Basic Research in Cardiology

, Volume 82, Issue 4, pp 326–340 | Cite as

Heart failure and Ca++ activation of the cardiac contractile system: hereditary cardiomyopathy in hamsters (BIO 14.6), isoprenaline overload and the effect of APP 201-533

  • J. W. Herzig
  • W. Gerber
  • R. Salzmann
Original Contributions

Summary

In the present paper, two experimental models of heart failure, namely hereditary cardiomyopathy in hamsters (BIO 14.6) and cardiac insufficiency due to mild (0.06 μM) isoprenaline overload of rabbit isolated perfused hearts, were compared in terms of resulting alterations at the level of the functionally isolated contractile system of detergent/glycerol treated skinned cardiac fibres. As the main features of Ca activation of tension in these models, the following were found:
  1. 1.

    Within the same species (RB hamsters, BIO 14.6 hamsters or rabbits), the Ca sensitivity, measured as pCa for half maximal Ca activation, was invariably higher in left than in right ventricular skinned fibres.

     
  2. 2.

    During the development of hereditary cardiomyopathy (BIO 14.6), maximum Ca-activated tension, measured per unit cross-sectional area, was reduced in an age-dependent manner, without any significant reduction in Ca sensitivity. This effect appeared to be more pronounced in left than in right ventricles.

     
  3. 3.

    In skinned fibres from right or left ventricular papillary muscles from in vitro isoprenaline pretreated rabbit hearts, no significant alteration in the maximum Ca-activated tension (per unit area) was observed in comparison to non-pretreated control hearts, whereas the Ca sensitivity was reduced. Treatment of control or failing heart skinned fibres with cAMP showed no additivity to the Ca desensitization induced by isoprenaline pretreatment.

     
  4. 4.

    Skinned fibres from isoprenaline pretreated left ventricular rabbit hearts showed a higher susceptibility to the Ca sensitizing effect of APP 201-533 than fibres from unpretreated control hearts.

     

Mild isoprenaline overload and hereditary cardiomyopathy both are forms of heart failure which are presumably not associated with a lack of activator Ca. It is concluded that cardiotonic agents increasing the cardiac myofibrillar sensitivity to Ca ions would be beneficial in both cases, representing a phenomenologically causative treatment in hearts failing due to isoprenaline pretreatment. A main advantage over “classical” cardiotonic agents like cardiac glycosides, beta adrenergic stimulants or phosphodiesterase inhibitors would be the absence of the risk of drug-induced Ca overload.

Key words

heart failure hereditarycardiomyopathy isoprenaline positiveinotropic effect myocardial skinnedfibres Ca−+ sensitivity APP 201-533 

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References

  1. 1.
    Bajusz E (1969) Hereditary cardiomyopathy: A new disease model. Am Heart J 77:686–696PubMedGoogle Scholar
  2. 2.
    Bhan A, Malhotra A, Sonnenblick EH, Scheuer J (1975) Decreased actomyosin ATPase activity in hamster myopathy. Circulation 51–52 Suppl:II-161Google Scholar
  3. 3.
    Bhan A, Malhotra A, Hatcher VB, Sonnenblick EH, Scheuer J (1978) Depressed myosin ATPase activity in hearts of myopathic hamsters: dissociation from neutral protease activity. J Mol Cell Cardiol 10:769–777PubMedGoogle Scholar
  4. 4.
    Cole HA, Frearson N, Moir AJG, Perry SV, Solaro RJ (1978) Phosphorylation of cardiac myofibrillar proteins. In: Kobayashi T et al (eds) Recent Advances in Studies on Cardiac Structure and Metabolism, Vol 11, Baltimore, University Park Press, pp 111–120Google Scholar
  5. 5.
    Dhalla NS, Sulakhe PF, Fedelsova M, Yates JC (1974) Molecular abnormalities in cardiomhopathy. Adv Cardiol 13:283–300Google Scholar
  6. 6.
    England PJ, Ray KP, Hibberd MG, Jeacocke SA, Murray KJ, Hollinworth DN (1979) The control of cardiac contractility by protein phosphorylation. In: Dumont J, Nunez J (eds) Hormones and Cell Regulation, Vol 3, pp 99–114. Elsevier/North Holland Biomedical PressGoogle Scholar
  7. 7.
    Fabiato A (1981) Myoplasmic free calcium concentration reached during the twitch of an intact isolated cardiac cell and during calcium induced release of calcium from the sarcoplasmic reticulum of a skinned cardiac cell from the adult rat or rabbit ventricle. J Gen Physiol 78:457–497PubMedGoogle Scholar
  8. 8.
    Factor SM, Minase T, Cho S, Dominitz R, Sonnenblick EH (1982) Microvascular spasm in the cardiomyopathic Syrian hamster: a preventable cause of focal myocardial necrosis. Circulation 66:342–354PubMedGoogle Scholar
  9. 9.
    Herzig JW, Rüegg JC (1980) Investigations on glycerinated cardiac muscle fibres in relation to the problem of regulation of cardiac contractility — Effects of Ca and cAMP. Basic Res Cardiol 75:26–33PubMedGoogle Scholar
  10. 10.
    Herzig JW, Feile K, Rüegg JC (1981) Activating effects of AR-L 115 BS on the Ca-sensitive force, stiffness and unloaded shortening velocity (Vmax) in isolated contractile structures from mammalian heart muscle. Arzneim Forsch/Drug Res 31:188–191Google Scholar
  11. 11.
    Herzig JW, Köhler G, Pfitzer G, Rüegg JC, Wölffle G (1981) Cyclic AMP inhibits contractility of detergent treated glycerol extracted cardiac muscle. Pflügers Arch Eur J Physiol 391:208–212Google Scholar
  12. 12.
    Herzig JW, Bormann G, Botelho L, Erdmann E, Salzmann R, Solaro RJ (1983) APP 201-533, a novel cardiotonic agent: Increase in Ca-sensitivity and economization of the myocardial contractile process. J Mol Cell Cardiol 15 Suppl I:244Google Scholar
  13. 13.
    Herzig JW, Quast U (1984) Increase in Ca-sensitivity of myocardial contractile structures by DPI 201-106. J Mol Cell Cardiol 16 Suppl 3:6Google Scholar
  14. 14.
    Herzig JW, Quast U (in press) Ca-sensitization of cardiac contractile proteins: Direct interaction with troponin C? In: Taira N et al (eds) Proceedings of the First International Conference on Search for New Positive Inotropic Agents at Sendai 1985Google Scholar
  15. 15.
    Hibberd MG, Jewell BR (1982) Calcium- and length-dependent force production in rat ventricular muscle. J Physiol (Lond) 329:527–540Google Scholar
  16. 16.
    Hirzel HO, Tuchschmid CR, Schneider J, Krayenbuehl HP, Schaub MC (1985) Relationship between myosin isocnzyme composition, hemodynamics, and myocardial structure in various forms of human cardiac hypertrophy. Circ Res 57:729–740PubMedGoogle Scholar
  17. 17.
    Holroyde MJ, Howe E, Solaro RJ (1979) Modification of calcium requirements for activation of cardiac myofibrillar ATPase by cyclic AMP dependent phosphorylation. Biochim Biophys Acta 586:63–69Google Scholar
  18. 18.
    Kleid JJ, Tada M, Repke DI, Katz AM (1972) Myosins from rat right and left ventricles. Comparison of ATPase activities and light fragments released by 8 M urea. J Mol Cell Cardiol 4:625–632PubMedGoogle Scholar
  19. 19.
    Kuo TH, Giacomelli F, Kithier K, Malhotra A (1981) Biochemical characterization and cellular localization of serine protease in myopathic hamster, J Mol Cell Cardiol 13:1035–1049PubMedGoogle Scholar
  20. 20.
    Ma TS, Bailey LE (1979) Excitation-contraction coupling in normal and myopathic hamster hearts I: Identification of a calcium pool involved in contraction. Cardiovasc Res 13:487–498PubMedGoogle Scholar
  21. 21.
    Ma TS, Bailey LE (1979) Excitation-contraction coupling in normal and myopathic hamster hearts II: Changes in contractility and Ca pools associated with development of cardiomyopathy. Cardiovasc Res 13:499–505PubMedGoogle Scholar
  22. 22.
    Marban E, Rink TJ, Tsien RW, Tsien RY (1980) Free calcium in the heart muscle at rest and during contraction measured with calcium sensitive microelectrodes. Nature 286:845–850PubMedGoogle Scholar
  23. 23.
    McClellan GB, Winegrad S (1978) The regulation of the calcium sensitivity of the contractile system in mammalian cardiac muscle. J Gen Physiol 72:737–767PubMedGoogle Scholar
  24. 24.
    Moir AJ, Solaro RJ, Perry SV (1980) The site of phosphorylation of troponin I in the perfused rabbit heart. The effect of adrenaline. Biochem J 185:505–513PubMedGoogle Scholar
  25. 25.
    Obah M, Sakamoto Y, Tomita T (1980) Negative inotropic effect of β-blockers in the guinea pig atrium after preincubation with isoprenaline. Eur J Pharmacol 65:257–266PubMedGoogle Scholar
  26. 26.
    Pang DC, Weglicki WB (1980) Alteration of myofibrillar ATPase activities in hearts of cardiomyopathic hamsters (BIO 53.58). J Mol Cell Cardiol 12:445–456PubMedGoogle Scholar
  27. 27.
    Paterson PA, Layberry RA, Nadkarni BB (1972) Cardiac failure in the hamster. A biochemical and electron microscopic study. Lab Invest 26:755–766PubMedGoogle Scholar
  28. 28.
    Perrin DD, Sayce IG (1967) Computer calculation of equilibrium concentrations in mixtures of metal ions and complexing species. Talanta 14:833–842Google Scholar
  29. 29.
    Quast U (1985) Effects of APP 201-533, amrinone and milrinone on the actomyosin ATPases from heart and skeletal muscle. Naunyn-Schmiedeberg's Arch Pharmacol 329 Suppl: R51Google Scholar
  30. 30.
    Resink TJ, Gevers W (1981) Altered adenosine triphosphatase activity of natural actomyosin from rat hearts perfused with isoprenaline and ouabain. Cell Calcium 2:105–123Google Scholar
  31. 31.
    Rupp H (1981) The adaptive changes in the isoenzyme pattern of myosin from hypertrophied rat myocardium as a result of pressure overload and physical training. Basic Res Cardiol 76:79–88PubMedGoogle Scholar
  32. 32.
    Salzmann R, Bormann G, Herzig JW, Markstein R, Scholtysik G (1985) Pharmacological actions of APP 201-533. a novel cardiotonic agent. J Cardiovasc Pharmacol 7:588–596PubMedGoogle Scholar
  33. 33.
    Schaub MC, Tuchschmid CR, Srihari T, Hirzel HO (1984) Myosin isoenzymes in human hypertrophic hearts. Shift in atrial myosin heavy chains and in ventricular light chains. Eur Heart J 5 Suppl F:85–93Google Scholar
  34. 34.
    Scholtysik G, Salzmann R, Berthold R, Herzig JW, Quast U, Markstein R (1985) DPI 201-106, a novel cardioactive agent. Combination of cAMP-independent positive inotropic, negative chronotropic, action potential prolonging and coronary dilatory properties. Naunyn-Schmiedeberg's Arch Pharmacol 329:316–325Google Scholar
  35. 35.
    Solaro RJ, Moir AJG, Perry SV (1976) Phosphorylation of troponin I and the inotropic effect of adrenaline in the perfused heart. Nature 246:615–617Google Scholar
  36. 36.
    Solaro RJ, Holroyde MJ, Herzig JW, Peterson J (1980) Cardiac relaxation and myofibrillar interactions with phosphate and vanadate. Eur Heart J 1 Suppl A:21–27Google Scholar
  37. 37.
    Solaro RJ, Rüegg JC (1982) Stimulation of Ca-binding and ATPase activity of dog cardiac myofibrils by AR-L 115 BS, a novel cardiotonic agent. Circ Res 51:290–294PubMedGoogle Scholar
  38. 38.
    Strobeck JE, Factor SM, Bhan A, Sole M, Liew CC, Fein F, Sonnenblick EM (1979) Hereditary and acquired cardiomyopathies in experimental animals: mechanical, biochemical and structural features. Ann NY Acad Sci 31:58–88Google Scholar
  39. 39.
    Syrovy I, Delcayre C, Swynghedauw B (1979) Comparison of ATPase activity and light subunits in myosins from left and right ventricles and atria in seven mammalian species. J Mol Cell Cardiol 11:1129–1135PubMedGoogle Scholar
  40. 40.
    Todd GL, Cullan GE, Cullan GM (1980) Isoproterenol-induced myocardial necrosis and membrane permeability alterations in the isolated perfused rabbit heart. Exp Mol Pathol 33:43–54PubMedGoogle Scholar
  41. 41.
    Toyo-oka T, Masaki T, Okamoto J, Tanaka T (1979) Calcium-activated neutral protease from bovine ventricular muscle: isolation and some of its properties, J Mol Cell Cardiol 11:769–786PubMedGoogle Scholar
  42. 42.
    Wada A, Yoneda H, Shibata N, Inui Y, Onishi S (1975) Morphological and biochemical studies on the heart of the cardiomyopathic Syrian hamster. Rec Adv. Stud Card Struct Metab 6:275–282Google Scholar
  43. 43.
    Wikman-Coffelt J, Fenner C, Smith A, Mason DT (1975) Comparative analyses of the kinetics and subunits of myosins from canine skeletal muscle and cardiac tissue. J Biol Chem 250:1257–1262PubMedGoogle Scholar
  44. 44.
    Wyborny LE, Reddy YS (1978) Phosphorylated cardiac myofibrils and their effect on ATPase activity, Biochem Biophys Res Comm 81:1175–1179PubMedGoogle Scholar
  45. 45.
    Yarom R, Hall TA, Oakley CM (1977) Localized concentrations of elements in hamster cardiomyopathy. Electron microscopic X-ray microanalysis of normal and sick myocardia, Basic Res Cardiol 72:660–670PubMedGoogle Scholar
  46. 46.
    Yuc DT, Marban E, Wier WG (1986) Relationship between force and intracellular [Ca] in tetanized mammalian heart muscle. J Gen Physiol 87:223–242PubMedGoogle Scholar

Copyright information

© Dr. Dietrich Steinkopff Verlag 1987

Authors and Affiliations

  • J. W. Herzig
    • 1
  • W. Gerber
    • 2
  • R. Salzmann
    • 2
  1. 1.Department Research CVSCiba-Geigy Ltd.BasleSwitzerland
  2. 2.Preclinical Research, Cardiovascular UnitSandoz Ltd.BasleSwitzerland

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