Cardiovascular Drugs and Therapy

, Volume 10, Issue 6, pp 657–665

Nicotine and sympathetic neurotransmission

  • Markus Haass
  • Wolfgang Kübler
Applied Pharmacology

Summary

Nicotine increases heart rate, myocardial contractility, and blood pressure. These nicotine-induced cardiovascular effects are mainly due to stimulation of sympathetic neurotransmission, as nicotine stimulates catecholamine release by an activation of nicotinic acetylcholine receptors localized on peripheral postganglionic sympathetic nerve endings and the adrenal medulla. The nicotinic acetylcholine receptor is a ligand-gated cation channel with a pentameric structure and a central pore with a cation gate, which is essential for ion selectivity and permeability. Binding of nicotine to its extracellular binding site leads to a conformational change of the central pore, which results in the influx of sodium and calcium ions. The resulting depolarization of the sympathetic nerve ending stimulates calcium influx through voltage-dependent N-type calcium channels, which triggers the nicotine-evoked exocytotic catecholamine release. In the isolated perfused guinea-pig heart, cardiac energy depletion sensitizes cardiac sympathetic nerves to the norepinephrine-releasing effect of nicotine, as indicated by a leftward shift of the concentration-response curve, a potentiation of maximum transmitter release, and a delay of the tachyphylaxis of nicotine-evoked catecholamine release. This sensitization was also shown to occur in the human heart under in vitro conditions. Through the intracardiac release of norepinephrine, nicotine induces a beta-adrenoceptormediated increase in heart rate and contractility, and an alpha-adrenoceptor-mediated increase in coronary vasomotor tone. The resulting simultaneous increase in oxygen demand and coronary resistance has a detrimental effect on the oxygen balance of the heart, especially in patients with coronary artery disease. Sensitization of the ischemic heart to the norepinephrine-releasing effect of nicotine may be a trigger for acute cardiovascular events in humans, such as acute myocardial infarction and/or life-threatening ventricular tachyarrhythmias.

Key Words

epinephrine intracellular calcium intracellular sodium myocardial ischemia neuropeptide Y nicotine nicotinic acetylcholine receptor norepinephrine protein kinase C voltage-dependent calcium channel 

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References

  1. 1.
    Augustine, GJ, Neher, E. Neuronal Ca2+ signalling takes the local route. Curr Opin Neurobiol 1992;2:302–307.Google Scholar
  2. 2.
    Benowitz, NL, Porchet, H, Sheiner, L, Jacob, P. Nicotine absorption and cardiovascular effects with smokeless tobacco use: Comparison with cigarettes and nicotine gum. Clin Pharmacol Ther 1988;44:23–28.Google Scholar
  3. 3.
    Benowitz, NL. Nicotine and coronary heart disease. Trends Cardiovasc Med 1991;1:315–321.Google Scholar
  4. 4.
    Bertrand, D, Galzi, JL, Devillers-Thiery, A, Bertrand, S, Changeux, J-P. Mutations at two distinct sites within the channel domain M2 alter calcium permeability of neuronal α7 nicotinic receptor. Proc Natl Acad Sci USA 1993;90: 6971–6975.Google Scholar
  5. 5.
    Boksa, P, Livett, BG. Desensitization to nicotinic cholinergic agonists and K+ agents, that stimulate catecholamine secretion, in isolated adrenal chromaffin cells. J Neurochem 1984; 42:607–617.Google Scholar
  6. 6.
    Brooks, JC. The isolated bovine adrenomedullary chromaffin cell: A model of neuronal excitation-secretion. Endocrinology 1977;101:1369–1378.Google Scholar
  7. 7.
    Changeux, J-P. The TiPS lecture. The nicotinic acetylcholine receptor: An allosteric protein prototype of ligand-gated ion channels. Trends Pharmacol Sci 1990;11:485–492.Google Scholar
  8. 8.
    Cheek, TR, Jackson, TR, O'Sullivan, AJ, Moreton, RB, Berridge, MJ, Burgoyne, MJ, Burgoyne, RD. Simultaneous measurements of cytosolic calcium and secretion in single bovine adrenal chromaffin cells by fluorescent imaging of fura-2 in cocultured cells. J Cell Biol 1989;109:1219–1227.Google Scholar
  9. 9.
    Cryer, PE, Haymond, MW, Santiago, JV, Shah, SD. Norepinephrine and epinephrine release and adrenergic mediation of smoking-associated hemodynamic and metabolic effects. N Engl J Med 1976;295:573–577.Google Scholar
  10. 10.
    Deanfield, JE, Shea, MJ, Wilson, RA, Horlock, P, deLandsheere, CM, Selwyn, AP. Direct effects of smoking on the heart: Silent ischemic disturbances of coronary flow. Am J Cardiol 1986;57:1005–1009.Google Scholar
  11. 11.
    Gerber, SH, Haunstetter, A, Krüger, C, Kaufmann, A, Nobiling, R, Haass, M. Role of [Na+]i and [Ca2+]i in nicotine-induced norepinephrine release from bovine adrenal chromaffin cells. Am J Physiol 1995;269(Cell Physiol 38): C572-C581.Google Scholar
  12. 12.
    Grassi, G, Seravalle, G, Calhoun, DA, Bolla, GB, Giannattasio, C, Marabini, M, Del, Bo, A, Mancia, G. Mechanisms responsible for sympathetic activation by cigarette smoking. Circulation 1994;90:248–253.Google Scholar
  13. 13.
    Haass, M, Hock, M, Richardt, G, Schömig, A. Neuropeptide Y differentiates between exocytotic and nonexocytotic noradrenaline release in guinea-pig heart. Naunyn-Schmiedebergs Arch Pharmacol 1989;340:509–515.Google Scholar
  14. 14.
    Haass, M, Förster, C, Richardt, G, Kranzhöfer, R, Schömig, A. Role of calcium channels and protein kinase C for release of norepinephrine and neuropeptide Y. Am J Physiol 1990; 259 (Regulatory Integrative Comp Physiol 28):R925-R930.Google Scholar
  15. 15.
    Haass, M, Richardt, G, Brenn, T, Schömig, E, Schömig, A. Nicotine-induced release of noradrenaline and neuropeptide Y in guinea-pig heart: Role of calcium channels and protein kinase C. Naunyn-Schmiedebergs Arch Pharmacol 1991; 344:527–531.Google Scholar
  16. 16.
    Haass, M, Richardt, G, Schömig, A. Potentiation of potassium-evoked noradrenaline and neuropeptide Y co-release by cardiac energy depletion: Role of calcium channels and sodium-proton exchange. Naunyn-Schmiedebergs Arch Pharmacol 1992;346:410–418.Google Scholar
  17. 17.
    Haass, M, Serf, C, Krüger, C, Haunstetter, A, Vahl, Ch-F, Kübler, W. Digitalis glycosides stimulate norepinephrine release from the human heart by a dual mechanism of action (abstr). Eur Heart J 1994;15(Suppl):173.Google Scholar
  18. 18.
    Haeusler, G, Thoenen, H, Haefely, W, Huerlimann, A. Electrical events in cardiac adrenergic nerves and noradrenaline release from the heart induced by acetylcholine and KCl. Naunyn-Schmiedebergs Arch Pharmacol Exp Path 1968; 261:389–411.Google Scholar
  19. 19.
    Hallstrom, AP, Cobb, LA, Ray, R. Smoking as a risk factor for recurrence of sudden cardiac arrest. N Engl J Med 1986; 314:271–275.Google Scholar
  20. 20.
    Haunstetter, A, Haass, M, Yi, X, Krüger, C, Kübler, W. Muscarinic inhibition of cardiac norepinephrine and neuropeptide Y release during ischaemia and reperfusion. Am J Physiol 1994;267 (Regulat Integrat Physiol 36):R1552-R1558.Google Scholar
  21. 21.
    Hernandez-Cruz, A, Salia, F, Adams, PR. Subcellular calcium transients visualized by confocal microscope in a voltage-clamped neuron. Science 1990;247:858–862.Google Scholar
  22. 22.
    Kao, L-S, Schneider, AS. Calcium mobilization and catecholamine secretion in adrenal chromaffin cells. J Biol Chem 1986;261:4881–4888.Google Scholar
  23. 23.
    Karlin, A. Structure of nicotinic acetylcholine receptors. Curr Opin Neurobiol 1993;3:299–309.Google Scholar
  24. 24.
    Kilpatrick, DL, Slepetis, R, Kirshner, N. Ion channels and membrane potential in stimulus-secretion coupling in adrenal medulla cells. J Neurochem 1981;36:1245–1255.Google Scholar
  25. 25.
    Klein, LW, Ambrose, J, Pichard, A, Holt, J, Gorlin, R, Teichholz, LE. Acute coronary hemodynamic response to cigarette smoking in patients with coronary artery disease. J Am Coll Cardiol 1984;3:879–886.Google Scholar
  26. 26.
    Knopf, H, Theissing, R, Hirche, H. Continuous determination of extracellular space and changes in K+, Na+, Ca2+, and H+ during global ischemia in isolated rat hearts. J Mol Cell Cardiol 1990;22:1259–1272.Google Scholar
  27. 27.
    Kottke, TE. Smoking cessation therapy for the patient with heart disease. J Am Coll Cardiol 1993;22:1168–1169.Google Scholar
  28. 28.
    Krüger, C, Haunstetter, A, Gerber, S, Serf, C, Kaufmann, A, Kübler, W, Haass, M. Nicotine-induced exocytotic norepinephrine release in guinea-pig heart, human atrium and bovine adrenal chromaffin cells: Modulation by single components of ischemia. J Mol Cell Cardiol 1995;27:1491–1506.Google Scholar
  29. 29.
    Kübler, W, Haass, M. Cardioprotection: Definition, classification, and fundamental principles. Heart 1996;75:330–333.Google Scholar
  30. 30.
    Kurz, T, Richard, G, Hagl, S, Seyfarth, M, Schömig, A. Two different mechanisms of noradrenaline release during normoxia and simulated ischemia in human cardiac tissue. J Mol Cell Cardiol 1995;27:1161–1172.Google Scholar
  31. 31.
    Löffelholz, K. Autoinhibition of nicotinic release of noradrenaline from postganglionic sympathetic nerves. Naunyn-Schmiedebergs Arch Pharmacol 1970;267:49–63.Google Scholar
  32. 32.
    Löffelholz, K. Release induced by nicotinic agents. In: Paton, DM, ed. The Release of Catecholamines from Adrenergic Neurons. Oxford: Pergamon Press, 1979:275–301.Google Scholar
  33. 33.
    McKenna, WJ, Chew, CY, Oakley, CM. Myocardial infarction with normal coronary angiogram: Possible mechanisms of smoking risk in coronary artery disease. Br Heart J 1980; 43:493–498.Google Scholar
  34. 34.
    Moliterno, DJ, Willard, JE, Lange, RA, et al. Coronary-artery vasoconstriction induced by cocaine, cigarette smoking, or both. N Engl J Med 1994;330:454–459.Google Scholar
  35. 35.
    Nooney, JM, Peters, JA, Lambert, JJ. A patch clamp study of the nicotinic acetylcholine receptor of adrenomedullary chromaffin cells in culture. J Physiol 1992;455:503–527.Google Scholar
  36. 36.
    Richardt, G, Haass, M, Neeb, S, Hock, M, Lang, RE, Schömig, A. Nicotine-induced release of noradrenaline and neuropeptide Y in guinea pig heart. Klin Wochenschr 1988;66(Suppl XI):21–27.Google Scholar
  37. 37.
    Richardt, G, Brenn, T, Seyfarth, M, Haass, M, Schömig, E, Schömig, A. Dual effect of nicotine on cardiac noradrenaline release during metabolic blockade. Basic Res Cardiol 1994; 89:524–534.Google Scholar
  38. 38.
    Robertson, D, Tseng, C-J, Appalsamy, M. Smoking and mechanisms of cardiovascular control. Am Heart J 1988; 115:258–262.Google Scholar
  39. 39.
    Role, LW. Diversity in primary structure and function of neuronal nicotinic acetylcholine receptor channels. Curr Opinion Neurobiol 1992;4:254–262.Google Scholar
  40. 40.
    Rosenberg, J, Benowitz, NL, Gacob, P, Wilson, M. Disposition kinetics and effects of intravenous nicotine. Clin Pharmacol Ther 1980;28:517–522.Google Scholar
  41. 41.
    Rosenberg, L, Kaufman, DW, Helmrich, SP, Shapiro, S. The risk of myocardial infarction after quitting smoking in men under 55 years of age. N Engl J Med 1985;313:1511–1514.Google Scholar
  42. 42.
    Rosenberg, L, Palmer, JR, Shapiro, S. Decline in the risk of myocardial infarction among women who stop smoking. N Engl J Med 1990;322:213–217.Google Scholar
  43. 43.
    Sargent, PB. The diversity of neuronal nicotinic acetylcholine receptors. Ann Rev Neurosci 1993;16:403–443.Google Scholar
  44. 44.
    Schömig, A, Dart, AM, 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;55:689–701.Google Scholar
  45. 45.
    Schömig, A, Haass, M, Richardt, G. Catecholamines and arrhythmias in acute myocardial ischemia. Eur Heart J 1991; 12(Suppl F):38–47.Google Scholar
  46. 46.
    Seyfarth, M, Feng, Y, Hagl, S, Sebening, F, Richardt, G, Schömig, A. Effect of myocardial ischemia on stimulation-evoked noradrenaline release. Modulated neurotransmission in rat, guinea pig, and human cardiac tissue. Circ Res 1993;73:496–502.Google Scholar
  47. 47.
    Sugiishi, M, Takatsu, F. Cigarette smoking is a major risk factor for coronary spasm. Circulation 1993;87:76–69.Google Scholar
  48. 48.
    Su, C, Bevan, JA. Blockade of the nicotine-induced norepinephrine release by cocaine, phenoxybenzamine and desipramine. J Pharmacol Exp Ther 1970;175:533–540.Google Scholar
  49. 49.
    Tsien, RY. Fluorescent probes of cell signalling. Ann Rev Neurosci 1989;12:227–253.Google Scholar
  50. 50.
    Unwin, N. Neurotransmitter action: Opening of ligandgated ion channels. Cell 1993;72(Suppl):31–41.Google Scholar
  51. 51.
    Verninino, S, Amador, M, Luetje, CW, Patrick, J, Dani, JA. Calcium modulation and high calcium permeability of neuronal nicotinic acetylcholine receptors. Neuron 1992;8: 127–134.Google Scholar
  52. 52.
    Wada, A, Takara, H, Izumi, F, Kobashi, H, Yanagihara, N. Influx of 22Na through acetylcholine receptor-associated Na channels: Relationship between 22Na influx, 45Ca influx and secretion of catecholamines in cultured bovine adrenal medulla cells. Neuroscience 1985;15:283–292.Google Scholar
  53. 53.
    Westfall, TC, Brasted, M. The mechanism of action of nicotine on adrenergic neurons in the perfused guinea-pig heart. J Pharmacol Exp Ther 1972;182:409–418.Google Scholar
  54. 54.
    Willett, WC, Green, A, Stampfer, MJ, et al. Relative and absolute excess risks of coronary heart disease among women who smoke. N Engl J Med 1987;317:1303–1309.Google Scholar
  55. 55.
    Winniford, MD, Wheelan, KR, Kremers, MS, et al. Smoking-induced coronary vasoconstriction in patients with atherosclerotic coronary artery disease: Evidence for adrenergically mediated alterations in coronary artery tone. Circulation 1986;73:662–667.Google Scholar

Copyright information

© Kluwer Academic Publishers 1996

Authors and Affiliations

  • Markus Haass
    • 1
  • Wolfgang Kübler
    • 1
  1. 1.Abteilung Innere Medizin III (Kardiologie, Angiologie und Pulmologie). Medical ClinicUniversity of HeidelbergHeidelbergGermany
  2. 2.Abteilung Innere Medizin III, Medical ClinicUniversity of HeidelbergHeidelbergGermany

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