpha-1 adrenergic receptors in the nonfailing and failing human heart. J Pharmacol Exp Ther. 1988 Dec;247(3):1039–1045. [PubMed] [Google Scholar]
  8. Bristow M. R., Sandoval A. B., Gilbert E. M., Deisher T., Minobe W., Rasmussen R. Myocardial alpha- and beta-adrenergic receptors in heart failure: is cardiac-derived norepinephrine the regulatory signal? Eur Heart J. 1988 Jun;9 (Suppl H):35–40. doi: 10.1093/eurheartj/9.suppl_h.35. [DOI] [PubMed] [Google Scholar]
  9. Brodde O. E., Schüler S., Kretsch R., Brinkmann M., Borst H. G., Hetzer R., Reidemeister J. C., Warnecke H., Zerkowski H. R. Regional distribution of beta-adrenoceptors in the human heart: coexistence of functional beta 1- and beta 2-adrenoceptors in both atria and ventricles in severe congestive cardiomyopathy. J Cardiovasc Pharmacol. 1986 Nov-Dec;8(6):1235–1242. doi: 10.1097/00005344-198611000-00021. [DOI] [PubMed] [Google Scholar]
  10. Brodde O. E., Zerkowski H. R., Doetsch N., Motomura S., Khamssi M., Michel M. C. Myocardial beta-adrenoceptor changes in heart failure: concomitant reduction in beta 1- and beta 2-adrenoceptor function related to the degree of heart failure in patients with mitral valve disease. J Am Coll Cardiol. 1989 Aug;14(2):323–331. doi: 10.1016/0735-1097(89)90181-2. [DOI] [PubMed] [Google Scholar]
  11. Böhm M., Gierschik P., Jakobs K. H., Schnabel P., Kemkes B., Erdmann E. Localization of a "postreceptor" defect in human dilated cardiomyopathy. Am J Cardiol. 1989 Oct 1;64(12):812–814. doi: 10.1016/0002-9149(89)90773-x. [DOI] [PubMed] [Google Scholar]
  12. 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]
  13. Chen L. A., Vatner D. E., Vatner S. F., Hittinger L., Homcy C. J. Decreased Gs alpha mRNA levels accompany the fall in Gs and adenylyl cyclase activities in compensated left ventricular hypertrophy. In heart failure, only the impairment in adenylyl cyclase activation progresses. J Clin Invest. 1991 Jan;87(1):293–298. doi: 10.1172/JCI114985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Cody R. J., Atlas S. A., Laragh J. H., Kubo S. H., Covit A. B., Ryman K. S., Shaknovich A., Pondolfino K., Clark M., Camargo M. J. Atrial natriuretic factor in normal subjects and heart failure patients. Plasma levels and renal, hormonal, and hemodynamic responses to peptide infusion. J Clin Invest. 1986 Nov;78(5):1362–1374. doi: 10.1172/JCI112723. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Cohn J. N., Levine T. B., Francis G. S., Goldsmith S. Neurohumoral control mechanisms in congestive heart failure. Am Heart J. 1981 Sep;102(3 Pt 2):509–514. doi: 10.1016/0002-8703(81)90739-0. [DOI] [PubMed] [Google Scholar]
  16. Cohn J. N., Levine T. B., Olivari M. T., Garberg V., Lura D., Francis G. S., Simon A. B., Rector T. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med. 1984 Sep 27;311(13):819–823. doi: 10.1056/NEJM198409273111303. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. Dooley D. J., Bittiger H., Reymann N. C. CGP 20712 A: a useful tool for quantitating beta 1- and beta 2-adrenoceptors. Eur J Pharmacol. 1986 Oct 14;130(1-2):137–139. doi: 10.1016/0014-2999(86)90193-7. [DOI] [PubMed] [Google Scholar]
  19. Dzau V. J., Colucci W. S., Hollenberg N. K., Williams G. H. Relation of the renin-angiotensin-aldosterone system to clinical state in congestive heart failure. Circulation. 1981 Mar;63(3):645–651. doi: 10.1161/01.cir.63.3.645. [DOI] [PubMed] [Google Scholar]
  20. Dzau V. J., Packer M., Lilly L. S., Swartz S. L., Hollenberg N. K., Williams G. H. Prostaglandins in severe congestive heart failure. Relation to activation of the renin--angiotensin system and hyponatremia. N Engl J Med. 1984 Feb 9;310(6):347–352. doi: 10.1056/NEJM198402093100603. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. Feldman A. M., Cates A. E., Veazey W. B., Hershberger R. E., Bristow M. R., Baughman K. L., Baumgartner W. A., Van Dop C. Increase of the 40,000-mol wt pertussis toxin substrate (G protein) in the failing human heart. J Clin Invest. 1988 Jul;82(1):189–197. doi: 10.1172/JCI113569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. 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]
  24. Gilbert E. M., Krueger S. K., Murray J. L., Renlund D. G., O'Connell J. B., Gay W. A., Bristow M. R. Echocardiographic evaluation of potential cardiac transplant donors. J Thorac Cardiovasc Surg. 1988 Jun;95(6):1003–1007. [PubMed] [Google Scholar]
  25. Gilman A. G. G proteins: transducers of receptor-generated signals. Annu Rev Biochem. 1987;56:615–649. doi: 10.1146/annurev.bi.56.070187.003151. [DOI] [PubMed] [Google Scholar]
  26. Hamill R. W., Woolf P. D., McDonald J. V., Lee L. A., Kelly M. Catecholamines predict outcome in traumatic brain injury. Ann Neurol. 1987 May;21(5):438–443. doi: 10.1002/ana.410210504. [DOI] [PubMed] [Google Scholar]
  27. Hasking G. J., Esler M. D., Jennings G. L., Burton D., Johns J. A., Korner P. I. Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity. Circulation. 1986 Apr;73(4):615–621. doi: 10.1161/01.cir.73.4.615. [DOI] [PubMed] [Google Scholar]
  28. Karliner J. S., Scheinman M. Adenylate cyclase activity coupled to the stimulatory guanine nucleotide binding protein in patients having electrophysiologic studies and either structurally normal hearts or idiopathic myocardial disease. Am J Cardiol. 1988 Nov 15;62(16):1129–1130. doi: 10.1016/0002-9149(88)90564-4. [DOI] [PubMed] [Google Scholar]
  29. Karliner J. S., Stevens M. B., Honbo N., Hoffman J. I. Effects of acute ischemia in the dog on myocardial blood flow, beta receptors, and adenylate cyclase activity with and without chronic beta blockade. J Clin Invest. 1989 Feb;83(2):474–481. doi: 10.1172/JCI113906. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Lands A. M., Arnold A., McAuliff J. P., Luduena F. P., Brown T. G., Jr Differentiation of receptor systems activated by sympathomimetic amines. Nature. 1967 May 6;214(5088):597–598. doi: 10.1038/214597a0. [DOI] [PubMed] [Google Scholar]
  31. Liang C. S., Fan T. H., Sullebarger J. T., Sakamoto S. Decreased adrenergic neuronal uptake activity in experimental right heart failure. A chamber-specific contributor to beta-adrenoceptor downregulation. J Clin Invest. 1989 Oct;84(4):1267–1275. doi: 10.1172/JCI114294. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Linden J., Patel A., Spanier A. M., Weglicki W. B. Rapid agonist-induced decrease of 125I-pindolol binding to beta-adrenergic receptors. Relationship to desensitization of cyclic AMP accumulation in intact heart cells. J Biol Chem. 1984 Dec 25;259(24):15115–15122. [PubMed] [Google Scholar]
  33. 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]
  34. Neumann J., Schmitz W., Scholz H., von Meyerinck L., Döring V., Kalmar P. Increase in myocardial Gi-proteins in heart failure. Lancet. 1988 Oct 22;2(8617):936–937. doi: 10.1016/s0140-6736(88)92601-3. [DOI] [PubMed] [Google Scholar]
  35. Packer M. Neurohormonal interactions and adaptations in congestive heart failure. Circulation. 1988 Apr;77(4):721–730. doi: 10.1161/01.cir.77.4.721. [DOI] [PubMed] [Google Scholar]
  36. 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]
  37. Peterson G. L. A simplification of the protein assay method of Lowry et al. which is more generally applicable. Anal Biochem. 1977 Dec;83(2):346–356. doi: 10.1016/0003-2697(77)90043-4. [DOI] [PubMed] [Google Scholar]
  38. Pierpont G. L., Francis G. S., DeMaster E. G., Olivari M. T., Ring W. S., Goldenberg I. F., Reynolds S., Cohn J. N. Heterogeneous myocardial catecholamine concentrations in patients with congestive heart failure. Am J Cardiol. 1987 Aug 1;60(4):316–321. doi: 10.1016/0002-9149(87)90234-7. [DOI] [PubMed] [Google Scholar]
  39. Port J. D., Gilbert E. M., Larrabee P., Mealey P., Volkman K., Ginsburg R., Hershberger R. E., Murray J., Bristow M. R. Neurotransmitter depletion compromises the ability of indirect-acting amines to provide inotropic support in the failing human heart. Circulation. 1990 Mar;81(3):929–938. doi: 10.1161/01.cir.81.3.929. [DOI] [PubMed] [Google Scholar]
  40. 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]
  41. Salomon Y., Londos C., Rodbell M. A highly sensitive adenylate cyclase assay. Anal Biochem. 1974 Apr;58(2):541–548. doi: 10.1016/0003-2697(74)90222-x. [DOI] [PubMed] [Google Scholar]
  42. Sobel B. E., Henry P. D., Robison A., Bloor C., Ross J., Jr Depressed adenyl cyclase activity in the failing guinea pig heart. Circ Res. 1969 Apr;24(4):507–512. doi: 10.1161/01.res.24.4.507. [DOI] [PubMed] [Google Scholar]
  43. Sole M. J., Helke C. J., Jacobowitz D. M. Increased dopamine in the failing hamster heart: transvesicular transport of dopamine limits the rate of norepinephrine synthesis. Am J Cardiol. 1982 May;49(7):1682–1690. doi: 10.1016/0002-9149(82)90246-6. [DOI] [PubMed] [Google Scholar]
  44. Strittmatter S., Neer E. J. Properties of the separated catalytic and regulatory units of brain adenylate cyclase. Proc Natl Acad Sci U S A. 1980 Nov;77(11):6344–6348. doi: 10.1073/pnas.77.11.6344. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Swedberg K., Viquerat C., Rouleau J. L., Roizen M., Atherton B., Parmley W. W., Chatterjee K. Comparison of myocardial catecholamine balance in chronic congestive heart failure and in angina pectoris without failure. Am J Cardiol. 1984 Oct 1;54(7):783–786. doi: 10.1016/s0002-9149(84)80208-8. [DOI] [PubMed] [Google Scholar]
  46. 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]
  47. Vatner D. E., Homcy C. J., Sit S. P., Manders W. T., Vatner S. F. Effects of pressure overload, left ventricular hypertrophy on beta-adrenergic receptors, and responsiveness to catecholamines. J Clin Invest. 1984 May;73(5):1473–1482. doi: 10.1172/JCI111351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Vatner D. E., Vatner S. F., Nejima J., Uemura N., Susanni E. E., Hintze T. H., Homcy C. J. Chronic norepinephrine elicits desensitization by uncoupling the beta-receptor. J Clin Invest. 1989 Dec;84(6):1741–1748. doi: 10.1172/JCI114357. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Wickline S. A., Thomas L. J., 3rd, Miller J. G., Sobel B. E., Pérez J. E. The dependence of myocardial ultrasonic integrated backscatter on contractile performance. Circulation. 1985 Jul;72(1):183–192. doi: 10.1161/01.cir.72.1.183. [DOI] [PubMed] [Google Scholar]

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