Clin Exp Otorhinolaryngol.  2013 Mar;6(1):12-17.

Evaluation of Thioperamide Effects Using Rat's Trachea Model

• Chiu FH
• Wang HW

Abstract

OBJECTIVES
Thioperamide is used as an antagonist to the histamine H3 receptor. During administration of the drug, the trachea may be affected via nasal or oral inhalation. This study was to determine the effects of thioperamide on the trachea of rats in vitro.
METHODS
We tested the effectiveness of thioperamide on isolated rat trachea submersed in Kreb's solution in a muscle bath. Changes in tracheal contractility in response to the application of parasympathetic mimetic agents were measured. The following assessments of thioperamide were performed: 1) effect on tracheal smooth muscle resting tension; 2) effect on contraction caused by 10(-6) M methacholine as a parasympathetic mimetic; 3) effect of the drug on electrically-induced tracheal smooth muscle contractions.
RESULTS
Thioperamide induced a significant relaxation response at a preparation concentration up to 10(-4) M. The drug also inhibited the electrical field stimulation induced spike contraction. However, thioperamide alone had a minimal effect on the basal tension of the trachea at increasing concentrations.
CONCLUSION
The study indicated that high concentrations of thioperamide might actually antagonize cholinergic receptors and block parasympathetic function of the trachea.

Keyword

Trachea; Asthma; In vitro; Thioperamide

MeSH Terms

Animals
Asthma
Baths
Contracts
Inhalation
Methacholine Chloride
Muscle, Smooth
Muscles
Piperidines
Rats
Receptors, Cholinergic
Receptors, Histamine H3
Relaxation
Trachea
Methacholine Chloride
Piperidines
Receptors, Cholinergic
Receptors, Histamine H3

Figure

• 

  Fig. 1 Schematic diagram and the actual photo of tension measurement in isolated rat tracheal smooth muscle.

• 

  Fig. 2 Tension changes in the rat trachea after the application of methacholine at various concentrations. The basal tension was 0.3 g.

• 

  Fig. 3 Effects of thioperamide on 10-6 M methacholine-induced contraction of rat trachea (n=6).

• 

  Fig. 4 Effects of thioperamide on 10-6 M methacholine-induced contraction (contraction area was calculated at 100% with no addition of thioperamide) of rat trachea. The inhibition of contraction was statically significant at 10-4 M as compared with that of the control (P< 0.01). The results are represented as the mean±SD (n=6).

• 

  Fig. 5 Effect of thioperamide on electrically-induced tracheal smooth muscle contractions (n=6).

• 

  Fig. 6 Effects of thioperamide on electrically-induced tracheal smooth muscle contractions (contraction area was calculated at 100% with no addition of thioperamide). The inhibition of spike contraction was statically significant at 10-4 M as compared with that of the control (P<0.01). The results are represented as the mean±SD (n=6).

Reference

1. Arrang JM, Garbarg M, Schwartz JC. Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor. Nature. 1983; 4. 302(5911):832–837. PMID: 6188956.

2. Bertaccini G, Coruzzi G, Poli E. Leurs R, Timmerman H, editors. Functional role of histamine H3 receptors in peripheral tissues. The histamine H₃ receptor: a target for new drugs. 1998. Amsterdam: Elsevier;p. 59–111.

3. Suzuki S, Takeuchi K, Majima Y. Localization and function of histamine H3 receptor in the nasal mucosa. Clin Exp Allergy. 2008; 9. 38(9):1476–1482. PMID: 18564330.

4. Valentine AF, Rizzo CA, Rivelli MA, Hey JA. Pharmacological characterization of histamine H3 receptors in human saphenous vein and guinea pig ileum. Eur J Pharmacol. 1999; 1. 366(1):73–78. PMID: 10064154.

5. Bratton DL, Tanaka DT, Grunstein MM. Effects of temperature on cholinergic contractility of rabbit airway muscle. J Appl Physiol. 1987; 11. 63(5):1933–1941. PMID: 3320012.

6. Gonzalez O, Santacana GE. Effect of low temperature on tracheal smooth muscle contractile and relaxing responses evoked by electrical field stimulation. P R Health Sci J. 2001; 9. 20(3):237–244. PMID: 11776725.

7. Wang HW, Wang YT, Wu CC. A modified in vitro method for studying tracheal smooth muscle response to drugs. J Med Sci. 2007; 27(5):203–206.

8. Kao CH, Chu YH, Wang HW. Effects of cetirizine on isolated rat's tracheal smooth muscle. Eur Arch Otorhinolaryngol. 2009; 5. 266(5):753–757. PMID: 18941763.

9. Yau KI, Ko FN, Chien CH. Effects of prokinetic agents on contractile responses to electrical field stimulation of isolated guinea pig trachea. J Formos Med Assoc. 1999; 8. 98(8):567–572. PMID: 10502911.

10. Yau KI, Hwang TL. The nonadrenergic noncholinergic system can modulate the effect of prokinetic agents on contractile response of isolated guinea-pig trachea segments to electrical field stimulation. J Formos Med Assoc. 2002; 10. 101(10):695–699. PMID: 12517043.

11. Schwartz JC, Arrang JM, Garbarg M, Pollard H. Plenary lecture. A third histamine receptor subtype: characterisation, localisation and functions of the H3-receptor. Agents Actions. 1990; 4. 30(1-2):13–23. PMID: 1695431.

12. Wang HW, Jackson RT. Do cholinergic neurons directly innervate nasal blood vessels? Rhinology. 1988; 6. 26(2):139–146. PMID: 3175457.

13. James AL, Pare PD, Moreno RH, Hogg JC. Quantitative measurement of smooth muscle shortening in isolated pig trachea. J Appl Physiol. 1987; 10. 63(4):1360–1365. PMID: 3693169.

14. Bakker RA, Leurs R. Seifert R, Wieland T, editors. Constitutively active histamine receptors. G protein-coupled receptors as drug targets: analysis of activation and constitutive activity. 2005. Weinheim: Wiley-VCH;p. 195–222.

15. Ash AS, Schild HO. Receptors mediating some actions of histamine. Br J Pharmacol Chemother. 1966; 8. 27(2):427–439. PMID: 4381779.

16. Black JW, Duncan WA, Durant CJ, Ganellin CR, Parsons EM. Definition and antagonism of histamine H₂-receptors. Nature. 1972; 4. 236(5347):385–390. PMID: 4401751.

17. Arrang JM, Garbarg M, Lancelot JC, Lecomte JM, Pollard H, Robba M, et al. Highly potent and selective ligands for histamine H3-receptors. Nature. 1987; 5. 327(6118):117–123. PMID: 3033516.

18. Passani MB, Lin JS, Hancock A, Crochet S, Blandina P. The histamine H3 receptor as a novel therapeutic target for cognitive and sleep disorders. Trends Pharmacol Sci. 2004; 12. 25(12):618–625. PMID: 15530639.

19. Witkin JM, Nelson DL. Selective histamine H3 receptor antagonists for treatment of cognitive deficiencies and other disorders of the central nervous system. Pharmacol Ther. 2004; 7. 103(1):1–20. PMID: 15251226.

20. Amaral MM, Alvarez CA, Langellotti C, Jancic C, Salamone G, Geffner J, et al. Thioperamide induces CD4 CD25 Foxp3 regulatory T lymphocytes in the lung mucosa of allergic mice through its action on dendritic cells. J Asthma Allergy. 2011; 4:93–102. PMID: 22034573.

21. Hansel TT, Barnes PJ, editors. New drugs for asthma, allergy and COPD. 2001. Basel: Karger.

22. Cardell LO, Edvinsson L. Characterization of the histamine receptors in the guinea-pig lung: evidence for relaxant histamine H3 receptors in the trachea. Br J Pharmacol. 1994; 2. 111(2):445–454. PMID: 7911715.

23. Ichinose M, Stretton CD, Schwartz JC, Barnes PJ. Histamine H3-receptors inhibit cholinergic neurotransmission in guinea-pig airways. Br J Pharmacol. 1989; 5. 97(1):13–15. PMID: 2541854.