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. 1990 Dec;86(6):2046–2053. doi: 10.1172/JCI114941

Role of intact cardiac nerves and reflex mechanisms in desensitization to catecholamines in conscious dogs.

J Nejima 1, N Uemura 1, D E Vatner 1, C J Homcy 1, T H Hintze 1, S F Vatner 1
PMCID: PMC329843  PMID: 2254459

Abstract

To study chronic catecholamine desensitization, mini-osmotic pumps were implanted subcutaneously to deliver NE, (0.5 micrograms/kg/min) or saline over 3-4 wk in dogs instrumented with left ventricular (LV) pressure gauges and arterial and left atrial pressure catheters. An acute challenge to NE (0.4 micrograms/kg/min) in intact, conscious dogs increased LV dP/dt by 1,531 +/- 208 mmHg/s before NE pumps, and by a similar amount, 1,340 +/- 166 mmHg/s, 3-4 wk after NE pumps. In contrast, an acute challenge to isoproterenol (ISO, 0.4 micrograms/kg/min) increased LV dP/dt by 5,344 +/- 532 mmHg/s before NE pumps, and significantly less (P less than 0.05; 2,425 +/- 175 mmHg/s) after NE pumps. In the presence of ganglionic and alpha 1-adrenergic blockades, NE (0.4 micrograms/kg/min) increased LV dP/dt by 3,656 +/- 468 mmHg/s before NE pumps and significantly less (P less than 0.01; 1,459 +/- 200 mmHg/s) after NE pumps. Confirming this, an acute challenge to NE (0.4 micrograms/kg/min) in dogs with arterial baroreceptor denervation increased LV dP/dt by 3,732 +/- 896 mmHg/s before NE pumps, and significantly less (P less than 0.05, 1,725 +/- 408 mmHg/s) after NE pumps. In addition, in cardiac denervated dogs, NE (0.4 micrograms/kg/min) increased LV dP/dt by 9,901 +/- 1,404 mmHg/s before NE pumps and significantly less (P less than 0.01, 2,690 +/- 306 mmHg/s) after NE pumps. Desensitization of heart rate responses to NE challenge was also more apparent in the absence of reflex mechanisms. Thus, neural reflex mechanisms play a major role in physiological expression of cardiac desensitization to catecholamines in conscious dogs.

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Selected References

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

  1. 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]
  2. Brush J. E., Jr, Eisenhofer G., Garty M., Stull R., Maron B. J., Cannon R. O., 3rd, Panza J. A., Epstein S. E., Goldstein D. S. Cardiac norepinephrine kinetics in hypertrophic cardiomyopathy. Circulation. 1989 Apr;79(4):836–844. doi: 10.1161/01.cir.79.4.836. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. Chang H. Y., Klein R. M., Kunos G. Selective desensitization of cardiac beta adrenoceptors by prolonged in vivo infusion of catecholamines in rats. J Pharmacol Exp Ther. 1982 Jun;221(3):784–789. [PubMed] [Google Scholar]
  5. 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]
  6. Cryer P. E. Physiology and pathophysiology of the human sympathoadrenal neuroendocrine system. N Engl J Med. 1980 Aug 21;303(8):436–444. doi: 10.1056/NEJM198008213030806. [DOI] [PubMed] [Google Scholar]
  7. Da Prada M., Zürcher Simultaneous radioenzymatic determination of plasma and tissue adrenaline, noradrenaline and dopamine within the femtomole range. Life Sci. 1976 Oct 15;19(8):1161–1174. doi: 10.1016/0024-3205(76)90251-4. [DOI] [PubMed] [Google Scholar]
  8. Downing S. E., Lee J. C. Effects of insulin on experimental catecholamine cardiomyopathy. Am J Pathol. 1978 Nov;93(2):339–352. [PMC free article] [PubMed] [Google Scholar]
  9. ESSEX H. E. Further observations of certain responses of tolerant and control animals to massive doses of epinephrine. Am J Physiol. 1952 Oct;171(1):78–86. doi: 10.1152/ajplegacy.1952.171.1.78. [DOI] [PubMed] [Google Scholar]
  10. Eckberg D. L., Drabinsky M., Braunwald E. Defective cardiac parasympathetic control in patients with heart disease. N Engl J Med. 1971 Oct 14;285(16):877–883. doi: 10.1056/NEJM197110142851602. [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. Ginsburg R., Bristow M. R., Billingham M. E., Stinson E. B., Schroeder J. S., Harrison D. C. Study of the normal and failing isolated human heart: decreased response of failing heart to isoproterenol. Am Heart J. 1983 Sep;106(3):535–540. doi: 10.1016/0002-8703(83)90698-1. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. Hayes J. S., Bowling N., Pollock G. D. Effects of beta adrenoceptor down-regulation on the cardiovascular responses to the stereoisomers of dobutamine. J Pharmacol Exp Ther. 1985 Oct;235(1):58–65. [PubMed] [Google Scholar]
  15. Hayes J. S., Pollock G. D., Fuller R. W. In vivo cardiovascular responses to isoproterenol, dopamine and tyramine after prolonged infusion of isoproterenol. J Pharmacol Exp Ther. 1984 Dec;231(3):633–639. [PubMed] [Google Scholar]
  16. 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]
  17. Hjemdahl P., Daleskog M., Kahan T. Determination of plasma catecholamines by high performance liquid chromatography with electrochemical detection: comparison with a radioenzymatic method. Life Sci. 1979 Jul 9;25(2):131–138. doi: 10.1016/0024-3205(79)90384-9. [DOI] [PubMed] [Google Scholar]
  18. King B. D., Sack D., Kichuk M. R., Hintze T. H. Absence of hypertension despite chronic marked elevations in plasma norepinephrine in conscious dogs. Hypertension. 1987 Jun;9(6):582–590. doi: 10.1161/01.hyp.9.6.582. [DOI] [PubMed] [Google Scholar]
  19. Laks M. M., Morady F., Swan H. J. Myocardial hypertrophy produced by chronic infusion of subhypertensive doses of norepinephrine in the dog. Chest. 1973 Jul;64(1):75–78. doi: 10.1378/chest.64.1.75. [DOI] [PubMed] [Google Scholar]
  20. Levine T. B., Francis G. S., Goldsmith S. R., Simon A. B., Cohn J. N. Activity of the sympathetic nervous system and renin-angiotensin system assessed by plasma hormone levels and their relation to hemodynamic abnormalities in congestive heart failure. Am J Cardiol. 1982 May;49(7):1659–1666. doi: 10.1016/0002-9149(82)90243-0. [DOI] [PubMed] [Google Scholar]
  21. Marsh J. D., Barry W. H., Neer E. J., Alexander R. W., Smith T. W. Evidence for uncoupling of the beta receptor-adenylate cyclase complex. Circ Res. 1980 Oct;47(4):493–501. doi: 10.1161/01.res.47.4.493. [DOI] [PubMed] [Google Scholar]
  22. Nanoff C., Freissmuth M., Tuisl E., Schütz W. A different desensitization pattern of cardiac beta-adrenoceptor subtypes by prolonged in vivo infusion of isoprenaline. J Cardiovasc Pharmacol. 1989 Feb;13(2):198–203. doi: 10.1097/00005344-198902000-00004. [DOI] [PubMed] [Google Scholar]
  23. Newman W. H. A depressed response of left ventricular contractile force to isoproterenol and norepinephrine in dogs with congestive heart failure. Am Heart J. 1977 Feb;93(2):216–221. doi: 10.1016/s0002-8703(77)80314-1. [DOI] [PubMed] [Google Scholar]
  24. Pasternac A., Tubau J. F., Puddu P. E., Król R. B., de Champlain J. Increased plasma catecholamine levels in patients with symptomatic mitral valve prolapse. Am J Med. 1982 Dec;73(6):783–790. doi: 10.1016/0002-9343(82)90758-6. [DOI] [PubMed] [Google Scholar]
  25. Pouleur H., Rousseau M. F., Hanet C., Marlow H. F., Charlier A. A. Left ventricular sensitivity to beta-adrenoceptor-stimulating drugs in patients with ischemic heart disease and varying degrees of ventricular dysfunction. Circ Res. 1987 Oct;61(4 Pt 2):I91–I95. [PubMed] [Google Scholar]
  26. Randall W. C., Kaye M. P., Thomas J. X., Barber M. J. Intrapericardial denervation of the heart. J Surg Res. 1980 Aug;29(2):101–109. doi: 10.1016/0022-4804(80)90027-x. [DOI] [PubMed] [Google Scholar]
  27. Siri F. M. Chronic norepinephrine infusion and adrenergic function of hypertrophied hearts. Am J Physiol. 1985 Apr;248(4 Pt 2):H485–H492. doi: 10.1152/ajpheart.1985.248.4.H485. [DOI] [PubMed] [Google Scholar]
  28. 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]
  29. Toews M. L. Comparison of agonist-induced changes in beta- and alpha 1-adrenergic receptors of DDT1 MF-2 cells. Mol Pharmacol. 1987 Jan;31(1):58–68. [PubMed] [Google Scholar]
  30. Tse J., Powell J. R., Baste C. A., Priest R. E., Kuo J. F. Isoproterenol-induced cardiac hypertrophy: modifications in characteristics of beta-adrenergic receptor, adenylate cyclase, and ventricular contraction. Endocrinology. 1979 Jul;105(1):246–255. doi: 10.1210/endo-105-1-246. [DOI] [PubMed] [Google Scholar]
  31. VIGRAN I. M., ESSEX H. E. Studies on physiologic effects of large doses of epinephrine. Am J Physiol. 1950 Jul 1;162(1):230–242. doi: 10.1152/ajplegacy.1950.162.1.230. [DOI] [PubMed] [Google Scholar]
  32. 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]
  33. 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]
  34. 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]
  35. Vatner S. F., Rutherford J. D., Ochs H. R. Baroreflex and vagal mechanisms modulating left ventricular contractile responses to sympathomimetic amines in conscious dogs. Circ Res. 1979 Feb;44(2):195–207. doi: 10.1161/01.res.44.2.195. [DOI] [PubMed] [Google Scholar]

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