tjhsl Turkish Journal of Health Science and Life 2687-2730 2687-2730 Mümin POLAT 10.56150/tjhsl.1297218 Health Care Administration Sağlık Kurumları Yönetimi Pinasidil ve Glimepirid'in birlikte iskemi ve reperfüzyon ile uyarılan aritmiler üzerine akut etkisi, “ATP Bağımlı Potasyum Kanalının Rolü” The acute combined effect of Pinacidil and Glimepiride on ischemia and reperfusion induced arrhythmia, “The Role of ATP- Dependent Potassium Channel” https://orcid.org/0000-0002-8031-9569 Daher Khatıb Mariam Abant Izzet Baysal University https://orcid.org/0000-0001-5073-0691 Bozdoğan Ömer ABANT IZZET BAYSAL UNIVERSITY https://orcid.org/0000-0002-9648-2811 Özdemir Şevval Abant Izzet Baysal University 08 30 2024 7 2 54 62 05 25 2023 05 02 2024 Copyright © 2018, Turkish Journal of Health Science and Life 2018 Turkish Journal of Health Science and Life

Bu çalışmada, akut iskemi-reperfüzyon ile uyarılan aritmiler sırasında, K-ATP kanal açıcı olarak Pinasidil ve kanal bloker olarak Glimepirid uygulaması ile, ATP bağımlı potasyum kanalının rolünü vurgulamak amaçlanmıştır. Çalışmada 4 grup olarak 6-7 aylık 58 adet erkek Sprague-Dawley türü sıçan kullanılmıştır. Cerrahi işleme trakeostomi ile başlanmıştır, ardından operasyon sırasında kan basıncını ölçmek için, sağ femoral arterden kanülasyon yapılmıştır. İpek iplikle koroner arter bağlanmıştır ve bu şekilde 6 dakika kadar iskemi oluşturulmuştur, bu ip gevşetilerek 6 dakika reperfüzyon yapılmıştır. Kontrol grubunda, iskeminin ikinci dakikasında ve reperfüzyon başlangıcında sadece ilaç çözücüleri uygulanmıştır. Gruplar arasında ilaç uygulama zamanı değiştirilmemiştir. Pinasidil grubunda, Pinasidil ilacı Glimepirid solventi ile uygulanmıştır ve aynı şekilde Glimepirid grubunda Pinasidil solventi uygulandı. Kombinasyon grubunda hem Pinasidil hem de Glimepirid ilaçları birlikte verilmiştir. Aritmi tipleri, süreleri ve aritmi skoru, tek yönlü ANOVA ve bağımsız t-testi kullanılarak yapılmıştır. Pinasidil tek başına reperfüzyon döneminde antiaritmik etki göstermiş, ama Glimepirid proaritmik etkili olmuştur. Kombinasyon durumunda Pinasidil'in koruyucu etkisi Glimepirid ile ortadan kalkmıştır. Sonuç olarak, kanal açıcı ve bloker kullanımı birlikte aritmiye karşı beklenen koruyucu etkiyi göstermemiştir. Bunun nedeninin iki ilacın aksiyon potansiyeli süresindeki farklı etkisiyle, normal ve iskemik hücreler arasındaki heterojenliğin artmasından kaynaklanabileceği düşünülmüştür. Pinasidilin tek başına aritmiye azaltıcı etkisi, ilacın hipotansif etkisiyle değil, onun aksiyon potansiyeli üzerine etkisiyle olabilir.

Aim: In previous studies, it was shown that both Pinacidil and Glimepiride have antiarrhythmic action in their pretreatment before ischemia. But there was no study found about their combined effect on the arrhythmia in the acute stage of ischemia and reperfusion. That is why in this study the combined acute effect of these two drugs on these arrhythmias was aimed to be researched. Main Method: 26 Anesthetized male Sprague-Dawley rats aged 6-7 years have been used in this study. Ischemia was performed for 6 min. by the ligation of left main coronary artery reperfusion by releasing the silk thread on the artery. Results: Pinacidil alone was anti-arrhythmic in reperfusion period, while Glimepiride was pro-arrhythmic. The protective effect of Pinacidil was abolished by Glimepiride in combination group, and the expected protective results against I/R induced arrhythmia were not observed. Conclusion: The result of this study showed that combination of KATP channel opener and blocker given in different time during ischemia and reperfusion period do not have synergic effect to decrease the arrhythmia. This might be increasing heterogeneity in action potential duration in ischemic or normal myocardium.

 myocardial ischemia reperfusion arrhythmia pinacidil glimepiride combination miyokardiyal iskemi reperfüzyon aritmi Pinacidil Glimepride kombinasyon Research fund grant from Abant Izzet Baysal University Grant No: 2022.03.01.1547 Baczkó, István, István Leprán, and Julius Gy Papp. “KATP channel modulators increase survival rate during coronary occlusion-reperfusion in anaesthetized rats.” European journal of pharmacology 324.1. 1997: 77-83.‏ D'Alonzo, Albert J., et al. “Effect of potassium on the action of the KATP modulators cromakalim, pinacidil, or glibenclamide on arrhythmias in isolated perfused rat heart subjected to regional ischaemia.” Cardiovascular research 28.6. 1994: 881-887 Ferrier, Gregory R., and Susan E. Howlett. “Pretreatment with pinacidil promotes arrhythmias in an isolated tissue model of cardiac ischemia and reperfusion.” Journal of Pharmacology and Experimental Therapeutics 313.2. 2005: 823-830. Gonca, Ersöz, and Ömer Bozdoğan. “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 15.4. 2010: 403-411. Trenor, B., J. M. Ferrero, and F. Montilla. “Pinacidil modifies the vulnerability to reentry during regional myocardial ischemia in a dose dependent manner: a simulation study.” Computers in Cardiology. IEEE, 2002 Vajda, Szilvia, István Baczkó, and István Leprán. “Selective cardiac plasma-membrane KATP channel inhibition is defibrillatory and improves survival during acute myocardial ischemia and reperfusion.” European journal of pharmacology 577.1-3. 2007: 115-123. Jia, Dalin. “The protective effect of mitochondrial ATP-Sensitive K+ channel opener, nicorandil, combined with Na+/Ca 2+ exchange blocker KB-R7943 on myocardial Ischemia–Reperfusion Injury in rat.” Cell biochemistry and biophysics 60. 2011: 219-224.‏ Manning, Allan S., and David J. Hearse. “Reperfusion-induced arrhythmias: mechanisms and prevention.” Journal of molecular and cellular cardiology 16.6. 1984: 497-518.‏ López-Barneo, José, Ricardo Pardal, and Patricia Ortega-Sáenz. “Cellular mechanism of oxygen sensing.” Annual review of physiology 63.1. 2001: 259-287 Rubart, Michael, and Douglas P. Zipes. “Mechanisms of sudden cardiac death.” The Journal of clinical investigation 115.9. 2005: 2305-2315.‏ Bartos, Daniel C., Eleonora Grandi, and Crystal M. Ripplinger. “Ion channels in the heart.” Comprehensive Physiology 5.3. 2015: 1423 Sag, Can M., Stefan Wagner, and Lars S. Maier. “Role of oxidants on calcium and sodium movement in healthy and diseased cardiac myocytes.” Free Radical Biology and Medicine 63. 2013: 338-349. Cohn, P. F. “Pharmacological treatment of ischaemic heart disease: monotherapy vs combination therapy.” European heart journal 18.suppl_B. 1997: 27-34.‏ 2 Brayden, Joseph E. “Functional roles of KATP channels in vascular smooth muscle.” Clinical and Experimental Pharmacology and Physiology 29.4. 2002: 312-316.‏ Nelson, Mark T., and John M. Quayle. “Physiological roles and properties of potassium channels in arterial smooth muscle.” American Journal of Physiology-Cell Physiology 268.4 1995: C799-C822.‏ Saltman, Adam E., et al. “Pharmacological preconditioning with the adenosine triphosphate–sensitive potassium channel opener pinacidil.” The Annals of thoracic surgery 70.2 2000: 595-601.‏ Friedel, Heather A., and Rex N. Brogden. “Pinacidil: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in the treatment of hypertension.” Drugs 39.6. 1990: 929-967.‏ Riveline, J. P., et al. “Sulfonylureas and cardiovascular effects: from experimental data to clinical use. Available data in humans and clinical applications.” Diabetes & metabolism 29.3. 2003: 207-222.‏ Du, Ren-Hong, et al. “Kir6. 2-containing ATP-sensitive K+ channel is required for cardioprotection of resveratrol in mice.” Cardiovascular diabetology 13.1. 2014: 1-9.‏ Adebiyi, Adebowale, Elizabeth M. McNally, and Jonathan H. Jaggar. “Sulfonylurea receptor-dependent and-independent pathways mediate vasodilation induced by ATP-sensitive K+ channel openers.” Molecular pharmacology 74.3. 2008: 736-743.‏ Wirth, Klaus J., et al. “HMR 1883, a cardioselective K ATP channel blocker, inhibits ischaemia-and reperfusion-induced ventricular fibrillation in rats.” Naunyn-Schmiedeberg's archives of pharmacology 360. 1999: 295-300.‏ Luzi, L., and G. Pozza. “Glibenclamide: an old drug with a novel mechanism of action?.” Acta diabetologica 34.4 .1997: 239-244.‏ Yaşar, S., Bozdoğan, Ö., Kaya, S. T., & Orallar, H. S. “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 18.2 (2015): 188.‏ Gross, Garrett J., and John A. Auchampach. “Blockade of ATP-sensitive potassium channels prevents myocardial preconditioning in dogs.” Circulation research 70.2. 1992: 223-233 Bozdogan Ö, Gonca E, Nebigil M, Tiryaki ES. Effect of Thimerosal on arrhythmia induced by coronary ligation. International Heart Journal. 2005;46(4):711–21. Walker, M. J. A., et al. “The Lambeth Conventions: guidelines for the study of arrhythmias in ischaemia, infarction, and reperfusion.” Cardiovascular research 22.7. 1988: 447-455.‏ Curtis MJ, Hancox JC, Farkas A, Wainwright CL, Stables CL, Saint DA, et al. The Lambeth Conventions (II): Guidelines for the study of animal and human ventricular and supraventricular arrhythmias. Pharmacology & Therapeutics. 2013 Aug 1;139(2):213–48. Das, B., and C. Sarkar. “Selective Mitochondrial K.” Methods Find Exp Clin Pharmacol 25.2. 2003: 97-110.‏ Watanabe, Ichiro, and Leonard S. Gettes. “Effects of pinacidil on ST-T wave alternans during acute myocardial ischemia in the in-situ pig heart.” in Journal of Nihon University Medical Association. 2017 Das, B., & Sarkar, C “Cardiomyocyte mitochondrial KATP channels participate in the antiarrhythmic and antiinfarct effects of KATP activators during ischemia and reperfusion in an intact anesthetized rabbit model.” Pol J Pharmacol 55.5. 2003: 771-86.‏ Das, Biswadeep, Chayna Sarkar, and K. Sudhakar Karanth. “Selective mitochondrial KATP channel activation results in antiarrhythmic effect during experimental myocardial ischemia/reperfusion in anesthetized rabbits.” European journal of pharmacology 437.3. 2002: 165-171.‏ Bozdoğan Ö, Yavuz E, Temi̇z A, Özdemi̇r Ş. The Acute Effects Of ATP-Sensitive Potassium Channel Opener (Pinacidil) And Blocker (Glimepride) On the Ischemia or Reperfusion-Induced Arrhythmias. Abant Med J. 2023 Apr 28;12(1):51–62. Simonovic N, Jakovljevic V, Jeremic J, Finderle Z, Srejovic I, Nikolic Turnic T, et al. Comparative effects of calcium and potassium channel modulators on ischemia/reperfusion injury in the isolated rat heart. Mol Cell Biochem. 2019 Jan 1;450(1):175–85. Skibsbye, L., & Ravens, U “Mechanism of proarrhythmic effects of potassium channel blockers.” Cardiac electrophysiology clinics 8.2 2016: 395-410.‏ Bernauer W. “Concerning the effect of the K+ channel blocking agent glibenclamide on ischaemic and reperfusion arrhythmias.” European journal of pharmacology 326.2-3 1997: 147-156.‏ del Valle, H. F., Lascano, E. C., Negroni, J. A., & Crottogini, A. J “Glibenclamide effects on reperfusion-induced malignant arrhythmias and left ventricular mechanical recovery from stunning in conscious sheep.” Cardiovascular research 50.3. 2001: 474-485.‏ Palácio, Plínio Bezerra, et al. “Pharmacological and molecular docking studies reveal that Glibenclamide competitively inhibits diazoxide-induced mitochondrial ATP-sensitive potassium channel activation and pharmacological preconditioning.” European Journal of Pharmacology 908. 2021: 174379.‏ Gute, Dean C., et al. “Inflammatory responses to ischemia, and reperfusion in skeletal muscle.” Molecular and cellular biochemistry 179. 1998: 169-187.‏ Sasaki, N., Sato, T., Ohler, A., O’Rourke, B., & Marbán, E. “Activation of mitochondrial ATP-dependent potassium channels by nitric oxide.” Circulation 101.4. 2000: 439-445.‏ Brayden, J. E., Quayle, J. M., Standen, N. B., & Nelson, M. T. “Role of potassium channels in the vascular response to endogenous and pharmacological vasodilators.” Journal of Vascular Research 28.1-3. 1991: 147-153.‏ Crestanello, Juan A., et al. “Opening of potassium channels protects mitochondrial function from calcium overload.” Journal of Surgical Research 94.2. 2000: 116-123. Eilertsen, E., et al. “Pharmacokinetics and distribution of the new antihypertensive agent pinacidil in rat, dog and man.” Xenobiotica 12.3. 1982: 177-185