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. 1989 Feb;83(2):474–481. doi: 10.1172/JCI113906

Effects of acute ischemia in the dog on myocardial blood flow, beta receptors, and adenylate cyclase activity with and without chronic beta blockade.

J S Karliner 1, M B Stevens 1, N Honbo 1, J I Hoffman 1
PMCID: PMC303703  PMID: 2563265

Abstract

We ligated the left anterior descending coronary artery for 1 or 2 h in 31 purebred beagles. We did not detect any changes in beta-adrenergic receptor density or affinity when normal and ischemic zones were compared, either in the subendocardium or in the subepicardium. In the ischemic zones, there was a significant decline in all measures of adenylate cyclase activity, including activity mediated by the beta-adrenergic receptor. By contrast, after chronic beta-adrenergic blockade (1.5 mg/kg propranolol i.v. twice daily for 7 d), there was an increase in adenylate cyclase activity stimulated by (-)-isoproterenol relative to adenylate cyclase activity stimulated by guanyl-5'imidodiphosphate (GppNHp) in both normal and ischemic tissue, suggesting that one effect of chronic beta blockade may be to enhance coupling between the stimulatory guanine nucleotide regulatory protein (Gs) and the beta-adrenergic receptor, despite a reduction in the number or function of Gs units. Chronic beta blockade also led to up regulation of beta-adrenergic receptor density in subepicardial regions. After 20 min of reperfusion following 2 h of ischemia, adenylate cyclase activity tended to return to control levels, particularly in the subepicardium, where (-)-isoproterenol-stimulated adenylate cyclase activity was not different from normal myocardium. We conclude that chronic beta-adrenergic blockade may have beneficial effects during prolonged episodes of myocardial ischemia by preserving signal transduction mediated by the beta-adrenergic receptor.

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Selected References

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  1. Aarons R. D., Molinoff P. B. Changes in the density of beta adrenergic receptors in rat lymphocytes, heart and lung after chronic treatment with propranolol. J Pharmacol Exp Ther. 1982 May;221(2):439–443. [PubMed] [Google Scholar]
  2. Aarons R. D., Nies A. S., Gal J., Hegstrand L. R., Molinoff P. B. Elevation of beta-adrenergic receptor density in human lymphocytes after propranolol administration. J Clin Invest. 1980 May;65(5):949–957. doi: 10.1172/JCI109781. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Baer R. W., Payne B. D., Verrier E. D., Vlahakes G. J., Molodowitch D., Uhlig P. N., Hoffman J. I. Increased number of myocardial blood flow measurements with radionuclide-labeled microspheres. Am J Physiol. 1984 Mar;246(3 Pt 2):H418–H434. doi: 10.1152/ajpheart.1984.246.3.H418. [DOI] [PubMed] [Google Scholar]
  4. Baker S. P., Potter L. T. Effect of propranolol on beta-adrenoceptors in rat hearts. Br J Pharmacol. 1980 Jan;68(1):8–10. doi: 10.1111/j.1476-5381.1980.tb10689.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Baumann G., Riess G., Erhardt W. D., Felix S. B., Ludwig L., Blümel G., Blömer H. Impaired beta-adrenergic stimulation in the uninvolved ventricle post-acute myocardial infarction: reversible defect due to excessive circulating catecholamine-induced decline in number and affinity of beta-receptors. Am Heart J. 1981 May;101(5):569–581. doi: 10.1016/0002-8703(81)90223-4. [DOI] [PubMed] [Google Scholar]
  6. Bolli R., Zhu W. X., Myers M. L., Hartley C. J., Roberts R. Beta-adrenergic stimulation reverses postischemic myocardial dysfunction without producing subsequent functional deterioration. Am J Cardiol. 1985 Dec 1;56(15):964–968. doi: 10.1016/0002-9149(85)90413-8. [DOI] [PubMed] [Google Scholar]
  7. Braasch W., Gudbjarnason S., Puri P. S., Ravens K. G., Bing R. J. Early changes in energy metabolism in the myocardium following acute coronary artery occlusion in anesthetized dogs. Circ Res. 1968 Sep;23(3):429–438. doi: 10.1161/01.res.23.3.429. [DOI] [PubMed] [Google Scholar]
  8. Buda A. J., Zotz R. J., Pace D. P., Krause L. C., Turla M. Immediate rebound followed by deterioration of regional left ventricular function with coronary reperfusion. J Am Coll Cardiol. 1986 Aug;8(2):333–341. doi: 10.1016/s0735-1097(86)80048-1. [DOI] [PubMed] [Google Scholar]
  9. Carlsson L., Abrahamsson T., Almgren O. Release of noradrenaline in myocardial ischemia--importance of local inactivation by neuronal and extraneuronal mechanisms. J Cardiovasc Pharmacol. 1986 May-Jun;8(3):545–553. doi: 10.1097/00005344-198605000-00017. [DOI] [PubMed] [Google Scholar]
  10. Chess-Williams R. G., Broadley K. J. Ex vivo examination of beta-adrenoceptor characteristics after propranolol withdrawal. J Cardiovasc Pharmacol. 1984 Jul-Aug;6(4):701–706. doi: 10.1097/00005344-198407000-00024. [DOI] [PubMed] [Google Scholar]
  11. Cooper G., 4th, Kent R. L., McGonigle P., Watanabe A. M. Beta adrenergic receptor blockade of feline myocardium. Cardiac mechanics, energetics, and beta adrenoceptor regulation. J Clin Invest. 1986 Feb;77(2):441–455. doi: 10.1172/JCI112323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Cramb G., Griffiths N. M., Aiton J. F., Simmons N. L. Biochemical and physiological adaptation to chronic propranolol treatment in the rat. Biochem Pharmacol. 1984 Jun 15;33(12):1969–1976. doi: 10.1016/0006-2952(84)90557-4. [DOI] [PubMed] [Google Scholar]
  13. Devos C., Robberecht P., Nokin P., Waelbroeck M., Clinet M., Camus J. C., Beaufort P., Schoenfeld P., Christophe J. Uncoupling between beta-adrenoceptors and adenylate cyclase in dog ischemic myocardium. Naunyn Schmiedebergs Arch Pharmacol. 1985 Oct;331(1):71–75. doi: 10.1007/BF00498853. [DOI] [PubMed] [Google Scholar]
  14. Drummond R. W., Sordahl L. A. Temporal changes in adenylate cyclase activity in acutely ischemic dog heart: evidence of functional subunit damage. J Mol Cell Cardiol. 1981 Mar;13(3):323–330. doi: 10.1016/0022-2828(81)90320-5. [DOI] [PubMed] [Google Scholar]
  15. Ellis S. G., Henschke C. I., Sandor T., Wynne J., Braunwald E., Kloner R. A. Time course of functional and biochemical recovery of myocardium salvaged by reperfusion. J Am Coll Cardiol. 1983 Apr;1(4):1047–1055. doi: 10.1016/s0735-1097(83)80107-7. [DOI] [PubMed] [Google Scholar]
  16. Freissmuth M., Schütz W., Weindlmayer-Göttel M., Zimpfer M., Spiss C. K. Effects of ischemia on the canine myocardial beta-adrenoceptor-linked adenylate cyclase system. J Cardiovasc Pharmacol. 1987 Nov;10(5):568–574. doi: 10.1097/00005344-198711000-00012. [DOI] [PubMed] [Google Scholar]
  17. Glaubiger G., Lefkowitz R. J. Elevated beta-adrenergic receptor number after chronic propranolol treatment. Biochem Biophys Res Commun. 1977 Sep 23;78(2):720–725. doi: 10.1016/0006-291x(77)90238-8. [DOI] [PubMed] [Google Scholar]
  18. Golf S., Hansson V. Effects of beta blocking agents on the density of beta adrenoceptors and adenylate cyclase response in human myocardium: intrinsic sympathomimetic activity favours receptor upregulation. Cardiovasc Res. 1986 Sep;20(9):637–644. doi: 10.1093/cvr/20.9.637. [DOI] [PubMed] [Google Scholar]
  19. Goodlett M., Dowling K., Eddy L. J., Downey J. M. Direct metabolic effects of isoproterenol and propranolol in ischemic myocardium of the dog. Am J Physiol. 1980 Oct;239(4):H469–H476. doi: 10.1152/ajpheart.1980.239.4.H469. [DOI] [PubMed] [Google Scholar]
  20. Hedberg A., Kempf F., Jr, Josephson M. E., Molinoff P. B. Coexistence of beta-1 and beta-2 adrenergic receptors in the human heart: effects of treatment with receptor antagonists or calcium entry blockers. J Pharmacol Exp Ther. 1985 Sep;234(3):561–568. [PubMed] [Google Scholar]
  21. Heymann M. A., Payne B. D., Hoffman J. I., Rudolph A. M. Blood flow measurements with radionuclide-labeled particles. Prog Cardiovasc Dis. 1977 Jul-Aug;20(1):55–79. doi: 10.1016/s0033-0620(77)80005-4. [DOI] [PubMed] [Google Scholar]
  22. Hjalmarson A., Elmfeldt D., Herlitz J., Holmberg S., Málek I., Nyberg G., Rydén L., Swedberg K., Vedin A., Waagstein F. Effect on mortality of metoprolol in acute myocardial infarction. A double-blind randomised trial. Lancet. 1981 Oct 17;2(8251):823–827. doi: 10.1016/s0140-6736(81)91101-6. [DOI] [PubMed] [Google Scholar]
  23. Jennings R. B., Hawkins H. K., Lowe J. E., Hill M. L., Klotman S., Reimer K. A. Relation between high energy phosphate and lethal injury in myocardial ischemia in the dog. Am J Pathol. 1978 Jul;92(1):187–214. [PMC free article] [PubMed] [Google Scholar]
  24. Karliner J. S., Motulsky H. J., Dunlap J., Brown J. H., Insel P. A. Verapamil competitively inhibits alpha 1-adrenergic and muscarinic but not beta-adrenergic receptors in rat myocardium. J Cardiovasc Pharmacol. 1982 May-Jun;4(3):515–520. doi: 10.1097/00005344-198205000-00025. [DOI] [PubMed] [Google Scholar]
  25. Karliner J. S., Simpson P. C., Honbo N., Woloszyn W. Mechanisms and time course of beta 1 adrenoceptor desensitisation in mammalian cardiac myocytes. Cardiovasc Res. 1986 Mar;20(3):221–228. doi: 10.1093/cvr/20.3.221. [DOI] [PubMed] [Google Scholar]
  26. Karliner J. S., Stevens M., Grattan M., Woloszyn W., Honbo N., Hoffman J. I. Beta-adrenergic receptor properties of canine myocardium: effects of chronic myocardial infarction. J Am Coll Cardiol. 1986 Aug;8(2):349–356. doi: 10.1016/s0735-1097(86)80050-x. [DOI] [PubMed] [Google Scholar]
  27. Kennedy R. H., Donnelly T. E., Jr Cardiac responsiveness after acute withdrawal of chronic propranolol treatment in rats. Gen Pharmacol. 1982;13(3):231–239. doi: 10.1016/0306-3623(82)90094-5. [DOI] [PubMed] [Google Scholar]
  28. Kloner R. A., Fishbein M. C., Braunwald E., Maroko P. R. Effect of propranolol on mitochondrial morphology during acute myocardial ischemia. Am J Cardiol. 1978 May 1;41(5):880–886. doi: 10.1016/0002-9149(78)90728-2. [DOI] [PubMed] [Google Scholar]
  29. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  30. Maisel A. S., Motulsky H. J., Insel P. A. Externalization of beta-adrenergic receptors promoted by myocardial ischemia. Science. 1985 Oct 11;230(4722):183–186. doi: 10.1126/science.2994229. [DOI] [PubMed] [Google Scholar]
  31. Maisel A. S., Motulsky H. J., Ziegler M. G., Insel P. A. Ischemia- and agonist-induced changes in alpha- and beta-adrenergic receptor traffic in guinea pig hearts. Am J Physiol. 1987 Nov;253(5 Pt 2):H1159–H1166. doi: 10.1152/ajpheart.1987.253.5.H1159. [DOI] [PubMed] [Google Scholar]
  32. Manning A. S., Yellon D. M., Coltart D. J., Hearse D. J. Abrupt withdrawal of chronic beta-blockade: adaptive changes in cyclic AMP and contractility. J Mol Cell Cardiol. 1981 Nov;13(11):999–1009. doi: 10.1016/0022-2828(81)90475-2. [DOI] [PubMed] [Google Scholar]
  33. 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]
  34. Mukherjee A., Bush L. R., McCoy K. E., Duke R. J., Hagler H., Buja L. M., Willerson J. T. Relationship between beta-adrenergic receptor numbers and physiological responses during experimental canine myocardial ischemia. Circ Res. 1982 May;50(5):735–741. doi: 10.1161/01.res.50.5.735. [DOI] [PubMed] [Google Scholar]
  35. Mukherjee A., Wong T. M., Buja L. M., Lefkowitz R. J., Willerson J. T. Beta adrenergic and muscarinic cholinergic receptors in canine myocardium. Effects of ischemia. J Clin Invest. 1979 Nov;64(5):1423–1428. doi: 10.1172/JCI109600. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Muntz K. H., Olson E. G., Lariviere G. R., D'Souza S., Mukherjee A., Willerson J. T., Buja L. M. Autoradiographic characterization of beta adrenergic receptors in coronary blood vessels and myocytes in normal and ischemic myocardium of the canine heart. J Clin Invest. 1984 Feb;73(2):349–357. doi: 10.1172/JCI111219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Mügge A., Reupcke C., Scholz H. Increased myocardial alpha 1 adrenoceptor density in rats chronically treated with propranolol. Eur J Pharmacol. 1985 Jun 7;112(2):249–252. doi: 10.1016/0014-2999(85)90503-5. [DOI] [PubMed] [Google Scholar]
  38. Ohyanagi M., Matsumori Y., Iwasaki T. Beta-adrenergic receptors in ischemic and nonischemic canine myocardium: relation to ventricular fibrillation and effects of pretreatment with propranolol and hexamethonium. J Cardiovasc Pharmacol. 1988 Jan;11(1):107–114. doi: 10.1097/00005344-198801000-00016. [DOI] [PubMed] [Google Scholar]
  39. Puri P. S., Varley K. G., Kim S. W., Barwinsky J., Cohen M., Dhalla N. S. Alterations in energy metabolism and ultrastructure upon reperfusion of the ischemic myocardium after coronary occlusion. Am J Cardiol. 1975 Aug;36(2):234–243. [PubMed] [Google Scholar]
  40. Rabinowitz B., Parmley W. W., Kligerman M., Norman J., Fujimura S., Chiba S., Matloff J. M. Myocardial and plasma levels of adenosine 3':5'-cyclic phosphate. Studies in experimental myocardial ischemia. Chest. 1975 Jul;68(1):69–74. doi: 10.1378/chest.68.1.69. [DOI] [PubMed] [Google Scholar]
  41. Ramachandran J. A new simple method for separation of adenosine 3',5'-cyclic monophosphate from other nucleotides and its use in the assay of adenyl cyclase. Anal Biochem. 1971 Sep;43(1):227–239. doi: 10.1016/0003-2697(71)90128-x. [DOI] [PubMed] [Google Scholar]
  42. Reimer K. A., Hill M. L., Jennings R. B. Prolonged depletion of ATP and of the adenine nucleotide pool due to delayed resynthesis of adenine nucleotides following reversible myocardial ischemic injury in dogs. J Mol Cell Cardiol. 1981 Feb;13(2):229–239. doi: 10.1016/0022-2828(81)90219-4. [DOI] [PubMed] [Google Scholar]
  43. Rhee H. M., Tyler L. Myocardial ischemic injury and beta-adrenergic receptors in perfused working rabbit hearts. Adv Exp Med Biol. 1985;191:281–288. doi: 10.1007/978-1-4684-3291-6_29. [DOI] [PubMed] [Google Scholar]
  44. Roberts R., Croft C., Gold H. K., Hartwell T. D., Jaffe A. S., Muller J. E., Mullin S. M., Parker C., Passamani E. R., Poole W. K. Effect of propranolol on myocardial-infarct size in a randomized blinded multicenter trial. N Engl J Med. 1984 Jul 26;311(4):218–225. doi: 10.1056/NEJM198407263110403. [DOI] [PubMed] [Google Scholar]
  45. Sakai K., Abiko Y. Attenuation by atenolol of myocardial acidosis during ischemia in dogs: contribution of beta-1 adrenoceptors to myocardial acidosis. J Pharmacol Exp Ther. 1985 Mar;232(3):810–816. [PubMed] [Google Scholar]
  46. Schömig A., Dart A. M., Dietz R., Mayer E., Kübler W. Release of endogenous catecholamines in the ischemic myocardium of the rat. Part A: Locally mediated release. Circ Res. 1984 Nov;55(5):689–701. doi: 10.1161/01.res.55.5.689. [DOI] [PubMed] [Google Scholar]
  47. Schömig A., Fischer S., Kurz T., Richardt G., Schömig E. Nonexocytotic release of endogenous noradrenaline in the ischemic and anoxic rat heart: mechanism and metabolic requirements. Circ Res. 1987 Feb;60(2):194–205. doi: 10.1161/01.res.60.2.194. [DOI] [PubMed] [Google Scholar]
  48. Swain J. L., Sabina R. L., McHale P. A., Greenfield J. C., Jr, Holmes E. W. Prolonged myocardial nucleotide depletion after brief ischemia in the open-chest dog. Am J Physiol. 1982 May;242(5):H818–H826. doi: 10.1152/ajpheart.1982.242.5.H818. [DOI] [PubMed] [Google Scholar]
  49. Vatner D. E., Knight D. R., Shen Y. T., Thomas J. X., Jr, Homcy C. J., Vatner S. F. One hour of myocardial ischemia in conscious dogs increases beta-adrenergic receptors, but decreases adenylate cyclase activity. J Mol Cell Cardiol. 1988 Jan;20(1):75–82. doi: 10.1016/s0022-2828(88)80180-9. [DOI] [PubMed] [Google Scholar]
  50. Whyte K., Jones C. R., Howie C. A., Deighton N., Sumner D. J., Reid J. L. Haemodynamic, metabolic, and lymphocyte beta 2-adrenoceptor changes following chronic beta-adrenoceptor antagonism. Eur J Clin Pharmacol. 1987;32(3):237–243. doi: 10.1007/BF00607569. [DOI] [PubMed] [Google Scholar]
  51. Wollenberger A., Krause E. G., Heier G. Stimulation of 3',5'-cyclic AMP formation in dog myocardium following arrest of blood flow. Biochem Biophys Res Commun. 1969 Aug 15;36(4):664–670. doi: 10.1016/0006-291x(69)90357-x. [DOI] [PubMed] [Google Scholar]

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