Ömer BOZDOĞAN, Esra YAVUZ, Anıl TEMİZ, Şevval ÖZDEMİR

ATP-Bağımlı Potasyum Kanal Açıcısı Pinasidil ve Blokeri Glimeprid’in İskemi ve Reperfüzyon ile Uyarılan Aritmiler Üzerine Akut Etkisi

Amaç: Miyokart enfarktüsünün akut döneminde koroner damar tıkanmasına bağlı olarak oluşan miyokardiyal iskemi ve arkasından damarın açılmasıyla oluşan reperfüzyon insanlarda öldürücü aritmilerin oluşmasına ve ani ölümlere yol açmaktadır. Bu nedenle bu aritmilerin azaltılması için farmokolojik ilaç araştırmaları yoğun bir şekilde yapılmaktadır. Bu çalışmada pinasidil ve glimepridin akut uygulamasının iskemi ve-reperfüzyon aritmileri üzerine etkisinin araştırılması amaçlanmıştır. Gereç ve Yöntemler: İki grup oluşturulmuştur; Birinci grupta sol koroner arter 20 dakika süreyle bağlanarak sadece iskemi oluşturulmuş, ikinci grupta damar bağlanarak 6 dakika iskemi ve arkasından tıkanan damar açılarak 15 dakika reperfüzyon yapılmıştır. İlaçlar intravenöz olarak birinci grupta, iskeminin ikinci dakikasında, ikinci grupta, hemen reperfüzyondan sonra uygulanmıştır. İskemi ve reperfüzyon süresince EKG ve kan basıncı kaydedilmiştir. Kayıtlardan aritmilerin tipi, süresi ve yoğunlukları, kalp atım hızı, kan basıncı ve ölüm oranı belirlenmiştir. Bütün veriler tek yönlü ANOVA ile karşılaştırılmıştır. Daha sonra ilaç grupları kendi kontrol gruplarıyla, ilaç ve kontrol grupları kendi aralarında ikili olarak tek kuyruklu t testi ile karşılaştırılmıştır. Aritmi yoğunlukları ve ölüm oranları Ki kare testi ile karşılaştırılmıştır. Bulgular: İskemi ve reperfüzyon sırasında intravenöz olarak verildiklerinde, pinasidil hem iskemi, hemde reperfüzyon periyodunda belirgin bir şekilde aritmi skorunu azaltmış, glimeprid ise etkisiz kalmıştır. Sonuç: Bu çalışma pinasidilin miyokart enfarktüsünün akut döneminde oluşan aritmileri azaltmada etkili bir ilaç olabileceğini ortaya koymuştur. Ancak glimepridin miyokart enfarktüsünün akut döneminde antiaritmik ya da proaritmik etkisinin ortaya konması için farklı dozları ile daha fazla çalışma gerekmektedir.

Anahtar Kelimeler:

İskemi, Reperfüzyon, Aritmi, Pinasidil, Glimeprid

The Acute Effects Of ATP-Sensitive Potassium Channel Opener (Pinacidil) And Blocker (Glimepride) On the Ischemia or Reperfusion-Induced Arrhythmias

Objective: Myocardial ischemia generated by coronary occlusion and myocardial reperfusion by the opening of occluded coronary vessel in the acute stage leads to lethal arrhythmia and sudden death in humans. That is why pharmacological drug research to decrease these arrhythmias have been researched intensively. In this study, the effect of acute administration of pinacidil and glimepride, on ischemia or reperfusion-induced arrhythmia was aimed to be researched. Materials and Methods: Two groups were designed; In the first group, only ischemia was produced by the ligation of the left coronary artery in 20 minutes, and in the second group 6 minutes of ischemia by the ligation of the artery and the subsequent 15 minutes of reperfusion were produced by the opening of the occluded artery. Drugs were administered intravenously at 2 minutes of ischemia in the first group and just following the reperfusion in the second group. The ECG and blood pressure were recorded during ischemia and reperfusion period. The type, duration, incidence of arrhythmia, heart rate, blood pressure, and the death rate from the recording were calculated. All data were first compared by one-way ANOVA. Then, the drug groups with their control, and control and drug groups with each other were compared by a one-tailed t-test. The incidence of arrhythmia and the death rate between groups was compared by the Ki square test. Results: Pinacidil significantly decreased the arrhythmia score both in the ischemia and reperfusion period but glimepiride was not effective when they were given intravenously in the acute stage of ischemia or reperfusion. Conclusion: This study suggests that pinacidil might be a candidate for drugs that can be used to decrease arrhythmia in the acute stage of myocardial infarction but more study is needed to reveal the antiarrhythmic or proarrhythmic effect of glimepride with different doses in the acute stage of myocardial infarction.

Keywords:

Ischemia, Reperfusion, Arrhythmia, Pinacidil, Glimepiride,

PDF

___

1. Sara JD, Eleid MF, Gulati R, Holmes DR Jr. Sudden cardiac death from the perspective of coronary artery disease. Mayo Clinic Proceedings 2014; 89(12):1685-98.
2. Gonca E, Bozdogan O. Both mitochondrial KATP channel opening and sarcolemmal KATP channel blockage confer protection against ischemia/reperfusion-induced arrhythmia in anesthetized male rats. Journal of Cardiovascular Pharmacology and Therapeutics 2010;15(4): 403-411.
3. Basit A, Riaz M, Fawwad A. Glimepiride: evidence-based facts, trends, and observations (GIFTS). Vascular Health and Risk Management 2012; 8: 463-472.
4. Aravind, S. R., Mittal, S., Venkatraman, S., Deka, N., Parmar, G., Amarnath, S., & Mohan, V. Cardiovascular Profile of Modern Sulfonylureas: Focus on Glimepiride. Journal of the Association of Physicians of India 2019; 67: 17
5. Mocanu MM, Maddock HL, Baxter GF, Lawrence CL, Standen NB, Yellon DM. Glimepiride, a novel sulfonylurea, does not abolish myocardial protection afforded by either ischemic preconditioning or diazoxide. Circulation 2001; 103(25): 3111-3116.
6. Ueba H, Kuroki M, Hashimoto S, Umemoto T, Yasu T, Ishikawa SE, Saito M, Kawakami M. Glimepiride induces nitric oxide production in human coronary artery endothelial cells via a PI3-kinase-Akt dependent pathway. Atherosclerosis 2005; 183(1): 35-39.
7. Végh A, Papp JG. Hemodynamic and other effects of sulphonylurea drugs on the heart. Diabetes Research and Clinical Practice 1996; 31: (Suppl 2); S43-53.
8. Bozdogan, O., Leprán, I., & Papp, J. G. Effect of glimepiride and glibenclamide, inhibitors of ATP-dependent K (+)-channel, on ischemia-reperfusion induced arrhythmias in rats. Acta Physiologica Hungarica 1996; 84(3): 265-266
9. El-Reyani NE, Bozdogan O, Baczkó I, Leprán I, Papp JG. Comparison of the efficacy of glibenclamide and glimepiride in reperfusion-induced arrhythmias in rats. European Journal of Pharmacology 1999; 365(2-3): 187-192.
10. Goldberg MR. Clinical pharmacology of pinacidil, a prototype for drugs that affect potassium channels. Journal Cardiovascular Pharmacology 1988; 12 (Suppl 2): S41-47.
11. Fish FA, Prakash C, Roden DM. Suppression of repolarization-related arrhythmias in vitro and in vivo by low-dose potassium channel activators. Circulation 1990; 82(4): 1362-1369.
12. Fedorov VV, Glukhov AV, Ambrosi CM, Kostecki G, Chang R, Janks D, Schuessler RB, Moazami N, Nichols CG, Efimov IR. Effects of KATP channel openers diazoxide and pinacidil in coronary-perfused atria and ventricles from failing and non-failing human hearts. Journal of Molecular and Cellular Cardiology 2011; 51(2): 215-225.
13. Cole WC, McPherson CD, Sontag D. ATP-regulated K+ channels protect the myocardium against ischemia/reperfusion damage. Circulation Research 1991; 69(3): 571-581.
14. Leprán I, Baczkó I, Varró A, Papp JG. ATP-sensitive potassium channel modulators: both pinacidil and glibenclamide produce antiarrhythmic activity during acute myocardial infarction in conscious rats. Journal of Pharmacology and Experimental Therapeutics 1996 Jun; 277(3):1215-20.
15. Antzelevitch, C., & Di Diego, J. M. Role of K+ channel activators in cardiac electrophysiology and arrhythmias. Circulation 1992; 85(4): 1627-1629
16. D'Alonzo AJ, Zhu JL, Darbenzio RB, Dorso CR, Grover GJ. Proarrhythmic effects of pinacidil are partially mediated through enhancement of catecholamine release in isolated perfused guinea-pig hearts. Journal of Molecular and Cellular Cardiology 1998; 30(2): 415-23.
17. Yaşar S, Bozdoğan Ö, Kaya ST, Orallar HS. The effects of ATP-dependent potassium channel opener; pinacidil, and blocker; glibenclamide, on the ischemia-induced arrhythmia in partial and complete ligation of coronary artery in rats. Iranian Journal of Basic Medical Sciences 2015;18(2):188-193.
18. Curtis MJ, Hancox JC, Farkas A, Wainwright CL, Stables CL, Saint DA, Clements-Jewelry H, Lambiase PD, Billman GE, Janse MJ, Pugsley MK, Ng GA, Roden DM, Camm AJ, Walker MJ. The Lambeth Conventions (II): guidelines for the study of animal and human ventricular and supraventricular arrhythmias. Pharmacol Ther. 2013 Aug;139(2):213-48.
19. Leprán, I., Koltai, M., & Szekeres, L. Coronary artery ligation, early arrhythmias, and determination of the ischemic area in conscious rats. Journal of Pharmacological Methods 1983; 9(3): 219-230
20. Leonard CE, Hennessy S, Han X, Siscovick DS, Flory JH, Deo R. Pro- and Antiarrhythmic Actions of Sulfonylureas: Mechanistic and Clinical Evidence. Trends Endocrinology Metabolism 2017; 28(8): 561-586.
21. Spinelli W, Sorota S, Siegal M, Hoffman BF. Antiarrhythmic actions of the ATP-regulated K+ current activated by pinacidil. Circulation Research 1991; 68(4): 1127-1137.
22. Friedel HA, Brogden RN. Pinacidil. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in the treatment of hypertension. Drugs 1990; 39(6): 929-967.
23. Iguchi, K., Saotome, M., Yamashita, K., Ikoma, T., Hasan, P., Maekawa, Y., & Watanabe, Y. The Effects of Pinacidil, an ATP Sensitive K+ Channel Opener on Cardiac Na+/Ca2+ Exchanger Function in Guinea Pig Cardiomyocytes. Biophysical Journal 2019; 116(3): 98a-99a.
24. Tosaki A, Szerdahelyi P, Das DK. Reperfusion-induced arrhythmias and myocardial ion shifts: a pharmacologic interaction between pinacidil and cicletanine in isolated rat hearts. Basic Research Cardiology 1992; 87(4): 366-384.
25. Antzelevitch, C., & Di Diego, J. M. Role of K+ channel activators in cardiac electrophysiology and arrhythmias. Circulation 1992; 85(4): 1627-1629
26. Frommeyer G, Hartmann J, Ellermann C, Deciphering DG, Kochhäuser S, Reinke F, Köbe J, Wasmer K, Eckardt L. Broad antiarrhythmic effect of mexiletine in different arrhythmia models. Europace 2018; 20(8): 1375-1381.
27. An MY, Sun K, Li Y, Pan YY, Yin YQ, Kang Y, Sun T, Wu H, Gao WZ, Lou JS. Therapeutic effects of a taurine-magnesium coordination compound on experimental models of type 2 short QT syndrome. Acta Pharmacologica Sinica 2018; 39(3): 382-392.
28. Cole WC, McPherson CD, Sontag D. ATP-regulated K+ channels protect the myocardium against ischemia/reperfusion damage. Circulation Research 1991; 69(3):571-81.
29. Di Diego, J. M., & Antzelevitch, C. Pinacidil-induced electrical heterogeneity and extrasystolic activity in canine ventricular tissues. Does activation of ATP-regulated potassium current promote phase 2 reentry? Circulation 1993; 88(3): 1177-1189
30. Yan GX, Antzelevitch C. Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogenesis associated with ST-segment elevation. Circulation 1999;100(15):1660-1666.
31. Ichiro Watanabe and Leonard S. Gettes. Effects of Pinacidil on ST-T Wave Alternans During Acute Myocardial Ischemia in the In-situ Pig Heart. J. Nihon University. Medical Association 2017; 76 (6): 273–279
32. Aravind, S. R., Mittal, S., Venkatraman, S., Deka, N., Parmar, G., Amarnath, S., & Mohan, V. Cardiovascular Profile of Modern Sulfonylureas: Focus on Glimepiride. Journal of the Association of Physicians of India 2019; 67: 17
33. Leonard CE, Brensinger CM, Aquilante CL, Bilker WB, Boudreau DM, Deo R, Flory JH, Gagne JJ, Mangaali MJ, Hennessy S. Comparative Safety of Sulfonylureas and the Risk of Sudden Cardiac Arrest and Ventricular Arrhythmia. Diabetes Care 2018; 41(4): 713-722.
34. Hausenloy, D. J., Wynne, A. M., Mocanu, M. M., & Yellon, D. M. Glimepiride treatment facilitates ischemic preconditioning in the diabetic heart. Journal of cardiovascular pharmacology and therapeutics 2013; 18(3): 263-269
35. Vajda S, Baczkó I, Leprán I. Selective cardiac plasma-membrane K(ATP) channel inhibition is defibrillator and improves survival during acute myocardial ischemia and reperfusion. European Journal of Pharmacology 2007; 577(1-3): 115-23.
36. Végh A, Papp Hemodynamic and other effects of sulphonylurea drugs on the heart. Diabetes Research and Clinical Practice 1996; 31 Suppl: S43-53.
37. Hayashi, H., Terada, H., & McDonald T. F. Electrical heterogeneity and conduction block in reoxygenated guinea pig papillary muscles. Japanese heart journal 1996; 37(3): 383-391