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. 1991 Dec;88(6):1940–1946. doi: 10.1172/JCI115518

Chronic nonocclusive coronary artery constriction in rats. Beta-adrenoceptor signal transduction and ventricular failure.

L G Meggs 1, H Huang 1, P Li 1, J M Capasso 1, P Anversa 1
PMCID: PMC295773  PMID: 1661293

Abstract

To determine the effects of chronic coronary artery constriction on the relationship between cardiac function and regulation of beta-adrenoceptor signal transduction, the left main coronary artery was narrowed in rats and the animals were killed 5 mo later. An average reduction in coronary luminal diameter of 44% was obtained and this change resulted in an increase in left ventricular end-diastolic pressure and a decrease in positive and negative dP/dt. Significant increases in left and right ventricular weights indicative of global cardiac hypertrophy were observed. Radioligand binding studies of beta-adrenoreceptors, agonist-stimulated adenylate cyclase activity, and ADP ribosylation of 45-kD substrate by cholera toxin were all depressed in the failing left ventricle. In contrast, in the hypertrophic non-failing right ventricle, beta-adrenoreceptor density was preserved and receptor antagonist affinity was increased. In spite of these findings at the receptor level, agonist stimulated cyclic AMP generation was reduced in the right ventricular myocardium. The quantity of the 45-kD substrate was also decreased. In conclusion, longterm nonocclusive coronary artery stenosis of moderate degree has profound detrimental effects on the contractile performance of the heart in association with marked attenuation of adrenergic support mechanisms.

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Selected References

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  1. Anversa P., Beghi C., Kikkawa Y., Olivetti G. Myocardial infarction in rats. Infarct size, myocyte hypertrophy, and capillary growth. Circ Res. 1986 Jan;58(1):26–37. doi: 10.1161/01.res.58.1.26. [DOI] [PubMed] [Google Scholar]
  2. Anversa P., Hiler B., Ricci R., Guideri G., Olivetti G. Myocyte cell loss and myocyte hypertrophy in the aging rat heart. J Am Coll Cardiol. 1986 Dec;8(6):1441–1448. doi: 10.1016/s0735-1097(86)80321-7. [DOI] [PubMed] [Google Scholar]
  3. Anversa P., Levicky V., Beghi C., McDonald S. L., Kikkawa Y. Morphometry of exercise-induced right ventricular hypertrophy in the rat. Circ Res. 1983 Jan;52(1):57–64. doi: 10.1161/01.res.52.1.57. [DOI] [PubMed] [Google Scholar]
  4. Anversa P., Loud A. V., Levicky V., Guideri G. Left ventricular failure induced by myocardial infarction. I. Myocyte hypertrophy. Am J Physiol. 1985 Jun;248(6 Pt 2):H876–H882. doi: 10.1152/ajpheart.1985.248.6.H876. [DOI] [PubMed] [Google Scholar]
  5. Anversa P., Palackal T., Sonnenblick E. H., Olivetti G., Capasso J. M. Hypertensive cardiomyopathy. Myocyte nuclei hyperplasia in the mammalian rat heart. J Clin Invest. 1990 Apr;85(4):994–997. doi: 10.1172/JCI114576. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Anversa P., Palackal T., Sonnenblick E. H., Olivetti G., Meggs L. G., Capasso J. M. Myocyte cell loss and myocyte cellular hyperplasia in the hypertrophied aging rat heart. Circ Res. 1990 Oct;67(4):871–885. doi: 10.1161/01.res.67.4.871. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. 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]
  9. 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]
  10. Capasso J. M., Jeanty M. W., Palackal T., Olivetti G., Anversa P. Ventricular remodeling induced by acute nonocclusive constriction of coronary artery in rats. Am J Physiol. 1989 Dec;257(6 Pt 2):H1983–H1993. doi: 10.1152/ajpheart.1989.257.6.H1983. [DOI] [PubMed] [Google Scholar]
  11. Capasso J. M., Li P., Anversa P. Nonischemic myocardial damage induced by nonocclusive constriction of coronary artery in rats. Am J Physiol. 1991 Mar;260(3 Pt 2):H651–H661. doi: 10.1152/ajpheart.1991.260.3.H651. [DOI] [PubMed] [Google Scholar]
  12. Capasso J. M., Palackal T., Olivetti G., Anversa P. Left ventricular failure induced by long-term hypertension in rats. Circ Res. 1990 May;66(5):1400–1412. doi: 10.1161/01.res.66.5.1400. [DOI] [PubMed] [Google Scholar]
  13. FRAJOLA W. J., WILLIAMS R. D., AUSTAD R. A. THE KINETIC SPECTROPHOTOMETRIC ASSAY FOR SERUM ALKALINE PHOSPHATASE. Am J Clin Pathol. 1965 Mar;43:261–264. doi: 10.1093/ajcp/43.3.261. [DOI] [PubMed] [Google Scholar]
  14. Feldman M. D., Copelas L., Gwathmey J. K., Phillips P., Warren S. E., Schoen F. J., Grossman W., Morgan J. P. Deficient production of cyclic AMP: pharmacologic evidence of an important cause of contractile dysfunction in patients with end-stage heart failure. Circulation. 1987 Feb;75(2):331–339. doi: 10.1161/01.cir.75.2.331. [DOI] [PubMed] [Google Scholar]
  15. Gwathmey J. K., Copelas L., MacKinnon R., Schoen F. J., Feldman M. D., Grossman W., Morgan J. P. Abnormal intracellular calcium handling in myocardium from patients with end-stage heart failure. Circ Res. 1987 Jul;61(1):70–76. doi: 10.1161/01.res.61.1.70. [DOI] [PubMed] [Google Scholar]
  16. Hammond H. K., Ransnas L. A., Insel P. A. Noncoordinate regulation of cardiac Gs protein and beta-adrenergic receptors by a physiological stimulus, chronic dynamic exercise. J Clin Invest. 1988 Dec;82(6):2168–2171. doi: 10.1172/JCI113840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hearse D. J., Garlick P. B., Humphrey S. M. Ischemic contracture of the myocardium: mechanisms and prevention. Am J Cardiol. 1977 Jun;39(7):986–993. doi: 10.1016/s0002-9149(77)80212-9. [DOI] [PubMed] [Google Scholar]
  18. Katz A. M., Tada M. The "stone heart": a challenge to the biochemist. Am J Cardiol. 1972 Apr;29(4):578–580. doi: 10.1016/0002-9149(72)90455-9. [DOI] [PubMed] [Google Scholar]
  19. Knoebel S. B., Elliott W. C., McHenry P. L., Ross E. Myocardial blood flow in coronary artery disease. Correlation with severity of disease and treadmill exercise response. Am J Cardiol. 1971 Jan;27(1):51–58. doi: 10.1016/0002-9149(71)90082-8. [DOI] [PubMed] [Google Scholar]
  20. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  21. Limas C. J. Increased number of beta-adrenergic receptors in the hypertrophied myocardium. Biochim Biophys Acta. 1979 Nov 15;588(1):174–178. doi: 10.1016/0304-4165(79)90382-9. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Maseri A., Chierchia S. Coronary artery spasm: demonstration, definition, diagnosis, and consequences. Prog Cardiovasc Dis. 1982 Nov-Dec;25(3):169–192. doi: 10.1016/0033-0620(82)90015-9. [DOI] [PubMed] [Google Scholar]
  24. Meggs L. G., Ben-Ari J., Gammon D., Choudhury M., Goodman A. I. Adaptive myocardial hypertrophy in the renal ablation model. Am J Hypertens. 1990 Jan;3(1):33–38. doi: 10.1093/ajh/3.1.33. [DOI] [PubMed] [Google Scholar]
  25. Meggs L. G., Tillotson J., Huang H., Sonnenblick E. H., Capasso J. M., Anversa P. Noncoordinate regulation of alpha-1 adrenoreceptor coupling and reexpression of alpha skeletal actin in myocardial infarction-induced left ventricular failure in rats. J Clin Invest. 1990 Nov;86(5):1451–1458. doi: 10.1172/JCI114861. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Momomura S., Bradley A. B., Grossman W. Left ventricular diastolic pressure-segment length relations and end-diastolic distensibility in dogs with coronary stenoses. An angina physiology model. Circ Res. 1984 Aug;55(2):203–214. doi: 10.1161/01.res.55.2.203. [DOI] [PubMed] [Google Scholar]
  27. Olivetti G., Melissari M., Capasso J. M., Anversa P. Cardiomyopathy of the aging human heart. Myocyte loss and reactive cellular hypertrophy. Circ Res. 1991 Jun;68(6):1560–1568. doi: 10.1161/01.res.68.6.1560. [DOI] [PubMed] [Google Scholar]
  28. Pantely G. A., Bristow J. D. Ischemic cardiomyopathy. Prog Cardiovasc Dis. 1984 Sep-Oct;27(2):95–114. doi: 10.1016/0033-0620(84)90021-5. [DOI] [PubMed] [Google Scholar]
  29. Paulus W. J., Grossman W., Serizawa T., Bourdillon P. D., Pasipoularides A., Mirsky I. Different effects of two types of ischemia on myocardial systolic and diastolic function. Am J Physiol. 1985 May;248(5 Pt 2):H719–H728. doi: 10.1152/ajpheart.1985.248.5.H719. [DOI] [PubMed] [Google Scholar]
  30. Pfeffer M. A., Pfeffer J. M., Fishbein M. C., Fletcher P. J., Spadaro J., Kloner R. A., Braunwald E. Myocardial infarct size and ventricular function in rats. Circ Res. 1979 Apr;44(4):503–512. doi: 10.1161/01.res.44.4.503. [DOI] [PubMed] [Google Scholar]
  31. 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]
  32. Schuster E. H., Bulkley B. H. Ischemic cardiomyopathy: a clinicopathologic study of fourteen patients. Am Heart J. 1980 Oct;100(4):506–512. doi: 10.1016/0002-8703(80)90663-8. [DOI] [PubMed] [Google Scholar]
  33. Serizawa T., Vogel W. M., Apstein C. S., Grossman W. Comparison of acute alterations in left ventricular relaxation and diastolic chamber stiffness induced by hypoxia and ischemia. Role of myocardial oxygen supply-demand imbalance. J Clin Invest. 1981 Jul;68(1):91–102. doi: 10.1172/JCI110258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Stiles G. L., Caron M. G., Lefkowitz R. J. Beta-adrenergic receptors: biochemical mechanisms of physiological regulation. Physiol Rev. 1984 Apr;64(2):661–743. doi: 10.1152/physrev.1984.64.2.661. [DOI] [PubMed] [Google Scholar]
  35. Stryer L., Bourne H. R. G proteins: a family of signal transducers. Annu Rev Cell Biol. 1986;2:391–419. doi: 10.1146/annurev.cb.02.110186.002135. [DOI] [PubMed] [Google Scholar]
  36. 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]
  37. 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]
  38. Vatner S. F. Correlation between acute reductions in myocardial blood flow and function in conscious dogs. Circ Res. 1980 Aug;47(2):201–207. doi: 10.1161/01.res.47.2.201. [DOI] [PubMed] [Google Scholar]
  39. Welch C. C., Proudfit W. L., Sheldon W. C. Coronary arteriographic findings in 1,000 women under age 50. Am J Cardiol. 1975 Feb;35(2):211–215. doi: 10.1016/0002-9149(75)90003-x. [DOI] [PubMed] [Google Scholar]
  40. Wexler L. F., Weinberg E. O., Ingwall J. S., Apstein C. S. Acute alterations in diastolic left ventricular chamber distensibility: mechanistic differences between hypoxemia and ischemia in isolated perfused rabbit and rat hearts. Circ Res. 1986 Nov;59(5):515–528. doi: 10.1161/01.res.59.5.515. [DOI] [PubMed] [Google Scholar]

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