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. 1992 Aug;106(4):900–905. doi: 10.1111/j.1476-5381.1992.tb14432.x

Blockade of Na+ current by promethazine in guinea-pig ventricular myocytes.

H Tanaka 1, Y Habuchi 1, M Nishimura 1, N Sato 1, Y Watanabe 1
PMCID: PMC1907677  PMID: 1327391

Abstract

1. To elucidate the antiarrhythmic mechanism of promethazine, its effects on the fast Na+ current (INa) were examined in single guinea-pig ventricular myocytes by whole-cell voltage clamp methods. 2. Promethazine blocked INa with a KD of 42.6 microM and Hill's coefficient of 1.1 at a holding potential of -140 mV. 3. The INa blockade was enhanced at a less negative holding potential of -80 mV with a change of KD to 4.4 microM. Although 10 microM promethazine did not change the inactivation time constants of INa, it shifted the steady-state inactivation curve (h infinity curve) toward more negative potentials by 19.5 mV with the slope factor unaffected. 4. Double pulse experiments revealed that the development of blockade followed two-exponential functions having time constants of 7 and 220 ms at -20 mV. 5. Promethazine slowed the repriming of INa. This was associated with the development of slow phase having a time constant of 1160 +/- 59 ms. 6. Promethazine produced a profound use-dependent block when the cell was repeatedly stimulated with interpulse intervals shorter than 1 s. However, short pulses of 2 ms duration hardly produced such a use-dependent block. Hence, open channel blockade is considered to play a minor role in the promethazine action on INa. 7. These results suggest that promethazine blocks cardiac INa in a manner similar to class I antiarrhythmic drugs and that this effect may account for its antiarrhythmic action.

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Selected References

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  1. Aronson C. E., Hanno E. R. Effects of promethazine on the isolated perfused rat heart. Gen Pharmacol. 1979;10(5):389–395. doi: 10.1016/0306-3623(79)90077-6. [DOI] [PubMed] [Google Scholar]
  2. Bean B. P., Cohen C. J., Tsien R. W. Lidocaine block of cardiac sodium channels. J Gen Physiol. 1983 May;81(5):613–642. doi: 10.1085/jgp.81.5.613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bezanilla F., Armstrong C. M. Inactivation of the sodium channel. I. Sodium current experiments. J Gen Physiol. 1977 Nov;70(5):549–566. doi: 10.1085/jgp.70.5.549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Buttar H. S., Frank G. B. Effects of antipsychotic drugs on action potential production in skeletal muscle. I. Chlorpromazine and promethazine. Can J Physiol Pharmacol. 1977 Jun;55(3):452–461. doi: 10.1139/y77-065. [DOI] [PubMed] [Google Scholar]
  5. Clarkson C. W., Follmer C. H., Ten Eick R. E., Hondeghem L. M., Yeh J. Z. Evidence for two components of sodium channel block by lidocaine in isolated cardiac myocytes. Circ Res. 1988 Nov;63(5):869–878. doi: 10.1161/01.res.63.5.869. [DOI] [PubMed] [Google Scholar]
  6. Davis R. S., McNeill J. H. The cardiac effects of cocaine and certain antihistamines and antidepressants. Arch Int Pharmacodyn Ther. 1973 Feb;201(2):262–279. [PubMed] [Google Scholar]
  7. DiGregorio G. J., Ruch E. Human whole blood and parotid saliva concentrations of oral and intramuscular promethazine. J Pharm Sci. 1980 Dec;69(12):1457–1459. doi: 10.1002/jps.2600691234. [DOI] [PubMed] [Google Scholar]
  8. Gupta S. C., Sharma V. N., Sharma H. L. Antiarrhythmic & antiparkinsonian activity of two new promethazine salts. Indian J Exp Biol. 1974 Nov;12(6):504–508. [PubMed] [Google Scholar]
  9. Habuchi Y., Furukawa T., Tanaka H., Tsujimura Y., Yoshimura M. Block of Na+ channels by imipramine in guinea-pig cardiac ventricular cells. J Pharmacol Exp Ther. 1991 Mar;256(3):1072–1081. [PubMed] [Google Scholar]
  10. Hamill O. P., Marty A., Neher E., Sakmann B., Sigworth F. J. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch. 1981 Aug;391(2):85–100. doi: 10.1007/BF00656997. [DOI] [PubMed] [Google Scholar]
  11. Hille B. Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction. J Gen Physiol. 1977 Apr;69(4):497–515. doi: 10.1085/jgp.69.4.497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hondeghem L. M., Katzung B. G. Time- and voltage-dependent interactions of antiarrhythmic drugs with cardiac sodium channels. Biochim Biophys Acta. 1977 Nov 14;472(3-4):373–398. doi: 10.1016/0304-4157(77)90003-x. [DOI] [PubMed] [Google Scholar]
  13. Hughes M. J., Coret I. A. On specificity of histamine receptors in the heart. Am J Physiol. 1972 Nov;223(5):1257–1262. doi: 10.1152/ajplegacy.1972.223.5.1257. [DOI] [PubMed] [Google Scholar]
  14. JOHNSON E. A. The effect of antifibrillatory drugs on the cat's heart in vivo. Br J Pharmacol Chemother. 1954 Sep;9(3):341–345. doi: 10.1111/j.1476-5381.1954.tb01690.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. MALINOW M. R., BATLLE F. F., MALAMUD B. The pharmacology of experimental ventricular arrhythmias in the rat. 1. Antihistaminic drugs. Arch Int Pharmacodyn Ther. 1955 Jun 1;102(1-2):55–64. [PubMed] [Google Scholar]
  16. NARANJO P., DE NARANJO E. B. Local anesthetic activity of some antihistamines and its relationship with the antihistaminic and anticholinergic activities. Arch Int Pharmacodyn Ther. 1958 Jan 1;113(3-4):313–335. [PubMed] [Google Scholar]
  17. Narahashi T., Tsunoo A., Yoshii M. Characterization of two types of calcium channels in mouse neuroblastoma cells. J Physiol. 1987 Feb;383:231–249. doi: 10.1113/jphysiol.1987.sp016406. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Reinhardt D., Borchard U. H1-receptor antagonists: comparative pharmacology and clinical use. Klin Wochenschr. 1982 Sep 1;60(17):983–990. doi: 10.1007/BF01716959. [DOI] [PubMed] [Google Scholar]
  19. Rigel D. F., Katona P. G. Effects of antihistamines and local anesthetics on excess tachycardia in conscious dogs. J Pharmacol Exp Ther. 1986 Jul;238(1):367–371. [PubMed] [Google Scholar]
  20. Rochette L., Yao-Kouame J., Bralet J., Opie L. H. Effects of promethazine on ischemic and reperfusion arrhythmias in rat heart. Fundam Clin Pharmacol. 1988;2(5):385–397. doi: 10.1111/j.1472-8206.1988.tb01004.x. [DOI] [PubMed] [Google Scholar]
  21. WINBURY M. M., ALWORTH B. L. Suppression of experimental atrial arrhythmias by several antihistamines. Arch Int Pharmacodyn Ther. 1959 Nov 1;122:318–322. [PubMed] [Google Scholar]

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