The Concentration-dependent Investigation of the Toxic Effects of the Anorectic Agent Sibutramine on the Electrical Activity of the Cardiomyocytes in Metabolic Syndrome Rat Heart

Abstract

Objectives: Sibutramine (SBT) has been intensely used for losing weight over the past decades. In addition to the known mode of its action through brown adipose tissue thermogenesis, systemic actions reveal some side effects including alterations in cardiac function. Despite various clinical findings, the effect of SBT on cellular levels remains elusive. This study aimed to investigate the possible effects of sibutramine on the electrical activity of the cardiomyocytes from freshly isolated metabolic syndrome (MetS) rat hearts. Materials and Methods: Wistar type 2-month-old male rats were used. The animals were fed (20-22 weeks) with tap water containing 32% sucrose in addition to standard feed (20-22 weeks). MetS were confirmed using higher body weight, higher fasting blood glucose, and impaired glucose tolerance test. Heart tissue sections were stained with Masson Trichrome and examined under light microscopy. All patch-clamp experiments were performed in whole-cell mode, but action potentials were recorded in current-clamp configuration and voltage-gated K+-channel currents in voltage-clamp configuration from freshly isolated MetS cardiomyocytes. Acute SBT treatment was performed in a concentration-dependent manner (10-8-10-5 M) for all cardiomyocytes. Results: Histological examinations reveal that MetS hearts are characterized by a marked increase in collagen depositions. Electrophysiological findings show the significant prolongation in action potential duration, indicate pro-arrhythmic action for SBT treatment in a concentrationdependent manner. As voltage-gated K+-channel currents (IK) are responsible for changes in the repolarization of the action potentials (AP) in ventricular cardiomyocytes acute SBT treatment reduced IK channels significantly. Conclusion: This study showed that the effects of SBT on prolongation of action potential and reduction in IK channel density include proarrhythmic and detrimental outcomes in overweighed MetS hearts.

Keywords

• Sibutramine
• Electrical Activity
• Action Potential
• K+- Current
• Obesity
• Metabolic Syndrome

Anorektik Ajan Sibutraminin Metabolik Sendromlu Sıçan Ventrikül Hücrelerinin Elektriksel Aktivitesine Toksik Etkilerinin Konsantrasyona Bağlı İncelenmesi

Abstract

Amaç: Son yıllarda kısa sürede kilo kaybetmek için kullanılan sibutraminin (SBT) sistemik etki mekanizmaları arasında kahverengi yağ dokusu termogenezi, önemli yan etkileri arasında ise kalp fonksiyonunu bozucu etkileri öne çıkmaktadır. Çeşitli klinik bulgulara karşın, SBT’nin hücre seviyesindeki etkilerini gösteren çalışmalar çok sınırlıdır. Bu çalışmada SBT’nin metabolik sendrom (MetS) gelişmiş kilolu ve kalp fonksiyonları bozulmuş olan sıçan kardiyomiyositlerinin elektriksel aktivitesine olası etkilerinin incelenmesi hedeflenmiştir. Gereç ve Yöntem: Wistar türü 2 aylık erkek sıçanlar standart yeme ek olarak %32 oranında sükroz içeren çeşme suyu ile (yüksek karbonhidrat içerikli diyet modeli) beslenerek (20-22 hafta) MetS oluşturulmuş ve vücut ağırlığı, açlık kan şekeri ile glukoz tolerans test verileri kullanılarak MetS gelişimi doğrulanmıştır. Kalp doku kesitleri masson trikrom ile boyanarak ışık mikroskobu ile incelenmiştir. İzole edilen ventrikül hücrelerinde aksiyon potansiyelleri patch-klamp yöntemi tüm hücre modunda ve akım-kenetleme konfigürasyonunda, voltaj-kapılı K+-kanal akımları volta-kenetleme konfigürasyonunda kaydedilmiş ve SBT etkileri in vitro konsantrasyona (10-8-10-5 M) bağlı olarak incelenmiştir. Bulgular: Belirgin kollejen artışı ile karakterize MetS kalplerden izole edilen kardiyomiyositlerde uzamış olan aksiyon potansiyeli süresinin SBT uygulaması sonunda konsantrasyona bağlı olarak daha da uzadığı, aritmik bir davranış sergilediği gözlenmiştir. Bu uzamanın altında yatan nedenlerden olan voltaj-kapılı K+-kanal akımları incelendiğinde SBT’nin bu akımları doza bağlı olarak inhibe ettiği gözlenmiştir. Sonuç: SBT’nin kilolu MetS kalp fonksiyonları üzerindeki zararlı ve aritmik etkileri arasında ventrikül hücrelerinde aksiyon potansiyelini uzatması ve bu uzamadan inhibe olan voltaj-kapılı K+-kanal akımları olduğu bu çalışmada gösterilmiştir.

Keywords

• Sibutramin
• Elektriksel Aktivite
• Aksiyon Potansiyeli
• K+-Kanal Akımları
• Obezite
• Metabolik Sendrom

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