SİNNAMİK ASİDİN SIÇAN İLEUM VE MESANE DÜZ KASLARI ÜZERİNDEKİ KASILMA VE GEVŞEME ETKİ MEKANİZMASININ ARAŞTIRILMASI

Öz

Sinnamik Asit, Cinnamomi cortex (Tarçın) bitkisinde yaygın olarak bulunan bir fenolik asit türevidir ve adını da tarçın bitkisinden almıştır. Antimikrobial, Antitümöral, Antikanserojen ve Antifungal özelliklerinin olduğu ve vazodilatör etkisi saptanmıştır.

Bu çalışma kontrol, atropin, fentolamin, propranolol, nifedipin, tetraetil amonyum ve atropin+fentolamin+propranolol uygulanan gruplar olmak üzere 7 farklı grupta ileum ve mesane için ayrı ayrı gerçekleşmiştir. Çalışmada KCl veya karbakol ile ön-kastırılmış ileum/mesane dokularına farklı antagonist ya da kanal blokörlerinin uygulanması sonrası ilgili dokuların sinnamik aside karşı kasılma-gevşeme cevapları incelenmiştir.

Sinnamik asit ileum ve mesanede doza bağlı kasılma ve gevşemeler oluşturmuştur. Atropin ileumu daha fazla kastırırken gevşeme cevaplarını değiştirmemiştir. Mesanede ise kasılma cevaplarını inhibe ederken gevşemeyi arttırmıştır. Fentolamin ileum ve mesanenin kasılma ve gevşeme cevapları değişmemiştir. Propranolol ileumun kasılma cevaplarını inhibe etmiş gevşeme cevapları değişmemiştir. Mesanede ise kasılma cevapları artarken gevşeme yanıtları değişmemiştir. Nifedipin ileumda sinnamik asidin kasılma cevaplarını inhibe ederken gevşeme cevaplarını değiştirmemiş, mesanede kasılma cevaplarını etkilemezken gevşeme cevaplarını arttırmıştır. TEA ileumda kasılma ve gevşeme cevaplarını değiştirmemiş mesanede de kasılma cevaplarını etkilemezken gevşeme cevaplarını arttırmıştır. Aynı anda yapılan adrenerjik ve kolinerjik reseptör blokajı ileumda ve mesanede kasılma ve gevşeme cevaplarını değiştirmiş fakat anlamlı olarak etkilememiştir.

Sonuç olarak sıçan ileum ve mesane düz kasları üzerinde uyguladığımız Sinnamik asidin kullandığımız reseptör antagonistleri ve kanal blokörlerinin dışında farklı reseptörler veya yolaklar aracılığı ile de etkide bulunduğu düşünülmektedir.

Anahtar Kelimeler

• Atropin
• Fentolamin
• İleum
• Mesane
• Nifedipin
• Propranolol
• Sinnamik Asit
• Tetraetil Amonyum

INVESTIGATION OF THE EFFECTION MECHANISM OF CINNAMIC ACID ON CONTRACTION AND RELAXATION OF SMOOTH MUSCLES OF ILEUM AND BLADDER OF RATS

Öz

Cinnamic Acid is a phenolic acid derivative commonly found in Cinnamomi cortex (Cinnamon) plant, and it is named after cinnamon plant. It have Antimicrobial, Antitumoral, Anticancer and Antifungal properties and beyond that its vasodilator effect were also detected. This study was performed separately for ileum and bladder in 7 different groups, namely atropine, phentolamine, propranolol, nifedipine, tetraethyl ammonium and atropine + phentolamine + propranolol applied groups. In the study, the contraction-relaxation responses to cinnamic acid of the relevant tissues were examined after application of different antagonists or channel blockers to KCl or carbachol pre-contracted ileum / bladder tissues. Cinnamic acid caused constraction and relaxation of the ileum and bladder as dosage dependent manner. Atropine did not change the relaxation response while further contracting the ileum. It increased relaxation while inhibiting contraction responses in bladder. The contraction and relaxation responses of phentolamine on ileum and bladder was not changed. The propranolol inhibited the contraction responses of ileum, but did not change the relaxation responses. In bladder, the contraction responses increased, but relaxation responses did not change. Nifedipine did not alter the relaxation responses while inhibiting the response of contraction to cinnamic acid in ileum, and increasing relaxation responses without affecting the contraction responses in the bladder. TEA increased relaxation responses while it did not affect the contraction responses in bladder, but did not change contraction and relaxation responses in ileum. At the same time, the adrenergic and cholinergic receptor blockade performed at the same time altered the contraction and relaxation responses in the ileum and bladder, but did not significantly affect them. In conclusion, it is thought that cinnamic acid applied on rat ileum and bladder smooth muscles, is also influenced by different receptors or pathways other than receptor antagonists and channel blockers preferred by us.

Anahtar Kelimeler

• Cinnamic Acid
• Tetraethyl Ammonium
• Atropine
• Ileum
• Bladder
• Nifedipine
• Phentolamine
• Propranolol

Kaynakça

1. [1] Alaygut, D., Kavukçu, S., (2013), Büyüme sürecinde işeme fizyolojisinin klinik önemi nedir? Türkiye Çocuk Hast. Derg./Turkish J Pediatr Dis. 1: 53-56.
2. [2] Alparslan, P., (2013), “Xanthium trumarium l. bitkisinden biyolojik aktif bileşiklerin izolasyonu, yapılarının aydınlatılması ve asetilkolinesteraz ve butirilkolinesteraz inhibisyon aktivitelerinin incelenmesi” Yüksek Lisans Tezi. Trakya Üni.
3. [3] Altınkurt, O., (1981), Farmakoloji I, Ankara Üniv Eczacılık Fak Yayınları No: 54.
4. [4] Andrade, E. L., Ferreira, J., Andre, E., Calixto, J. B., (2006), Contractile mechanisms coupled to TRPA1 receptor activation in rat urinary bladder, biochemical pharmacology 72, 104–114.
5. [5] Berridge, M. J., (2008), Smooth muscle cell calcium activation mechanisms, The Journal of physiology, 586, 5047-5061.
6. [6] Borrelli, F., Capasso, R., Pinto, A., Izzo, A. A., (2004), Inhibitory effect of ginger (Zingiber officinale) on rat ileal motility in vitro, Life Sci.; 74:2889–96.
7. [7] Bökesoy TA, Çakıcı Ġ, Melli M.Farmakoloji Ders Kitabı.1.Baskı, Ankara, Gazi Kitabevi, 2000; 380-5.
8. [8] Chen, G., Suzuki, H., Weston, A. H., (1988), Acetylcholine releases endothelium-derived hyperpolarizing factor and EDRF from rat blood vessels, Br J Pharmacol, 95:1165-1174.

9. [9] Clapham, D. E., (2003), TRP channels as cellular sensors, Nature, 426(6966), 517-24.
10. [10] Corey, D. P., (2003), New TRP channels in hearing and mechanosensation, Neuron, 39(4), 585-8.
11. [11] Çabadak, H., (2006), Muskarinik asetilkolin reseptörlerinin dağılımı ve ilişkili sinyal ileti yolları, Türk Biyokimya Dergisi. 31(3): 141-150.
12. [12] Delmas, P.,(2004), Polycystins: from mechanosensation to gene regulation, Cell, 118(2), 145-8.
13. [13] Demirel, E., Rusko, J., Laskey, R. E., Adams, D. J., Van B., C., (1994), TEA inhibits Ach-induced EDRF release: endothelial Ca+2-dependent K+ channels contribute to vascular tone, Am J Physiol, 267:H1135-H1141.
14. [14] Dhein, S., Salameh, A., Berkels, R., Klaus, W., (1999). Dula mode of action of dihiydropyridine calcium antagonists: a role for nitric oxide, Drugs. 58(3):397-404.
15. [15] Dobarro, M., Orejana, L., Aguirre, N. ve Ramirez, M. J., (2013), Propranolol restores cognitive deficits and improves amyloid and Tau pathologies in a senescence-accelerated mouse model, Neuropharmacology, 64, 137- 144.
16. [16] Durant, P. A., Lucas, P. C., Yaksh, T. L., (1988), Micturition in the unanaesthetized rat: spinal vs peripheral pharmacology of the adrenergic system, J. Pharmacol. Ex p.Th er., 245, 426–435.
17. [17] Emre, M., Özcal, I., Şan M., (2004), Endoteldeki iyon kanalları ve işlevleri, Erciyes Tıp Dergisi (Erciyes Medical Journal) 26(4). 186-193.
18. [18] Goth, A., (1974), Medical Pharmacology, Principles and Concepts. 7th edition, The C.V. Mosby Company, Saint Louis.
19. [19] Gottlieb, A. I., Langille, B. L., Wong, M. K., Kim, D. W., (1991), Structure and function of the endothelial cytoskeleton, Lab Invest, 65:123-137.
20. [20] Grasa, L., Rebollar, E., Arruebo, M. P., Plaza, M. A., Murillo, M. D., (2004), The role of Ca2+ in the contractility of rabbit small intestine in vitro, Journal Of Physıology and Pharmacology, 55(3): 639-650.
21. [21] Hata, T., Tazawa, S., Ohta, S., Rhyu, M. R., Misaka, T., Ichihara, K., Artepillin, C., (2011), A Major Ingredient of Brazilian Propolis, Induces a Pungent Taste by Activating TRPA1 Channels, Plos one 7(11): e48072. doi:10.1371/journal. pone.0048072.
22. [22] Ishizuka, O., Mattiasson, A., Andersson, K. E., (1996), Role of spinal and peripheral alpha2 adrenoceptors in micturition in normal conscious rats, J. U rol., 156, 1853–1857.
23. [23] Izzo, A. A., Capasso, R., Aviello, G., Borelli, F., Romano, B., Piscitelli, F., Gallo, L., Capasso, F., Orlando, P., Di Marzo, V., (2012), Inhibitory effecet of cannabichromene, a majör non-psychotropic cannabinoid extracted from Cannabis sativa, on inflammation-induced hypermotility in mice,BritishJournalofPharmacology,1661444–1460.
24. [24] Joseph, R. D., (1989), Temel tıp farmakolojisi, basic pharmacology in medicine, Alaeddin Akcasu, Zeki Özüner, Esat Eşkazan, gözden geçirilmiş 2.baskı.
25. [25] Kang, Y. H., Kang, J. S., Shin, H. M., (2013), Vasodilatory effects of cinnamic acid via the nitric oxide-cGMP-PKG pathway in rat thoracic aorta. Phytother Res.Feb;27(2):205-211.
26. [26] Kayaalp, S. O., (1993), Düz kas fizyolojisi ve farmakolojide kullanılan ölçüm yöntemleri, Türk Farmakoloji Eğitim Sempozyumları Dizisi II, Türk Farmakoloji Derneği Yayınları, Ankara.
27. [27] Kayaalp, S. O., Ulus, İ. H., (2005), Rasyonel tedavi yönünden tıbbi farmakoloji, Otonom Sinir Sistemi İle İlişkili İlaçlar, Ankara.s.924-939
28. [28] Kirschstein, T., Protzel, C., Porath, K., Sellmann, T., Köhling, R., Hakenberg, O. W., (2014), Age-dependent contribution of Rho kinase in carbachol-induced contraction of human detrusor smooth muscle in vitro,Acta Pharmacologica Sinica, 35: 74–81.
29. [29] Kontani, H., Tsuji, T., Kimura, S., (2000), Effects of adrenergic a2-receptor agonists on urinary bladder contraction in conscious rats, Jpn. J. Pharmacol., 84, 381–390.
30. [30] Korstanje, C., (2000), Barnidipine, a long-acting slow onset calcium antagonist, Int J Clin Pract, Nov; (114):2-5
31. [31] Kravtsov, G. M., Kwan, C. Y., (1995), A revisitation on the mechanism of action of KCl induced vascular smooth muscle contraction: A key role of cation binding to the plasma membrane, Biol Signals. 4:160–167.
32. [32] Kumar, S., Mahaseth, R. K., Tiwari, M., Sehgal, R., Rajora, P., Mathur, R., (2015), Interaction of Aqueous Leaf Extractof Aegle marmelos (L.) Corr. with Cholinergic, Serotonergic and Adrenergic Receptors: An ex vivo study, Indian Journal Pharmacology, ; 47(1): 109-113.
33. [33] Lai, H., Yan, Q. T., Cao, H., Chen, P., Xu, Y., Jiang, W., Wu, Q., Huang, P., Tan, B., (2016), Effect of SQW on the bladder function of mice lacking TRPV1, BMC Complementary and Alternative Medicine, 16:465.
34. [34] Lai, H. H.,Smith, C. P., Munoz, A., Boone, T. B., Szigeti, G. P., Somogyi, G. T., (2008), Activation of cholinergic receptors blocks non-adrenergic noncholinergic contractions in the rat urinary bladder, Brain Res Bull. December 16; 77(6): 420–426.
35. [35] Langley, JN. A. H. K., (1896), On The Innervatıon Of The Pelvıc And Adjoining Viscera, Part VII. Anatomical Observations. J Physiol. Oct 19;20(4-5):372-406.
36. [36] Leaute-Labreze C., Dumas de la Rooque E., Hubiche T., (2008), Propranolol for severe hemangiomas of infancy, N Engl J Med 358:2649-2651.
37. [37] Leclere, P. G. Lefebvre, R. A., (2002), Presynaptic modulation of cholinergic neurotransmission in the human proximal stomach, Br. J. Pharmacol, s.135:135-142.
38. [38] Liu, L., Hudgins, W. R., Shack, S., Yin, M. Q., Samid, D., (1995). Cinnamic acid: a natural product with potential use in cancer intervention, Int J Cancer 62: 345–350.
39. [39] Masters, J. G., Neal, D. E., Gillespie, J. I., (1999), The contribution of intracellular Ca2+release to contraction in human bladder smooth muscle, Br J Pharmacol; 127: 996–1002.
40. [40] Materazzi, S., Minocci, D., De Siena, G., Benemei, S., Nassini, R., (2015), Ureteral relaxation through calcitonin gene-related peptide release from sensory nerve terminals by hypotonic solution, International Journal of Urology, 22, 878—883.
41. [41] Matsuzawa, Y., Kwon TG., Lennon RJ., Lerman LO., Lerman A., (2015) Prognostic Value of Flow-Mediated Vasodilation in Brachial Artery and Fingertip Artery for Cardiovascular Events: A Systematic Review and Meta-Analysis, Am Heart Assoc. 4(11).
42. [42] Michel, M. C., Vrydag, W., (2006), a1-, a2- and b-adrenoceptors in the urinary bladder, urethra and prostate, British Journal of Pharmacology, 147, S.88–S.119.
43. [43] Minke, B., (2006), TRP channels and Ca2+ signaling. Cell Calcium, 40(3), 261-75.
44. [44] Montell, C., Birnbaumer, L., ve Flockerzi, V., (2002), The TRP channels, a remarkably functional family, Cell, 108(5), 595-8.
45. [45] Moqrich, A., Hwang, S. W., Earley, T. J., Petrus, M. J., Murray, A. N., Spencer, K. S., Andahazy, M., Story, G. M., Patapoutian, A., (2005), Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin. Science, 307(5714), 1468- 72.
46. [46] Moradi, M. T., Rafieian-Koupaei, M., Imani-Rastabi, R., Nasiri, J., Shahrani, M., Rabiei, Z., Alibabaei, Z., (2013), Antispasmodic effects of yarrow (Achillea millefolium L.) extract in the isolated ileum of rat, Afr J. Tradit Complement Altern Med. 10(6):499-503.
47. [47] Nozawa, K., Kawabata-Shoda, E., Doihara, H., Kojima, R., Okada, H., Mochizuki, S., (2009), TRPA1 regulates gastrointestinal motility through serotonin release from enterochromaffin cells, Proc Natl Acad SciUSA 106: 3408–3413.
48. [48] Olasupo, N. A., Fitzgerald, D. J., Gasson, M. J., Narbad, A.,(2003), Activity of natural antimicrobial compounds against Escherichia coli and Salmonella enterica serovar Typhimurium, Lett Appl Microbiol 37: 448–451.
49. [49] Olesen, S. P., Bundgaard, M., (1993), ATP-dependent closure and reactivation of inward rectifier K+ channels in endothelial cells, Circ Res, 73:492-495.
50. [50] Penuelas, A., Tashima, K., Tsuchiya, S., Matsumoto, K., Nakamura, T., Horie, S, Yano, S., (2007). Contractile effect of TRPA1 receptor agonists in the isolated mouse intestine, Eur J Pharmacol 576: 143–150.
51. [51] Pereira-leite, C., Carneiro, C., Soares, J. X., Afonso, C., Nunes, C., Lucio, M. Reis, S., (2013), Biophysical characterization of the drugsmembrane interaction: the case of propranolol and acebutolol, European journal of pharmaceutics and biopharmaceutics; 84(1):183-191
52. [52] Ratz, P. H., Berg, K. M., Urban, N. H. ve Miner, A. S., (2005), Regulation of smooth muscle calcium sensitivity: KCl as a calcium-sensitizing stimulus, American journal of physiology. Cell physiology, 288, C769-C783.
53. [53] Richard, Y. Richard A., (2009), Glennon, S(−)Propranolol as a discriminative Ştimulus and its comparison to the stimulus effects of cocaine in rats, Psychopharmacology, 203:369–382.
54. [54] Sadofsky, L. R., Boa, A. N., Maher, S. A., Birrell, M. A., Belvisi, M. G., Morice, A. H., (2011), TRPA1 is activated by direct addition of cysteine residues to the N-hydroxysuccinyl esters of acrylic and cinnamic acids, Pharmacological Research 63, 30–36.
55. [55] Sakakibara, F., Kiniwa, M., Nanri, M., (2011), Are Antimuscarinic Drugs Effective Against Urinary Frequency Mediated by Atropine-Resistant Contractions?, J Pharmacol Sci 115, 364 – 373.
56. [56] Sasaguri, T., Watson, S. P., (1988), Lowering of the extracellular Na+ concentration enhances high K+ -induced formation of inositol phosphates in the guinea-pig ileum, Biochem. J., 252, 883-888.
57. [57] Schneider, T., Fetscher, C., Krege, S., Michel, M. C., (2004), Signal transduction underlying carbachol-induced contraction of human urinary bladder, J Pharmacol Exp Ther; 309: 1148–1153.
58. [58] Sedighi, M., Rafieian-Kopaei, M., Noori-Ahmadabadi, M., (2012), Effect of Allium ampeloprasum on ileum function: Involvement of beta- adrenergic receptors and voltage dependent calcium channels, Life Science Journal; 9(4):1660-1667.
59. [59] Sedighi, M., Rafieian-Kopaei, M., Noori-Ahmadabadi, M., Godarzi, I., Baradaran, A., (2014), In Vitro Impact of Hydroalcoholic Extract of Rosa damascena Mill. on Rat Ileum Contractions and the Mechanisms Involved, Int J Prev Med. Jun; 5(6): 767–775.
60. [60] Seiler, R., Rickenbacher, A., Shaw, S., Balsiger, B. M., (2005), α - and β -Adrenergic Receptor Mechanisms in Spontaneous Contractile Activity of Rat Ileal Longitudinal Smooth Muscle, J Gastroıntest Surg; 9:227–235.
61. [61] Şeker, E., (1999), Origanumonites L. uçucu yağ altı suyunun sçan mide, fundus, duodenum, ileum üzerine etkileri, Yüksek Lisans Tezi, Anadolu Üniversitesi Sağlık Bilimleri Entitüsü, Eskişehir.
62. [62] Tamer, M., (2007), Fare, sıçan ve kobay ileumlarının nonadrenerjik non-kolinerjik yanıtlarında taşikininlerin rolü, Trakya Üniversitesi Sağlık Bilimleri Enstitüsü Farmakoloji Anabilim Dalı, Doktora Tezi, s.1-10, Edirne.
63. [63] Tawata, S., Taira, S., Kobamoto, N., Zhu, J., Ishihara, M., Toyama, S., (1996), Synthesis and antifungal activity of cinnamic acid esters, Biosci Biotechnol Biochem 60: 909–910.
64. [64] Vanhoutte, P. M., Rubanyi, G. M., Miller, V. M. Houston D. S. (1986), Modulation of vascular smooth muscle contractions by the endothelium, Annu Rev Physiol, 48:307-320.
65. [65] Wang, G. J., Wu, X. C., Lin, Y. L., Ren, J., Shum, A. Y., Wu, Y. Y., Chen, C., F., (2002) Ca channel blocking effect of isoSpetasin in rat aortic smooth muscle cells, Eur J Pharmacol. 445:239–45.
66. [66] Wuest, M., Hiller, N., Braeter, M., Hakenberg, O. W., Wirth, M. P., Ravens, U., (2007), Contribution of Ca2+influx to carbachol-induced detrusor contraction is different in human urinary bladder compared to pig and Mouse, Eur J Pharmacol; 565: 180–189.