Drugs

, Volume 29, Supplement 3, pp 1–10 | Cite as

Amiodarone

Biochemical Aspects and Haemodynamic Effects
  • J. P. Gagnol
  • C. Devos
  • M. Clinet
  • P. Nokin
Article

Summary

The mechanisms underlying the non-competitive β-antagonistic properties of amiodarone were investigated, and the haemodynamic responses to exercise following the administration of oral amiodarone or intravenous propranolol were compared in dogs with a healed myocardial infarction submitted to a graded treadmill exercise

In radioligand binding studies, amiodarone, up to 10 μmol/L did not compete with 125I-iodocyanopindolol for binding to rat heart β-adrenoceptors, Exposure of cardiac membranes to greater concentrations of amiodarone induced a significant decrease in the number of β-adrenoceptors without affecting their affinity for 125I-iodocyanopindolol, Similar results were observed ex vivo, in rats after single or multiple dose administration, When added in vitro to rat heart membranes, amiodarone non-competitively inhibited the activation of adenylate cyclase by isoprenaline, glucagon and secretin, Stimulation of adenylate cyclase by those agents which act at more internal sites in the sarcolemmal membrane such as GppNHp, sodium fluoride or forskolin, was much less affected by amiodarone

In dogs performing at a submaximal work level, amiodarone significantly reduced heart rate and tended to increase coronary flow and to reduce left ventricular end-diastolic pressure, but did not affect left ventricular dP/dt, During submaximal exercise, propranolol had similar effects on heart rate, but dramatically reduced myocardial contractility

Keywords

Amiodarone Adenylate Cyclase Secretin Isoprenaline Haemodynamic Effect 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Aarons, R,D, and Molinoff, P,B,: Changes in the density of betaadrenergic receptors in rat lymphocytes, heart and lungs after chronic treatment with propranolol, Journal of Pharmacology and Experimental Therapeutics 221: 439–443 (1982)PubMedGoogle Scholar
  2. Bellotti, G,; Silva, L,; Filho, A,E,; Ratti, M,; V, De Morales, A,; Ramires, J,A,; Da Luz, P, and Peleggi, F,: Haemodynamic effects of intravenous administration of amiodarone in congestive heart failure from chronic Chaga’s disease, American Journal of Cardiology 52: 1046–1049 (1983)PubMedCrossRefGoogle Scholar
  3. Boudoulus, H,; Lewis R,P,; Kates R,E, and Lalamangas, G,: Hypersensitivity to adrenergic stimulation after propranolol withdrawal in normal subjects, Annals of Internal Medicine 87: 433–436(1977)Google Scholar
  4. Burger, A,: Dinichert, D,; Nicod P,; Jenny M,; Lemarchand-Berand T, and Vallotton M,B,: Effect of amiodarone on serum triiodothyronine, reverse triiodothyronine, thyroxin and thyrotropin, Journal of Clinical Investigation 58: 255–259 (1976)PubMedCrossRefGoogle Scholar
  5. Chatelain, P,: Robbercht, P,; De Neef, P,; Deschodt-Lanckman, M,; Konig W, and Christophe J,: Secretin and VIP-stimulated adenylate cyclase from rat heart, 1, General properties and structural requirements for enzyme activation, Pflügers Archiv 389: 21–27(1980)PubMedCrossRefGoogle Scholar
  6. Charlier, R,: Cardiac actions in the dog of a new antagonist of adrenergic excitation which does not produce competitive blockade of adrenoceptors, British Journal of Pharmacology 39: 668–674(1970)PubMedCrossRefGoogle Scholar
  7. Charlier, R,; Delaunois G, and Bauthier, J,: Incidence de l’amiodarone et de quelques agents beta-bloquants sur la contractilitè du ventricule gauche chez le chien, Journal de Pharmacologie 4: 57–68 (1973)Google Scholar
  8. Charlier, R,: Deltour, G,; Baudine, A, and Chaillet, F,: Pharmacology of amiodarone, an anti-anginal drug with a new biological profile, Arzneimittel-Forschung 18: 1408–1417 (1968)PubMedGoogle Scholar
  9. Cote, P,; Bourassa M,G,; Delaye J,; Janin A,; Froment R, and David P,: Effects of amiodarone on cardiac and coronary hemodynamics and on myocardial metabolism in patients with coronary artery disease, Circulation 59: 6 (1979)CrossRefGoogle Scholar
  10. De Boer, L,; Nosta J,; Kloner R, and Braunwald E,: Studies of amiodarone during experimental myocardial infarction: Beneficial effects on hemodynamics and infarct size, Circulation 65: 508–512 (1982)CrossRefGoogle Scholar
  11. Gagnol J,P,; Billman G,E,; Schwanz P,J, and Stone H,L,: Enhanced sympathetic activity during exercise in post myocardial infarction dogs at high risk for sudden death, Federation Proceedings 43: 626 (1984)Google Scholar
  12. Gagnol, J,P,; Schwartz P,J,; Billman G,E, and Stone H,L,: Hemodynamic response to exercise following oral administration of amiodarone, Federation Proceedings 42(5): 1289 (1983)Google Scholar
  13. Glaubiger G, and Lefkowitz R,J,: Elevated beta-adrenergic receptor number after chronic propranolol treatment, Biochemical and Biophysical Research Communications 78: 720–725 (1977)PubMedCrossRefGoogle Scholar
  14. Gould, W,; Zeiler R,; Barreca P,; El-Sherif N,: Hypotensive action of commercial intravenous amiodarone and polysorbate 80 in dogs, Journal of Cardiovascular Pharmacology 4: 375–380 (1982)CrossRefGoogle Scholar
  15. Haffajee, C,I,; Love J,C,; Albert J,S,; Asdourian G,K,, and Sloan K,C,: Efficacy and safety of long term amiodarone in treatment of cardiac arrhythmias: Dosage experience, American Heart Journal 106(4): part 2 (1983)Google Scholar
  16. Lefkowitz, R,J,: Clinical physiology of adrenergic receptor regulation, American Journal of Physiology 243: E43–E47 (1981)Google Scholar
  17. Lefkowitz, R,J,; Stadel J,M, and Caron M,G,: Adenylate cyclasecoupled beta-adrenergic receptors: Structure and mechanisms of activation and desensitization, Annual Review of Biochemistry 52: 159–186(1983)PubMedCrossRefGoogle Scholar
  18. Lowry, O,H,; Rosebrough N,J,; Farr A,L, and Randall, R,J,: Protein measurement with the Folin phenol reagent, Journal of Biological Chemistry 193: 265–267 (1951)PubMedGoogle Scholar
  19. McConnanghey, M,M,; Jones, L,R,; Watanabe, A,M,; Besch, H,R,; Williams, L,T, and Lefkowitz, R,J,: Thyroxine and propylthiouracil effects on alpha and beta adrenergic receptor number ATPase activities and sialic acid content of rat cardiac membrane vesicles, Journal of Cardiovascular Pharmacology 1: 609–623 (1979)CrossRefGoogle Scholar
  20. Melmed, S,; Nademanee K; Reed A,W,; Hendrickson J,A,; Singh B,N, and Hershman J,M,: Hyperthroxinemia with bradycardia and normal thyrotropin secretion after chronic amiodarone administration, Journal of Clinical Endocrinology and Metabolism 53: 997–1001 (1981)PubMedCrossRefGoogle Scholar
  21. Minneman K,P,; Hegstrand L,R, and Molinoff, P,B,: The pharmacological specificity of beta-1 and beta-2 adrenergic receptors in rat heart and lung in vitro, Molecular Pharmacology 16: 21–33 (1979)PubMedGoogle Scholar
  22. Nattel, S,; Rangno R,E, and Van Loon G,: Mechanism of propranolol withdrawal phenomena, Circulation 59: 1158–1164 (1979)PubMedCrossRefGoogle Scholar
  23. Nokin, P,; Clinet M, and Schoenfeld, P,H,: Cardiac beta-adrenoceptor modulation by amiodarone, Biochemical Pharmacology 32: 2473–2477 (1983)PubMedCrossRefGoogle Scholar
  24. Ourbak, P,; Rocher R,; Aziza J,P,; Manin J,P,; Vagner D,; Leclerc M, and Maurice, P,: Effets hemodynamiques de l’injection intraveineuse de chlorhydrate d’amiodarone chez le sujet normal et le coronarien, Archives des Maladies du Coeur et des Vaisseaux 3: 293–298 (1976)Google Scholar
  25. Petta, J, and Zaccheo, V,: Comparative profile of L 3428 and other antianginal agents on caidiac hemodynamics, Journal of Pharmacology and Experimental Therapeutics 176(2): 328–338 (1371)Google Scholar
  26. Polster, P, and Broekhuysen, J,: The adrenergic antagonism of amiodarone, Biochemical Pharmacology 25: 131–134 (1976)PubMedCrossRefGoogle Scholar
  27. Remme, W,; Van Hoogenhuyze D, and Kruyssen, D,: Acute hemodynamic and anti-ischemic effects of intravenous amiodarone in man, Circulation 68: 111–280 (1983)Google Scholar
  28. Salomon, Y,; Londos C, and Rodbell, M,: A highly sensitive adenylate cyclase assay, Analytical Biochemistry 58: 541–548 (1974)PubMedCrossRefGoogle Scholar
  29. Schwartz, A,; Shen, E,; Morady, F,; Gillespie, K,; Scheinman, M, and Chatterjee, K,: Hemodynamic effects of intravenous amiodarone in patients with depressed left ventricular tachycardia, American Heart Journal 106 (4): part 2 (1983b)Google Scholar
  30. Schwartz, A,; Shen E,; Scheinman M,; Morady F, and Chatterjee K,: Hemodynamic effects of intravenous amiodarone in patients with recurrent ventricular tachycardia and depressed left ventricular function, Clinical Research 31(1): 81A (1983a)Google Scholar
  31. Schwartz, P,J,; Billman G,E,; Gagnol J,P, and Stone, H,L,: Vagal reflexes elicited by acute myocardial ischemia during exercise in dogs with a healed myocardial infarction, Federation Proceedings 43(3): 695 (1984)Google Scholar
  32. Seamon, K,B, and Daly, J,W,: Guanidine 5’-(beta 1 gamma-imido) triphosphate inhibition of forskolin-activated adenylate cyclase is mediated by the putative inhibitory guanine nucleotide regulatory protein, Journal of Biological Chemistry 257: 11591–11596(1982)PubMedGoogle Scholar
  33. Sharma, A,D, and Corr, P,B,: Modulation by amiodarone of cardiac adrenergic receptors and their electrophysiologic responsivity to catecholamines (Abstr #393), Circulation 68 (Suppl, III): 99 (1983)Google Scholar
  34. Sicart, M,; Besse P,; Choussat A, and Bricaud, H,: Action hemodynamique de l’amiodarone intra-veineuse chez l’homme, Archives des Maladies du Coeur et des Vaisseaux 3:219–227 (1977)Google Scholar
  35. Singh, B,N,: Amiodarone: Historical development and pharmacologic profile, American Heart Journal 106: 787–964 (1983)CrossRefGoogle Scholar
  36. Singh, B,N,; Jewitt D,E,; Downey J,M,; Kirt E,S, and Sonnenblick E,H,: Effects of amiodarone and L8040, novel antianginal and antiarrhythmic drugs on cardiac and coronary haemodynamics and on cardiac intracellular potentials, Clinical and Experimental Pharmacology and Physiology 3: 427–442 (1976)PubMedCrossRefGoogle Scholar
  37. Stone, L,: Effect of heart rate on left atrial systolic shortening in the dog, Journal of Applied Physiology 38: 1110–1116(1975)PubMedGoogle Scholar
  38. Trobough,G,B,; Gorham,J,R,; Greene,H,L,; Cross,B,W,; Werner, J,A,; Tutt,R,C,; Graham,E,L, and Sears,G,K,: Radionuclide evaluation of cardiac function in patients receiving amiodarone, Communication au Congres de DALLAS, Novembre 1982Google Scholar
  39. Van Hoogenhuyze D,; Van De Burgh P,; De Wilde A,; Remme W,J, and Krauss X,H,: Acute effects of intravenous amiodarone in patients with complex ventricular dysrhythmias (Abstract), American Journal of Cardiology 49: 1001 (1982)Google Scholar

Copyright information

© ADIS Press Limited 1985

Authors and Affiliations

  • J. P. Gagnol
    • 1
    • 2
  • C. Devos
    • 1
    • 2
  • M. Clinet
    • 1
    • 2
  • P. Nokin
    • 1
    • 2
  1. 1.Centre de Recherches Clin-MidySanofiMontpellier
  2. 2.Centre de Recherches Labaz-SanofiLabaz-SanofiBruxellesBelgium

Personalised recommendations