Skip to main content
PMC home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1988 Dec;95(4):1241–1254. doi: 10.1111/j.1476-5381.1988.tb11761.x

Effects of the myocardial-selective alpha 1-adrenoceptor antagonist UK-52046 and atenolol, alone and in combination, on experimental cardiac arrhythmias in dogs.

A G Uprichard 1, D W Harron 1, R Wilson 1, R G Shanks 1
PMCID: PMC1854280  PMID: 2905912

Abstract

1. Adrenaline-induced arrhythmias in anaesthetized dogs respired with halothane were attenuated in 3 groups of 6 dogs by either UK-52046, 3.8 +/- 1.4 micrograms kg-1 (mean +/- s.e.mean), atenolol 14.6 +/- 2.1 micrograms kg-1, or a combination containing equal amounts of the two drugs of 0.36 +/- 0.1 microgram kg-1. The pressor response to adrenaline was reduced (P less than 0.01) by UK-52046 but not by atenolol or the combination of both drugs. 2. In a group of 6 dogs with multiventricular ectopic beats 24 h after coronary artery ligation (CAL), UK-52046, 32 micrograms kg-1, increased the number of sinus beats in each 5 min period from 137 +/- 47 to 662 +/- 99 (P less than 0.01); this was associated with a significant (P less than 0.01) fall in blood pressure. Atenolol in doses of up to 800 micrograms kg-1 had no effect. 3. UK-52046, 3.7 +/- 1.4 micrograms kg-1, prevented adrenaline-induced arrhythmias 3-4 days after CAL in 6/6 conscious dogs; atenolol in doses of up to 100 micrograms kg-1 produced an 84.4 +/- 7.4% reduction in the number of ventricular ectopic beats. A combination containing 3.7 +/- 1.1 micrograms kg-1 of each drug prevented the arrhythmia in 6/6 dogs. The pressor response to adrenaline was attenuated (P less than 0.05) by UK-52046, but resting blood pressure was unaffected by the different treatments. An increase (P less than 0.01) in heart rate was associated with both UK-52046 and the combination. 4. Neither UK-52046 (doses up to 64 micrograms kg-1) nor atenolol (up to 800 micrograms kg-1) had any effect upon ouabain-induced arrhythmias in 2 groups of 6 anaesthetized dogs. 5. In a study of the early (1a/1b) arrhythmias of acute myocardial ischaemia, the total number of ventricular ectopic beats occurring within 30 min of CAL was not reduced by 4 micrograms kg-1 UK-52046 but fell (P less than 0.01 compared with placebo) after 8 micrograms kg-1 [median values with ranges for placebo, 4 micrograms kg-1 and 8 micrograms kg-1 respectively 190 (4-674), 246 (9-1204) and 12 (1-154)]. Both doses of UK-52046 were associated with significant falls in blood pressure. 6. The arrhythmias produced by programmed electrical stimulation were studied in 2 groups of 6 conscious dogs, 7-30 days after CAL. With placebo, 4/6 dogs remained unchanged and 2 died: UK-52046 prevented arrhythmias in 2/6, 2 remained unchanged and 2 died (P = 0.29).(ABSTRACT TRUNCATED AT 400 WORDS)

Full text

PDF
1241

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alkondon M., Ray A., Sen P. Role of vagus in the antagonism of ouabain induced arrhythmias in dogs by beta-adrenoceptor antagonists and related drugs. J Pharm Pharmacol. 1984 Oct;36(10):702–704. doi: 10.1111/j.2042-7158.1984.tb04851.x. [DOI] [PubMed] [Google Scholar]
  2. Allen J. D., Shanks R. G. Effects of tiprenolol, practolol and propranolol on experimental ventricular tachyarrhythmias. Br J Pharmacol. 1974 Jun;51(2):179–185. doi: 10.1111/j.1476-5381.1974.tb09645.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Allen J. D., Shanks R. G., Zaidi S. A. Effects of lignocaine and propranolol on experimental cardiac arrhythmias. Br J Pharmacol. 1971 May;42(1):1–12. doi: 10.1111/j.1476-5381.1971.tb07081.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Benfey B. G., Elfellah M. S., Ogilvie R. I., Varma D. R. Anti-arrhythmic effects of prazosin and propranolol during coronary artery occlusion and re-perfusion in dogs and pigs. Br J Pharmacol. 1984 Jul;82(3):717–725. doi: 10.1111/j.1476-5381.1984.tb10811.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Benfey B. G. Function of myocardial alpha-adrenoceptors. Life Sci. 1982 Jul 12;31(2):101–112. doi: 10.1016/0024-3205(82)90421-0. [DOI] [PubMed] [Google Scholar]
  6. Corr P. B., Shayman J. A., Kramer J. B., Kipnis R. J. Increased alpha-adrenergic receptors in ischemic cat myocardium. A potential mediator of electrophysiological derangements. J Clin Invest. 1981 Apr;67(4):1232–1236. doi: 10.1172/JCI110139. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Damato A. N., Lau S. H., Bobb G. A. Digitalis-induced bundle-branch ventricular tachycardia studied by electrode catheter recordings of the specialized conducting tissues of the dog. Circ Res. 1971 Jan;28(1):16–22. doi: 10.1161/01.res.28.1.16. [DOI] [PubMed] [Google Scholar]
  8. Davis L. D., Temte J. V., Murphy Q. R. Epinephrine--cyclopropane effects on Purkinje fibers. Anesthesiology. 1969 Apr;30(4):369–377. doi: 10.1097/00000542-196904000-00004. [DOI] [PubMed] [Google Scholar]
  9. Dukes I. D., Vaughan Williams E. M. Electrophysiological effects of alpha-adrenoceptor antagonists in rabbit sino-atrial node, cardiac Purkinje cells and papillary muscles. Br J Pharmacol. 1984 Oct;83(2):419–426. doi: 10.1111/j.1476-5381.1984.tb16502.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Ebert P. A., Vanderbeek R. B., Allgood R. J., Sabiston D. C., Jr Effect of chronic cardiac denervation on arrhythmias after coronary artery ligation. Cardiovasc Res. 1970 Apr;4(2):141–147. doi: 10.1093/cvr/4.2.141. [DOI] [PubMed] [Google Scholar]
  11. El-Sherif N., Hope R. R., Scherlag B. J., Lazzara R. Re-entrant ventricular arrhythmias in the late myocardial infarction period. 2. Patterns of initiation and termination of re-entry. Circulation. 1977 May;55(5):702–719. doi: 10.1161/01.cir.55.5.702. [DOI] [PubMed] [Google Scholar]
  12. Friedman P. L., Stewart J. R., Wit A. L. Spontaneous and induced cardiac arrhythmias in subendocardial Purkinje fibers surviving extensive myocardial infarction in dogs. Circ Res. 1973 Nov;33(5):612–626. doi: 10.1161/01.res.33.5.612. [DOI] [PubMed] [Google Scholar]
  13. Govier W. C. A positive inotropic effect of phenylephrine mediated through alpha adrenergic receptors. Life Sci. 1967 Jul 1;6(13):1361–1365. doi: 10.1016/0024-3205(67)90182-8. [DOI] [PubMed] [Google Scholar]
  14. Govier W. C. Myocardial alpha adrenergic receptors and their role in the production of a positive inotropic effect by sympathomimetic agents. J Pharmacol Exp Ther. 1968 Jan;159(1):82–90. [PubMed] [Google Scholar]
  15. HARRIS A. S. Delayed development of ventricular ectopic rhythms following experimental coronary occlusion. Circulation. 1950 Jun;1(6):1318–1328. doi: 10.1161/01.cir.1.6.1318. [DOI] [PubMed] [Google Scholar]
  16. Hashimoto K., Hashimoto K. The mechanism of sensitization of the ventricle to epinephrine by halothane. Am Heart J. 1972 May;83(5):652–658. doi: 10.1016/0002-8703(72)90405-x. [DOI] [PubMed] [Google Scholar]
  17. Josephson M. E., Horowitz L. N., Farshidi A., Kastor J. A. Recurrent sustained ventricular tachycardia. 1. Mechanisms. Circulation. 1978 Mar;57(3):431–440. doi: 10.1161/01.cir.57.3.431. [DOI] [PubMed] [Google Scholar]
  18. Kaplinsky E., Ogawa S., Balke C. W., Dreifus L. S. Two periods of early ventricular arrhythmia in the canine acute myocardial infarction model. Circulation. 1979 Aug;60(2):397–403. doi: 10.1161/01.cir.60.2.397. [DOI] [PubMed] [Google Scholar]
  19. LUCCHESI B. R. THE EFFECTS OF PRONETHALOL AND ITS DEXTRO ISOMER UPON EXPERIMENTAL CARDIAC ARRHYTHMIAS. J Pharmacol Exp Ther. 1965 Apr;148:94–99. [PubMed] [Google Scholar]
  20. Langer S. Z. Sixth gaddum memorial lecture, National Institute for Medical Research, Mill Hill, January 1977. Presynaptic receptors and their role in the regulation of transmitter release. Br J Pharmacol. 1977 Aug;60(4):481–497. doi: 10.1111/j.1476-5381.1977.tb07526.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. MALING H. M., COHN V. H., Jr, HIGHMAN B. The effects of coronary occlusion in dogs treated with reserpine and in dogs treated with phenoxybenzamine. J Pharmacol Exp Ther. 1959 Nov;127:229–235. [PubMed] [Google Scholar]
  22. MALING H. M., MORAN N. C. Ventricular arrhythmias induced by sympathomimetic amines in unanesthetized dogs following coronary artery occlusion. Circ Res. 1957 Jul;5(4):409–413. doi: 10.1161/01.res.5.4.409. [DOI] [PubMed] [Google Scholar]
  23. Maze M., Smith C. M. Identification of receptor mechanism mediating epinephrine-induced arrhythmias during halothane anesthesia in the dog. Anesthesiology. 1983 Oct;59(4):322–326. doi: 10.1097/00000542-198310000-00009. [DOI] [PubMed] [Google Scholar]
  24. Miletich D. J., Khan A., Albrecht R. F., Jozefiak A. Use of heart cell cultures as a tool for the evaluation of halothane arrhythmia. Toxicol Appl Pharmacol. 1983 Sep 15;70(2):181–187. doi: 10.1016/0041-008x(83)90093-5. [DOI] [PubMed] [Google Scholar]
  25. ROBERTS J., ITO R., REILLY J., CAIROLI V. J. INFLUENCE OF RESERPINE AND BETA TM 10 ON DIGITALIS-INDUCED VENTRICULAR ARRHYTHMIA. Circ Res. 1963 Aug;13:149–158. doi: 10.1161/01.res.13.2.149. [DOI] [PubMed] [Google Scholar]
  26. Rosen M. R., Gelband H., Merker C., Hoffman B. F. Mechanisms of digitalis toxicity. Effects of ouabain on phase four of canine Purkinje fiber transmembrane potentials. Circulation. 1973 Apr;47(4):681–689. doi: 10.1161/01.cir.47.4.681. [DOI] [PubMed] [Google Scholar]
  27. SOMANI P., LUM B. K. THE ANTIARRHYTHMIC ACTIONS OF BETA ADRENERGIC BLOCKING AGENTS. J Pharmacol Exp Ther. 1965 Feb;147:194–204. [PubMed] [Google Scholar]
  28. Scherlag B. J., el-Sherif N., Hope R., Lazzara R. Characterization and localization of ventricular arrhythmias resulting from myocardial ischemia and infarction. Circ Res. 1974 Sep;35(3):372–383. doi: 10.1161/01.res.35.3.372. [DOI] [PubMed] [Google Scholar]
  29. Schümann H. J., Wagner J., Knorr A., Reidemeister J. C., Sadony V., Schramm G. Demonstration in human atrial preparations of alpha-adrenoceptors mediating positive inotropic effects. Naunyn Schmiedebergs Arch Pharmacol. 1978 May;302(3):333–336. doi: 10.1007/BF00508304. [DOI] [PubMed] [Google Scholar]
  30. Sharma A. D., Saffitz J. E., Lee B. I., Sobel B. E., Corr P. B. Alpha adrenergic-mediated accumulation of calcium in reperfused myocardium. J Clin Invest. 1983 Sep;72(3):802–818. doi: 10.1172/JCI111051. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Sheridan D. J., Culling W. Electrophysiological effects of alpha-adrenoceptor stimulation in normal and ischemic myocardium. J Cardiovasc Pharmacol. 1985;7 (Suppl 5):S55–S60. doi: 10.1097/00005344-198500075-00012. [DOI] [PubMed] [Google Scholar]
  32. Sheridan D. J., Penkoske P. A., Sobel B. E., Corr P. B. Alpha adrenergic contributions to dysrhythmia during myocardial ischemia and reperfusion in cats. J Clin Invest. 1980 Jan;65(1):161–171. doi: 10.1172/JCI109647. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Uprichard A. C., Allen J. D., Harron D. W. Effects of tocainide enantiomers on experimental arrhythmias produced by programmed electrical stimulation. J Cardiovasc Pharmacol. 1988 Feb;11(2):235–241. [PubMed] [Google Scholar]
  34. VASSALLE M., GREENSPAN K., HOFFMAN B. F. AN ANALYSIS OF ARRHYTHMIAS INDUCED BY OUABAIN IN INTACT DOGS. Circ Res. 1963 Aug;13:132–148. doi: 10.1161/01.res.13.2.132. [DOI] [PubMed] [Google Scholar]
  35. Vaughan Williams E. M. Cardiac electrophysiological effects of selective adrenoceptor stimulation and their possible roles in arrhythmias. J Cardiovasc Pharmacol. 1985;7 (Suppl 5):S61–S64. doi: 10.1097/00005344-198500075-00013. [DOI] [PubMed] [Google Scholar]
  36. WILLIAMS E. M., SEKIYA A. Prevention of arrhythmias due to cardiac glycosides by block of sympathetic beta receptors. Lancet. 1963 Feb 23;1(7278):420–421. doi: 10.1016/s0140-6736(63)92306-7. [DOI] [PubMed] [Google Scholar]
  37. Watanabe A. M., Hathaway D. R., Besch H. R., Jr, Farmer B. B., Harris R. A. alpha-Adrenergic reduction of cyclic adenosine monophosphate concentrations in rat myocardium. Circ Res. 1977 Jun;40(6):596–602. doi: 10.1161/01.res.40.6.596. [DOI] [PubMed] [Google Scholar]
  38. Wilber D. J., Lynch J. J., Montgomery D. G., Lucchesi B. R. Alpha-adrenergic influences in canine ischemic sudden death: effects of alpha 1-adrenoceptor blockade with prazosin. J Cardiovasc Pharmacol. 1987 Jul;10(1):96–106. doi: 10.1097/00005344-198707000-00014. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES