Skip to main content
SpringerLink
Log in

Down regulation of myocardial β1-adrenoceptor signal transduction system in pacing-induced failure in dogs with aortic stenosis-induced left ventricular hypertrophy

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

We recently demonstrated that rapid ventricular pacing caused cardiac failure (Failure) in dogs with aortic stenosis-induced left ventricular hypertrophy (Hypertrophy) and isoproterenol caused no significant increases in function, O2 consumption and intracellular cyclic AMP level in the failing hypertrophied hearts. We tested the hypothesis that alterations in the β1-adrenoceptor-signal transduction pathway would correlate with the reduced functional and metabolic responses to β-adrenergic stimulation during the transition from the compensated hypertrophy to failure. Pressure overload-induced left ventricular hypertrophy was created using aortic valve plication in 10 dogs over a 6-month period. Five months after aortic valve plication, congestive heart failure was induced in 5 dogs by rapid ventricular pacing at 240 bpm for 4 weeks. The density of myocardial β1-adrenoceptors (fmoles/mg membrane protein; fmoles/g wet tissue) was significantly reduced in the Failure dogs (176 ± 19; 755 ± 136) when compared to those of the Control (344 ± 51; 1,551 ± 203) and the Hypertrophy (298 ± 33; 1,721 ± 162) dogs. The receptor affinities were not significantly different among all groups. There was a small but significant decrease in the percentage of β1-adrenoceptors of the failing hypertrophied hearts (62 ± 3%) when compared to that of the hypertrophied hearts (77 ± 5%). The basal myocardial adenylyl cyclase activity (rmoles/mg protein/min) was significantly lower in the Failure dogs (45 ± 4) than in the Control (116 ± 14) and Hypertrophy (86 ± 6) dogs. The forskolin (0.1 mM)-stimulated adenylyl cyclase activity was also significantly lower in the Failure dogs (158 ± 17) than in the Control dogs (296 ± 35) and slightly lower than in the Hypertrophy dogs (215 ± 10). There were no significant differences in low Km cyclic AMP-phosphodiesterase activities among all groups. We conclude that down regulation of β1-adrenoceptors and reduced adenylyl cyclase activities contribute to the decreases in myocardial functions and β-adrenergic responses in the failing hypertrophied hearts induced by rapid ventricular pacing.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Ayobe MH, Tarazi RC: β-receptors and contractile reserve in left ventricular hypertrophy. Hypertension 5(suppl I): 192–197, 1983

    Google Scholar 

  2. Kumano K, Upsher ME, Khairallah PA: β-adrenergic receptor response coupling in hypertrophied hearts. Hypertension: 5(suppl I): 175–183, 1983

    Google Scholar 

  3. Tse J, Powell JR, Baste CA, Priest RE, Kuo JF: Isoproterenol-induced cardiac hypertrophy: Modifications in characteristics of beta-adrenergic receptor, adenylate cyclase, and ventricular contraction. Endocrinol 105: 246–255, 1979

    Google Scholar 

  4. Vatner DE, Homcy CL, Sit SP, Manders WT, Vatner SF: Effects of pressure-overload, left ventricular hypertrophy on β-adrenergic receptors and responsiveness to catecholamines. J Clin Invest 73: 1473–1482, 1984

    PubMed  Google Scholar 

  5. Scholz PM, Upsher ME, Eliades D, Kedem J, Weiss HR: Alterations in β adrenergic system in experimental left ventricular hypertrophy. Cardiovasc Res 24: 65–71, 1990

    PubMed  Google Scholar 

  6. Wright CC, Kedem J, Weiss HR, Rodriguez E, Wong J, Mackenzie JW, Scholz PM: Relationship between adenylate cyclase activity and regional myocardial energetics in experimental left ventricular hypertrophy. J Surg Res 50: 537–544, 1991

    Article  PubMed  Google Scholar 

  7. Armstrong PW, Stopps TP: Experimental studies of congestive cardiac failure. Circulation 70(suppl II): II354–II363, 1983

    Google Scholar 

  8. Wilson JW, Douglas P, Hickey WF, Lanoce V, Ferraro N, Muhammad A, Reichek N: Experimental congestive heart failure produced by rapid ventricular pacing in the dog: Cardiac effects. Circulation 75: 857–867, 1987

    PubMed  Google Scholar 

  9. Calderone A, Bouvier M, Li K, Juneau C, de Champlain J, Rouleau J: Dysfunction of the β-and α-adrenergic systems in a model of congestive heart failure-the pacing overdrive dog. Circ Res 69: 332–343, 1991

    PubMed  Google Scholar 

  10. Marzo KP, Frey ML, Wilson JR, Liang BT, Manning DR, Lanoce V, Molinoff PB: β-adrenergic receptor-G-protein-adenylate cyclase complex in experimental canine congestive heart failure produced by rapid ventricular pacing. Circ Res 69: 1546–1556, 1991

    PubMed  Google Scholar 

  11. Kiuchi K, Shannon RP, Komamura K, Cohen DJ, Bianchi C, Homcy CJ, Vatner SF, Vatner DE: Myocardial β-adrenergic receptor function during the development of pacing-induced heart failure. J Clin Invest 91: 907–914, 1993

    PubMed  Google Scholar 

  12. Huang MW, Leone R, Weiss HR, Tse J, Scholz PM: Pacing-induced cardiac failure of hypertrophic hearts reduces functional and metabolic effects of isoproterenol. FASEB J 12: A977, 1998

    Google Scholar 

  13. Sink JD, Attarian DE, Chitwood WR, Hill RC, Pellham GL, Wechsler AS: An improved technique for producing left ventricular hypertrophy with a subcoronary valvular aortic stenosis model. Ann Thorac Surg 30: 285–90, 1980

    PubMed  Google Scholar 

  14. Devos C, Robberecht P, Waelbroeck M, Clienet M, Beaufort P, Schoenfield P, Christopher J: Uncoupling between β-adrenoceptors and adenylate cyclase in dog ischemia myocardium. Naunyn-Schm Arch Pharmacol 331: 71–75, 1985

    Article  Google Scholar 

  15. Narayanan N, Sulake PV: 5′-Guanylylimdodiphosphate-activated adenylate cyclase of cardiac sarcolemma displays higher affinity for magnesium ions. Mol Pharmacol 13: 1033–1047, 1977

    PubMed  Google Scholar 

  16. Tse J, Brackett NL, Kuo JF: Alterations in activities of cyclic nucleotide systems and in beta-adrenergic receptor-mediated activation of cyclic AMP-dependent protein kinase during progression and regression of isoproterenol-induced cardiac hypertrophy. Biochim Biophys Acta: 542: 399–411, 1978

    PubMed  Google Scholar 

  17. Thompson WJ, Appleman MM: Multiple cyclic nucleotide phosphodiesterase activities from rat brain. Biochem 10: 311–316, 1971

    Google Scholar 

  18. Bristow MR, Hershberger RE, Port JD, Gilbert EM, Sandoval A, Rasmussen R, Cates AE, Felman AM: β-adrenergic pathways in nonfailing and failing human ventricular myocardium. Circulation 82(suppl I): I-12–25, 1990

    Google Scholar 

  19. Bö hm M, Pieske B, Schnabel P, Schwinger R, Kemkes B, Klö vekorn WP, Erdmann E: Reduced effects of dopexamine on force of contraction in the failing human heart despite preserved β2-adrenoceptor subpopulation. J Cardiovasc Pharmacol 14: 549–559, 1989

    PubMed  Google Scholar 

  20. Brodde OE, Zerkowski HR, Borst HG, Maier W, Michel MC: Drugand disease-induced changes of human cardiac β1-and β2-adrenoceptors. Eur Heart J 10(suppl B): 38–44, 1989

    Google Scholar 

  21. Brodde OE: Cardiac beta-adrenergic receptors. ISI Atlas Sci Pharmacol 1: 107–112, 1987

    Google Scholar 

  22. Buxton BF, Jones CR, Monlenaar P, Summers RJ: Characterization and autoradiographic location of β-adrenoceptor subtypes in human cardiac tissues. Br J Pharmacol 92: 299–310, 1987

    PubMed  Google Scholar 

  23. Lemoine H, Schö nell H, Kaumann AJ: Contribution of β1-and β2-adrenoceptors of human atrium and ventricle to the effects of noradrenaline and adrenaline as assessed with (–)-atenolol. Br J Pharmacol 95: 55–66, 1988

    PubMed  Google Scholar 

  24. Steinfath M, Geertz B, Schmitz W, Scholz H, Haverich A, Breil I, Hanrath P, Reupcke C, Sigmund M, Lo H-B: Distinct down-regulation of cardiac β1-and β2-adrenoceptors in different human heart diseases. Naunyn-Schmiedeberg's Arch Pharmacol 343: 217–220, 1991

    Article  Google Scholar 

  25. Bristow MR, Ginsburg R, Umans V, Fowler M, Minobe W, Rasmussen R, Zera P, Menlove R, Shah P, Jamieseon S, Stinson EB: β1-and β2-adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: Coupling of both receptor subtypes ``to muscle contraction and selectiveε b1-receptor downregulation in heart failure. Circ Res 59: 297–309, 1986

    PubMed  Google Scholar 

  26. Brodde OE, Schü ler S, Kretsch R, Brinkmann M, Borst HG, Hetzer R, Reidemeister JC, Warnecke H, Zerkowski HR: Regional distribution Φ b-adrenoceptors in human heart: co-existence of functionaλ b1-anδ b2-adrenoceptors in both atria and ventricles in severe congestive cardiomyopathy. J Cardiovasc Pharmacol 8: 1235–1242, 1986

    PubMed  Google Scholar 

  27. Fowler, Laser JA, Hopkins GL, Minobe W, Bristow MR: Assessment of the b-adrenergic receptor pathway in the intact failing human heart: Progressive receptor down-regulation and subsensitivity to agonist response. Circulation 74: 1290–1302, 1986

    PubMed  Google Scholar 

  28. Brodde OE, Zerkowski HR, Doetsch N, Motomura S, Khamssi M, Michel MC: 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, 1989

    Article  PubMed  Google Scholar 

  29. Karliner JS, Barnes P, Brown M, Dollery C: Chronic heart failure in the guinea pig increases cardiac α1 and β-adrenoceptors. Eur J Pharmacol 67: 115–118, 1980

    Article  PubMed  Google Scholar 

  30. Ishikawa Y, Sorota S, Kiuchi K, Shannon RP, Komamura K, Katsushika S, Vatner DE, Vatner SF, Homcy CJ: Downregulation of adenylylcyclase type V and VI mRNA levels in pacing-induced heart failure in dogs. J Clin Invest 93: 2224–2229, 1994

    PubMed  Google Scholar 

  31. Beavo JA: Multiple isozymes of cyclic nucleotide phosphodiesterase. In: Greengard P. and Robinson G.A. (eds). Advances in Second Messenger and Phosphoprotein Research, vol. 22. Raven Press, New York, 1988, pp 1–38

    Google Scholar 

  32. Silver PJ, Allen P, Etzler JH, Hamel LT, Bentley RG, Pagani ED: Cellular distribution and pharmacological sensitivity of low Km cyclic nucleotide phosphodiesterase isozymes in human cardiac muscle from normal and cardiomyopathic subjects. Second Messengers and Phosphoproteins 13: 13–25, 1990

    PubMed  Google Scholar 

  33. Movsesian MA, Smith CJ, Krall J, Bristow R, Manganiello VC: Sarcoplasmic reticulum-associated cyclic adenosine 5′-monophosphate phosphodiesterase activity in normal and failing human hearts. J Clin Invest 88: 15–19, 1991

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Anesthesia, Heart and Brain Circulation Laboratory, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ, USA

    James Tse & Yi Qi He

  2. Department of Surgery, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ, USA

    Mark W. Huang, Richard J. Leone Jr & Peter M. Scholz

  3. Department of Physiology & Biophysics, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ, USA

    Harvey R. Weiss

Authors
  1. James Tse
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mark W. Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Richard J. Leone Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Harvey R. Weiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yi Qi He
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Peter M. Scholz
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tse, J., Huang, M.W., Leone, R.J. et al. Down regulation of myocardial β1-adrenoceptor signal transduction system in pacing-induced failure in dogs with aortic stenosis-induced left ventricular hypertrophy. Mol Cell Biochem 205, 67–73 (2000). https://doi.org/10.1023/A:1007085027234

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1007085027234

Search

Navigation