Mehmet BOĞA, Erdem Ali ÖZKISACIK, Tünay KURTOĞLU, Uğur GÜRCÜN, Selim DURMAZ, Berent DİŞCİGİL, M. İsmail BADAK

The effects of clopidogrel, acetyl salicylic acid and tirofiban on acetylcholine-induced dilation in rat thoracic aorta segments

Amaç: Bu çalışmada, asetilsalisilik asit (ASA), klopidogrel ve tirofiban gibi antitrombositer ajanların sıçan torasik aort segmentinde asetilkolin (ACh) ile uyarılan gevşeme yanıtları üzerine olan etkileri araştırıldı. Çalışma planı: Yirmi sekiz adet ağırlıkları 250-300 g arasında olan Wistar-albino türü yetişkin erkek sıçan çalışmaya alındı. Sıçanlar randomize olarak dört gruba ayrıldı: ASA grubu (n=7), klopidogrel grubu (n=7), tirofiban grubu (n=7) ve kontrol grubu (n=7). Deneyden 12 saat önce intraperitoneal (İP) ASA (1.5 mg/kg) veya klopidogrel (1 mg/kg) enjeksiyonları yapıldı. Tirofiban grubunda, 150 μgr/kg tirofiban İP deneyden 1 ve 12 saat önce olmak üzere, iki kez verildi. Kontrol grubundaki sıçanlara herhangi bir ilaç verilmedi. Sıçanlar dekapite edildikten sonra torasik aort segmentleri çıkartıldı ve oksijenize Krebs çözeltisi içinde organ banyosuna asıldı ve aort halkalarında asetilkolin ile uyarılan gevşeme yanıtının doza bağımlı değişimleri incelendi. Bulgular: Asetilkolinin en düşük molar konsantrasyonu (10-9) ile elde edilen gevşeme yanıtının ASA (%94.3±3.3) ve klopidogrel (%94.6±3.1) grubunda kontrol (%86.7±8.1) grubuna göre azalmış olduğu bulundu (p

Klopidogrel, asetilsalisilik asit ve tirofibanın sıçan torasik aort segmentlerinde asetilkolin ile uyarılan gevşeme üzerine etkisi

Background: In this article, we aimed to investigate the effects of antithrombotic agents, including acetyl salicylic acid (ASA), clopidogrel, and tirofiban on the acetylcholine (ACh)- induced dilation responses in rat thoracic aorta segments. Methods: Twenty-eight Wistar albino male rats weighing between 250-300 g were included in the study. The rats were randomly divided into four groups: the ASA group (n=7), the clopidogrel group (n=7), the tirofiban group (n=7), and the control group (n=7). Intraperitoneal (IP) injection of ASA (1.5 mg/kg) or clopidogrel (1 mg/kg) was administered 12 hours before the experiment. In the tirofiban group, 150 μgr/kg tirofiban IP was given twice at one and 12 hours before the experiment. The rats in the control group did not receive any medication. After the rats were decapitated, the segments of the thoracic aorta were removed and suspended in an oxygenated Krebs solution in a tissue bath, and the dose dependency in the responses to the ACh-induced dilation in the aortic rings were studied. Results: The dilation responses of the aortic rings to ACh in the lowest molar concentration (10-9) were found to be reduced in the ASA (94.3%±3.3) and clopidogrel (94.6%±3.1) groups when compared with the control group (86.7%±8.1) (p

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1. Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman JS, et al. ACC/AHA guideline update for the management of patients with unstable angina and non-STsegment elevation myocardial infarction-2002: summary article: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). Circulation 2002;106:1893-900.
2. Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarctionexecutive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction). Circulation 2004;110:588-636.
3. Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG,et al. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg 2007;45 Suppl S:S5-67.
4. Chaturvedi S, Bhattacharya P. New insights in antiplatelet therapy for patients with ischemic stroke. Neurologist 2011;17:255-62.
5. Ueno M, Kodali M, Tello-Montoliu A, Angiolillo DJ. Role of platelets and antiplatelet therapy in cardiovascular disease. J Atheroscler Thromb 2011;18:431-42.
6. Vane JR, Anggård EE, Botting RM. Regulatory functions of the vascular endothelium. N Engl J Med 1990;323:27-36.
7. Jaffe EA. Cell biology of endothelial cells. Hum Pathol 1987;18:234-9.
8. Discigil B, Evora PR, Pearson PJ, Viaro F, Rodrigues AJ, Schaff HV. Ionic radiocontrast inhibits endotheliumdependent vasodilation of the canine renal artery in vitro: possible mechanism of renal failure following contrast medium infusion. Braz J Med Biol Res 2004;37:259-65.
9. Evora PR, Pearson PJ, Discigil B, Oeltjen MR, Schaff HV. Pharmacological studies on internal mammary artery bypass grafts. Action of endogenous and exogenous vasodilators and vasoconstrictors. J Cardiovasc Surg (Torino) 2002;43:761-71.
10. Evora PR, Pearson PJ, Chua YL, Discigil B, Schaff HV. Exogenous hyaluronidase induces release of nitric oxide from the coronary endothelium. J Thorac Cardiovasc Surg 2000;120:707-11.
11. Lee TK, Chen YC, Lien IN, Liu MC, Huang ZS. Inhibitory effect of acetylsalicylic acid on platelet function in patients with completed stroke or reversible ischemic neurologic deficit. Stroke 1988;19:566-70.
12. Yasuda O, Takemura Y, Kawamoto H, Rakugi H. Aspirin: recent developments. Cell Mol Life Sci 2008;65:354-8.
13. Schrör K. Aspirin and platelets: the antiplatelet action of aspirin and its role in thrombosis treatment and prophylaxis. Semin Thromb Hemost 1997;23:349-56.
14. Bilgen I, Oner G, Eren E. Dietary L-arginine restores aspirin-induced endothelial dysfunction in rat aorta. Arch Physiol Biochem 2003;111:232-8.
15. Iida H, Iida M, Takenaka M, Fukuoka N, Dohi S. Comparative effects of cilostazol and aspirin on the impairment of endothelium-dependent cerebral vasodilation caused by acute cigarette smoking in rats. J Thromb Thrombolysis 2010;29:483-8.
16. Magen E, Viskoper JR, Mishal J, Priluk R, London D, Yosefy C. Effects of low-dose aspirin on blood pressure and endothelial function of treated hypertensive hypercholesterolaemic subjects. J Hum Hypertens 2005;19:667-73.
17. Dorsam RT, Kunapuli SP. Central role of the P2Y12 receptor in platelet activation. J Clin Invest 2004;113:340-5.
18. Storey RF, Judge HM, Wilcox RG, Heptinstall S. Inhibition of ADP-induced P-selectin expression and platelet-leukocyte conjugate formation by clopidogrel and the P2Y12 receptor antagonist AR-C69931MX but not aspirin. Thromb Haemost 2002;88:488-94.
19. Wihlborg AK, Wang L, Braun OO, Eyjolfsson A, Gustafsson R, Gudbjartsson T, et al. ADP receptor P2Y12 is expressed in vascular smooth muscle cells and stimulates contraction in human blood vessels. Arterioscler Thromb Vasc Biol 2004;24:1810-5.
20. Buvinic S, Briones R, Huidobro-Toro JP. P2Y(1) and P2Y(2) receptors are coupled to the NO/cGMP pathway to vasodilate the rat arterial mesenteric bed. Br J Pharmacol 2002;136:847-56.
21. Guns PJ, Korda A, Crauwels HM, Van Assche T, Robaye B, Boeynaems JM, et al. Pharmacological characterization of nucleotide P2Y receptors on endothelial cells of the mouse aorta. Br J Pharmacol 2005;146:288-95.
22. Hess CN, Kou R, Johnson RP, Li GK, Michel T. ADP signaling in vascular endothelial cells: ADP-dependent activation of the endothelial isoform of nitric-oxide synthase requires the expression but not the kinase activity of AMPactivated protein kinase. J Biol Chem 2009;284:32209-24.
23. Yang LH, Hoppensteadt D, Fareed J. Modulation of vasoconstriction by clopidogrel and ticlopidine. Thromb Res 1998;92:83-9.
24. Jakubowski A, Chlopicki S, Olszanecki R, Jawien J, Lomnicka M, Dupin JP, et al. Endothelial action of thienopyridines and thienopyrimidinones in the isolated guinea pig heart. Prostaglandins Leukot Essent Fatty Acids 2005;72:139-45.
25. Froldi G, Bertin R, Dorigo P, Montopoli M, Caparrotta L. Endothelium-independent vasorelaxation by ticlopidine and clopidogrel in rat caudal artery. J Pharm Pharmacol 2011;63:1056-62. doi: 10.1111/j.2042-7158.2011.01313.x.
26. Offermanns S. Activation of platelet function through G protein-coupled receptors. Circ Res 2006;99:1293-304.
27. Sajid M, Stouffer GA. The role of alpha(v)beta3 integrins in vascular healing. Thromb Haemost 2002;87:187-93.
28. Kleiman NS. Pharmacokinetics and pharmacodynamics of glycoprotein IIb-IIIa inhibitors. Am Heart J 1999;138:263-75.
29. Iliodromitis EK, Andreadou I, Markantonis-Kyroudis S, Mademli K, Kyrzopoulos S, Georgiadou P, et al. The effects of tirofiban on peripheral markers of oxidative stress and endothelial dysfunction in patients with acute coronary syndromes. Thromb Res 2007;119:167-74.
30. Heitzer T, Ollmann I, Köke K, Meinertz T, Munzel T. Platelet glycoprotein IIb/IIIa receptor blockade improves vascular nitric oxide bioavailability in patients with coronary artery disease. Circulation 2003;108:536-41.
31. Warnholtz A, Ostad MA, Heitzer T, Goldmann BU, Nowak G, Munzel T. Effect of tirofiban on percutaneous coronary intervention-induced endothelial dysfunction in patients with stable coronary artery disease. Am J Cardiol 2005;95:20-3.
32. Kintscher U, Kappert K, Schmidt G, Doerr G, Grill M, Wollert-Wulf B, et al. Effects of abciximab and tirofiban on vitronectin receptors in human endothelial and smooth muscle cells. Eur J Pharmacol 2000;390:75-87.