Basic Research in Cardiology

, Volume 92, Issue 6, pp 391–401 | Cite as

The negative functional and metabolic effects of muscarinic stimulation are enchanced byβ-adrenergic activation in control and hypertrophic dog hearts in vivo

  • P. M. Scholz
  • P. Rabindranauth
  • K. L. Naim
  • H. R. Weiss
  • J. Tse
Original contribution


The aim of the current study was to determine if the effects of muscarinic stimulation on left ventricular function and metabolism are greater during β-adrenergic activation, whether a cyclic GMP-mediated mechanism is responsible, and if this is altered by left ventricular hypertrophy (LVH) induced by aortic valve stenosis. Acetylcholine (Ach) (5 μg/kg/min) and/or isoproterenol (Iso) (0.1 μg/kg/min) was infused into a branch of the left anterior descending (LAD) artery in 8 control and 8 LVH open-chest anesthetized dogs. LVH increased heart weight, heart-to-body weight ratio and systolic left ventricular pressure. LVH reduced muscarinic receptor density (fmol/mg protein) (control: 149.2±18.6; LVH: 77.8±8.6), but not affinity. Alone, Ach had no effect on regional force, work or metabolism. Iso increased peak force (g) (control: baseline-7.4±0.4; Iso-12.4±2.2; LVH: baseline-6.7±0.8; Iso-16.3±2.7, regional work (g mm/min)) (control: baseline-1250±186; Iso-1813±409; LVH: baseline-927±235; Iso-1244±222), and O2 consumption (ml O2/min/100 g) (control: baseline-3.3±0.2; Iso-8.1±2.0; LVH: baseline-4.8±1.0; Iso-8.3±1.1). During Iso, Ach reduced segment shortening (control: Iso-14.5±1.2; Iso+Ach-10.5±1.8; LVH: Iso-10.4±1.5; Iso+Ach-7.6±1.3) and peak force (control: Iso+Ach-7.7±1.0; LVH: Iso+Ach-10.5±1.4). Ach also reduced work (control: Iso+Ach-875±217; LVH: Iso+Ach-776±180) and O2 consumption (control: Iso+Ach-3.4±0.7; LVH: Iso+Ach-3.6±0.6) in the presence of Iso. Cyclic GMP was higher in the LVH animals during all treatments and was elevated from baseline by Ach in both groups. Neither Iso nor Iso+Ach had a significant effect on cyclic GMP. Thus, the negative functional and metabolic effects of muscarinic stimulation are enhanced during β-adrenergic activation. This does not, however, appear to be dependent on a cyclic GMP-mediated mechanism. Despite reduced number of muscarinic receptors, this response was not altered by pressure-induced cardiac hypertrophy.

Key words

Cardiac hypertrophy acetylcholine dog β-adrenergic stimulation myocardial O2 consumption regional myocardial function 


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  1. 1.
    Acad BA, Weiss HR (1989) Regional myocardial O2 consumption and coronary blood flow responses to acetylcholine in rabbit heart. Arch Int Physiol Biochim 97: 197–204Google Scholar
  2. 2.
    Boyett MR, Kirby MS, Orchard CH, Roberts A (1988) The negative inotropic effect of acetylcholine on ferret ventricular myocardium. J Physiol (London) 404: 613–635Google Scholar
  3. 3.
    Fields JZ, Roeske WR, Morkin E, Yamamura HI (1978) Cardiac muscarinic cholinergic receptors. Biochemical identification and characterization. J Biol Chem 253: 3251–3258Google Scholar
  4. 4.
    Fischmeister R, Hartzell HF (1986) Mechanism of action of acetylcholine on calcium current in single cells from frog ventricle. J Physiol (London) 376: 183–202Google Scholar
  5. 5.
    Fleming JW, Watanabe AM (1988) Muscarinic cholinergic-receptor stimulation of specific GTP hydrolysis related to adenylate cyclase activity in canine cardiac sarcolemma. Circ Res 63: 340–350Google Scholar
  6. 6.
    George WJ, Polson JB, O'Toole AG, Goldberg ND (1970) Elevation of guanosine 3′,5′-cyclic phosphate in rat heart after perfusion with acetylcholine. Proc Natl Acad Sci 66: 398–402Google Scholar
  7. 7.
    Groschner K, Holzmann S, Kukovetz WR (1986) Lack of second messenger function of cyclic GMP in acetylcholine-induced negative inotropoism. J Cardiovasc Pharmacol 8: 1154–1157Google Scholar
  8. 8.
    Guo X, Kedem J, Scholz PM, Weiss HR (1996) Action of acetylcholine on regional myocardial work and metabolismin vivo: association with cyclic GMP. Can J Physiol Pharmacol 74: 73–79Google Scholar
  9. 9.
    Kedem J, Lee W, Weiss HR (1994) An experimental technique for quantitative determination of regional myocardial segment workin vivo. Ann Biomed Eng 22: 58–65Google Scholar
  10. 10.
    Kent KM, Epstein SE, Cooper T, Jacobowitz DM (1974) Cholinergic innervation of the canine and human ventricular conduction system: anatomic and physiologic correlations. Circ 50: 948–955Google Scholar
  11. 11.
    Levy MN, Martin PJ (1984) Parasympathetic control of the heart. In: Randall WC (ed) Nervous Control of Cardiovascular Function. Oxford University Press New York: 89–107Google Scholar
  12. 12.
    Mansier P, Chevalier B, Barnett DB, Swynghedauw B (1993) Beta adrenergic and muscarinic receptors in compensatory cardiac hypertrophy of the adult rat. Pflugers Arch—Eur J Physiol 424: 354–360Google Scholar
  13. 13.
    McIvor ME, Orchard CH, Lakatta E (1988) Dissociation of changes in apparent myofibrillar Ca2+ sensitivity and twitch relaxation induced by adrenergic and cholinergic stimulation in isolated ferret cardiac muscle. J Gen Physiol 94: 509–529Google Scholar
  14. 14.
    Mondry A, Bourgeois F, Carre F, Swynghedauw B, Moalic JM (1995) Decrease in beta 1-adrenergic and M2-muscarinic receptor mRNA levels and unchanged accumulation of mRNAs coding for G alpha i-2 and G alpha s proteins in rat cardiac hypertrophy. J Mol Cell Cardiol 27: 2287–2294Google Scholar
  15. 15.
    Nichols JR, Gonzalez NC (1982) Increase in myocardial cell cGMP concentration in pressure-induced myocardial hypertrophy. J Mol Cell Cardiol 14: 181–183Google Scholar
  16. 16.
    Pappano AJ, Hartigan PM, Coutu MD (1982) Acetylcholine inhibits positive inotropic effect of cholera toxin in ventricular muscle. Am J Physiol 243: H434-H441Google Scholar
  17. 17.
    Roitstein A, Kedem J, Cheinberg B, Weiss HR, Tse J, Scholz PM (1994) The effect of intracoronary nitroprusside on cyclic GMP and regional mechanics is altered in a canine model of left ventricular hypertrophy. J Surg Res 57: 584–590Google Scholar
  18. 18.
    Scholz PM, Chiu WC, Kedem J, Weiss HR (1993) Relationship between cyclic-AMP content, regional myocardial function and O2 consumption in experimental left ventricular hypertrophy: effect of negative inotropes. Life Sci 53: 1847–1858Google Scholar
  19. 19.
    Scholz PM, Grover GJ, Mackenzie JW, Weiss HR (1990) Regional oxygen supply and consumption balance in experimental left ventricular hypertrophy. Bas Res Cardiol 85: 575–84Google Scholar
  20. 20.
    Standish A, Enquist LW, Schwaber JS (1994) Innervation of the heart and its central medullary origin defined by viral tracing. Science 263: 232–234Google Scholar
  21. 21.
    Stein B, Drogemuller A, Mulsch A, Schmitz W, Scholz H (1993) Ca++-dependent constitutive nitric oxide synthase is not involved in the cyclic GMP-increasing effects of carbachol in ventricular cardiomyocytes. J Pharmacol Exp Ther 266: 919–925Google Scholar
  22. 22.
    Vatner DE, Lee DL, Schwarz KR, Longabaugh JP, Fujii AM, Vatner SF, Homcy CJ (1988) Impaired cardiac muscarinic receptor function in dogs with heart failure. J Clin Invest 81: 1836–1842Google Scholar
  23. 23.
    Wahler GM, Rusch NJ, Sperelakis N (1990) 8-Bromo-cyclic GMP inhibits the calcium cahnnel current in embryonic chick ventricular myocytes. Can J Physiol Pharmacol 68: 531–534Google Scholar
  24. 24.
    Watanabe AM, Besch HR (1975) Interaction between cyclic adenosine monophosphate and cyclic guanosine monophosphate in guinea pig ventricular myocardium. Circ Res 37: 309–317Google Scholar
  25. 25.
    Weiss HR, Tse J (1995) Myocardial metabolic and functional responses to acetylcholine are altered in thyroxine-induced cardiac hypertrophy. Can J Physiol Pharmacol 73: 729–735Google Scholar
  26. 26.
    Weiss HR, Rodriguez E, Tse J (1995) Relationship between cyclic GMP and myocardial O2 consumption is altered in T4-induced cardiac hypertrophy. Am J Physiol 268: H686-H691Google Scholar
  27. 27.
    Wright CC, Kedem J, Weiss HR, Rodriguez E, Wong J, Mackenzie JW, Scholz PM (1991) Relationship between adenylate cyclase activity and regional myocardial energetics in experimental left ventricular hypertrophy. J Surg Res 50: 537–54Google Scholar

Copyright information

© Steinkopff Verlag 1997

Authors and Affiliations

  • P. M. Scholz
    • 1
  • P. Rabindranauth
    • 1
  • K. L. Naim
    • 2
  • H. R. Weiss
    • 2
  • J. Tse
    • 3
  1. 1.Department of SurgeryUMDNJ-Robert Wood Johnson Medical SchoolNew BrunswickUSA
  2. 2.Departments of Physiology & BiophysicsUMDNJ-Robert Wood Johnson Medical SchoolPiscatawayUSA
  3. 3.Department of AnesthesiaUMDNJ-Robert Wood Johnson Medical SchoolPiscatawayUSA

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