THE INVESTIGATION OF THE ACTION MECHANISM OF AMMONIUM PYRROLIDINE DITHIOCARBAMATE ON RAT AORTA SMOOTH MUSCLE CONTRACTION-RELAXATION RESPONSES

Abstract

Ammonium Pyrrolidine Dithiocarbamate (APDTC) is an inhibitor of nuclear factor kappa b (NF-κB). Beside of these function, its antitumoral, antioxidant, anticarcinogenic and antiviral properties and also apoptosis inhibiting effect in smooth muscle cells were determined. Our experiments aimed to investigate the mechanism of action of APDTC on rat aortic smooth muscle. Some adrenergic and cholinergic receptors, l-type Ca2+ channels and K+ channels were blocked in 7 different groups, and therefore the action mechanism of APDTC whether is used or not on which channels and receptors and the extent to which they are effective were aimed to be determined. The contraction-relaxation responses after the administration of APDTC, atropine, phentolamine, propranolol, nifedipine, tetraethylammonium (TEA) and mix (atropine+phentolamine+propranolol) on living state controlled with potassium chloride (KCl) and blocked nitric oxide (NO) synthesis with l-ng-nitro arginine methyl ester (L-NAME) in the pre-contraction-induced aortic preparations with phenylephrine were investigated. The obtained data were evaluated by kruskal wallis and mann-whitney u tests. APDTC created the relaxation response in the aortic smooth muscle. Cholinergic receptor blocker atropine, α-adrenergic receptor blocker fentolamine, β-adrenergic receptor blocker propranolol, l-type calcium channel blocker nifedipine and potassium channel blocker TEA did not alter the relaxation response of APDTC. In the mix group consisting of atropine+phentolamine+propranolol, APDTC created a significant contraction response. It has been determined that APDTC can be effective on these systems via different mechanisms.

Keywords

• APDTC
• aorta
• non‐adrenergic non‐cholinergic (NANC) system
• L-NAME
• phenylephrine
• adrenergic
• cholinergic
• calcium channels
• potassium channels

References

1. [1] Barrett, K.E., Barman, S.M., Boitano,S., Brooks, H., (2010), Ganong's Review of Medical Physiology, 23. Baskı, New York: McGraw-Hill Higher Education, s.110, 111 , 112, 544, 563, 564.
2. [2] https://www.sigmaaldrich.com, https://www.sigmaaldrich.com, https://www.sigmaaldrich.com,
3. [3] Parlak, N., (2009), Pirolizidin Alkaloidinin Neden Olduğu Hepatotoksisitede Nükleer Faktör Kappa B İnhibitörü Pirolidin Ditiyokarbamat’ın Koruyucu Etkinliğinin Değerlendirilmesi, Uzmanlık Tezi, Abant İzzet Baysal Üniversitesi Tıp Fakültesi, Fizyoloji Anabilim Dalı, Bolu.
4. [4] Parlaktaş, S.B., Fırat, F., Erdemir, F., (2010), Erektil Disfonksiyonunun Medikal Tedavisindeki Yeni Gelişmeler, Türk Üroloji Seminerleri, s. 1, 92-98.
5. [5] Wan, D., Wu, Q., Qu, W., Liu, G., Wang, X., (2018), Pyrrolidine Dithiocarbamate (PDTC) Inhibits DON-Induced Mitochondrial Dysfunction and Apoptosis via the NF-κB/iNOS Pathway, Oxidative Medicine and Cellular Longevity, 1324173:8.
6. [6] Kovacich, J.C., Boyle, E.M.Jr., Morgan, E.N., Canty, T.G.Jr., Farr, A.L., Caps, M.Y., Frank, N., Pohlman, T.H., Verrier, E.D., (1999), Inhibition Of The Transcriptional Activator Protein Nuclear Factor Kappa B Prevents Hemodynamic Instability Associated With The Wholebody İnflammatory Response Syndrome. J. Thorac, Cardiovasc, Surg., 118, s.154–162.
7. [7] Hagar, H.H., Medany, A.E., Eter, E.E., Arafa, M., (2007), Ameliorative Effect Of Pyrrolidinedithiocarbamate On Acetic Acid–Induced Colitis In Rats, European Journal Of Pharmacology, 554, s.69–77.
8. [8] Cao, S., Li. Q., Hou. J., Li, Z., Cao, X., Liu, X., Qin, B., ( 2019), Intrathecal TRPM8 blocking attenuates cold hyperalgesia via PKC and NF-κB signaling in the dorsal root ganglion of rats with neuropathic pain, Journal of Pain Research, 18;12:1287-1296.

9. [9] Yang, H., Ma. S., , Guo. Y., Cui. D., Yao. J.,(2019), Bidirectional Effects of Pyrrolidine Dithiocarbamate on Severe Acute Pancreatitis in a Rat Model, Dose Response, 31;17(1):1559325819825905.
10. [10] Zhang, B., Xu, J., Quan, Z., Qian, M., Liu, W., Zheng, W., Yin, F., Du, J., Zhi, Y., Song, N., (2018), Klotho Protein Protects Human Keratinocytes from UVB-Induced Damage Possibly by Reducing Expression and Nuclear Translocation of NF-κB, Medical Sciense Monitor, 24: 8583–8591.
11. [11] Sun, H, Z., Gong, X, Y., Wu, L., Wang, X, X., Nie , Y, N., Shang, R., Wang, H., Li. Y, C., Sun ,QF., Gao, PF., Bi .JX., (2018), Journal of Physıology and Pharmacology, 69, 3, 419-422.
12. [12] Berne, R.M., Levy, M.N., Koeppen, B.M., Stanton, B.A., (2008), Fizyoloji (Çeviri. Türk Fizyolojik Bilimler Derneği ), Beşinci baskı, Güneş Kitabevi, İstanbul, s. 223-358.
13. [13] Ackermann, U., (2006), Fizyoloji, (çev. Alican, İ.), İstanbul Medikal Yayıncılık, s,36, 199, 191.
14. [14] Akçay , M., (1971), Kas Fizyolojisi ders Kitabı, Güven matbaası, Ankara, s. 1-10.
15. [15] Guyton, A.C., Hall, J. E., (2007), Tıbbi Fizyoloji, ( çev. Yeğen B. Çavuşoğlu, H), Onbirinci baskı, Nobel Tıp Kitabevi, İstanbul, s. 72, 92, 94.
16. [16] Widmaier, E, P. , Raff, H. , Strong, K.T., (2004), Vander’s Human Psikology: the Mescanisms of Body Function, 10. Baskı, San Fransisco: Mc Graw- Hill Higher Education, s. 304.
17. [17] Webb, R, C., (2003), Smooth Muscle contraction and Relaxion, American physiological society, 27 (1-4):201-6.
18. [18] Barrett, K.E., Barman, S.M., Boitano,S., Brooks, H., (2010), Ganong's Review of Medical Physiology, 23.Baskı, New York: McGraw-Hill Higher Education, s.110,111,112, 544, 563, 564.
19. [19] Dökmeci, Ġ., (2000), Kısaltılmış Bilgiler ve Sınav Hazırlık Soruları, Nobel Tıp Kitabevleri, s.81, 75, 96, 248.
20. [20] Altınkurt, O., (1981), Farmakoloji I, Ankara üniversitesi Basımevi, Ankara, s. 35, 105.
21. [21] Guyton A. C., Hall, J.E., (1996) Tıbbi Fizyoloji (çev. ÇavuĢoğlu, H.), 9. Baskı, Nobel Tıp Kitabevleri, İstanbul, s. 780, 781.
22. [22] Bökesoy, T. A., Çakıvı, İ., Melli, M., (2000), Farmakoloji Ders Kitabı, Ankara: Gazi Kitabevi Yayınları, s. 46, 165, 166.
23. [23] Süzer, Ö., (2005), Premium Süzer Farmakoloji, 3. Baskı Klinisyen Kitabevleri, S.78, 65, 72.
24. [24] Niu, L.G., Zhang, M. S., Liu, Y., Xue, W. X., Liu, D. B., Zhang, J., Liang, Y. Q., (2008), Vasorelaxant effect of taurine is diminished by tetraethylammonium in rat isolated arteries, European Journal of Pharmacology, 580: 169–174.
25. [25] Bisset, D., Chung, S.H., (2008), Efficacy of external tetraethylammonium block of the KcsA potassium channel: Molecular and Brownian dynamics studies, Biochimica et Biophysica Acta (BBA) - Biomembranes, 1778(10): 2273-82.
26. [26] Ackermann, U., (2006), Fizyoloji, İstanbul Medikal Yayıncılık, s.36, 199, 191.
27. [27] Chien, K.R., (1996), Genes and physiology: molecular physiology in genetically engineered animals, J. Clin. Investigation 97:901-909.
28. [28] Blinks, J.R., (1965), Convenient apparatus for recording contractions of isolated muscle. J. Appl. Physiol. 20:755-7.
29. [29] https://www.adinstruments.com, https://www.adinstruments.com https://www.adinstruments.com
30. [30] Yin, J., Wu, M., Duan, J., Liu, G., Cui, Z., Zheng, J., Chen, S., Ren, W., Deng, J., Tan, X., Al-Dhabi, N. A., Duraipandiyan, V., Liao, P., Li, T., Yulong, Y., (2015), Pyrrolidine Dithiocarbamate Inhibits NF-KappaB Activation and Upregulates the Expression of Gpx1, Gpx4, Occludin, and ZO-1 in DSS-Induced Colitis, Applied Biochemistry and Biotechnology, 177(8): 1716-1728.
31. [31] Kan, S., Zhou, H., Jin, C., Yang, H., (2015), Effects of PDTC on NF-κB expression and apoptosis in rats with severe acute pancreatitis-associated lung injury, International journal of clinical & experimental medicine, 8(3): 3258–3270.
32. [32] Akca, S. D., (2015), L-NAME Uygulanmış Sıçan Aortunda Atorvastatin Ca, Kafeik Asit Fenil Ester, Ammonium Pyrrolidine Dithiocarbamate ve SG-Benz’ in Kasılma-Gevşeme Üzerine Etkisi, Yüksek Lisans Tezi, Dumlupınar Üniveristesi Fen Bilimleri Enstitüsü, Kütahya, s. 45.
33. [33] Hikaru Hashitani, Hiroyasu Fukuta, Emma J Dickens, and Hikaru Suzuki, (2002), Cellular mechanisms of nitric oxide-induced relaxation of corporeal smooth muscle in the guinea-pig, J. Physiol. ; 538(Pt 2): 573–581. doi: 10.1113/jphysiol.2001.013049, PMCID: PMC2290081, PMID: 11790820.
34. [34] Kwan, C. Y., Zhang, W. B., Kwan, T. K., Sakai, Y., (2003), In vitro relaxation of vascular smooth muscle by atropine: involvement of K+ channels and endothelium, Naunyn-Schmiedeberg’s Arch Pharmacol, 368: 1-9.
35. [35] Choi, Y. D., Chung, W. S., Choi, H. K., (1999), The action mechanism of relaxation effect of atropine on the isolated rabbit corpus cavernosum, The Journal of Urology, 161(6): 1976-79.
36. [36] N Satake 1, S Kiyoto, S Shibata, V Gandhi, D J Jones, M Morikawa, (1992), Possible mechanisms of inhibition with atropine against noradrenaline-induced contraction in the rabbit aorta,
37. [37] Br J Pharmacol;107(2):553-8. doi: 10.1111/j.1476-5381.1992.tb12782.x. PMID: 1330185 PMCID: PMC1907863.
38. [38] Campos, R., Justo, A.F.O., Mónica, F.Z., Cogo, J.C., Moreno, R.A., de Souza, V.B., Schenka, A.A., De Nucci, G., (2018), Electrical field-induced contractions on Crotalus durissus terrificus and Bothrops jararaca aortae are caused by endothelium-derived catecholamine, Plos one, 10;13(9):e0203573.
39. [39] [38] Campos R, Justo AFO, Mónica FZ, Cogo JC, Moreno RA, de Souza VB, et al., (2018), Electrical field-induced contractions on Crotalus durissus terrificus and Bothrops jararaca aortae are caused by endothelium-derived catecholamine. PLoS ONE 13(9): e0203573.
40. [40] Shiina, S., Kanemura, A., Suzuki, C., Yamaki, F., Obara, K., Chino, D., Tanaka, Y., (2018), β-Adrenoceptor subtypes and cAMP role in adrenaline- and noradrenaline-induced relaxation in the rat thoracic aorta, Journal of smooth muscle research, 54: 1–12.
41. [41] Shunsuke Shiina, Ayaka Kanemura, Chihiro Suzuki, Fumiko Yamaki, Keisuke Obara, Daisuke Chino, and Yoshio Tanaka, (2018), β-Adrenoceptor subtypes and cAMP role in adrenaline- and noradrenaline-induced relaxation in the rat thoracic aorta, J Smooth Muscle Res.; 54: 1–12. doi: 10.1540/jsmr.54.1. PMCID: PMC5863045. PMID: 29540622.
42. [42] Takahara, A., Nozaki, S., Ishiguro, A., Okamura, K., Cao, X., Aimoto, M., Nagasawa, Y., (2018), Selectivity of Ca2+ channel blockers for dilator actions on the isolated lower esophageal sphincter and aorta from rats, Journal of pharmacological sciences, 137(1): 98-100.
43. [43] Gomart, S., Gaudreau-Ménard, C., Jespers, P., Dilek, O. G., Hupkens, E., Hanthazi, A., Naeije, R., Melot, C., Labranche, N., Dewachter, L., Mc Entee, K., (2017), Leptin-Induced Endothelium-Independent Vasoconstriction in Thoracic Aorta and Pulmonary Artery of Spontaneously Hypertensive Rats: Role of Calcium Channels and Stores, Plos one, 12(1): e0169205.
44. [44] Rodríguez A, Frühbeck G, Gómez-Ambrosi J, Catalán V, Sáinz N, Díez J, Zalba G, Fortuño A., (2006), The inhibitory effect of leptin on angiotensin II-induced vasoconstriction is blunted in spontaneously hypertensive rats, Journal of Hypertension, 24(8):1589-1597. DOI: 10.1097/01.hjh.0000239295.17636.6e PMID: 16877962.
45. [45] de Carvalho, E. F., Nunes, A. F., Silva, N. C. B., da Silva Gomes, J. P., de Sousa, R. P., Silva, V. G., Nunes, P. H. M., Santos, R. F., Chaves, M. H., Oliveira, A. P., Oliveira, R. C. M., (2019), Terminalia fagifolia Mart. & Zucc. elicits vasorelaxation of rat thoracic aorta through nitric oxide and K+ channels dependent mechanism, Biology open, 27; 8(2).
46. [46] Paulo Humberto M Nunes, Maria do Carmo C Martins, Rita de Cássia M Oliveira, Mariana H Chaves, Elcilene A Sousa, José Roberto S A Leite, Leiz Maria Véras, Fernanda Regina CAlmeida, (2014), Gastric antiulcerogenic and hypokinetic activities of Terminalia fagifolia Mart. & Zucc. (Combretaceae), Biomed Res Int.;2014:261745. doi: 10.1155/2014/261745. PMID: 24900960. PMCID: PMC4036414.