Investigation of the Effect of the Antiaggregant Agent Ticagrelor on the Electrical and Mechanical Activities of Rat Heart With Type 1 Diabetes

Abstract

Objectives: Diabetes mellitus (DM) is presently a worldwide health problem and leads to high risks for cardiovascular disfunction. Besides vascular disorders independent diabetic-cardiomyopathy, high thrombocyte reactivity is developed in DM. In this study, we aimed to examine the effect ofP2Y12 receptor blocker ticagrelor (TICA) on heart function of DM rats. Materials and Methods: DM was induced by a single-dose of streptozotocin (STZ) injection in 3-month-old Wistar male rats (250-300g) andconfirmed by blood glucose level, 48-hour following STZ-injection. After DM confirmation, those animals were kept for 8 weeks and then, they weredivided into two groups. One half DM rats was treated with TICA (150 mg/kg/day, orally) for 4 weeks (DM+TICA group), while the second half groupwas treated with water (DM group). A third group of rats was treated with only water (Con-group). In situ electrocardiography (ECG)-recording wasperformed under mild anesthesia and mechanical activities of isolated hearts wereexamined by Langendorff-perfusion-system. Results: The body weight of the DM group was significantly reduced compared to the Con group (p<0.05), while their blood glucose level was about 4-fold higher thanthe Con-group. However, TICA treatment of the DM group had no significant effect on both low body weight andhigh blood glucose level. The calculated values for QT- and RR-intervals from ECGs and low heart-rate in the DM group could not be recovered with TICA treatment (p>0.05). Furthermore, TICA treatment did not affect reduced left ventricular pressure and increased left ventricular enddiastolic pressure of the DM group. However, TICA treatment was further prolonged half relaxation time of left ventricular pressure, which was also prolonged in the DM group (p<0.05). Moreover, the β-adrenergic response of left ventricular pressure was even further reduced in TICA-treated DM group compared to the untreated DM group. Conclusion: Our data demonstrated that TICA treatment could not improve the depressed electrical and mechanical activity of DM rat heart, even with some negative effects. Overall, our study emphasized the importance of performing additional TICA treatment experiments either with different doses, different treatment periods, or both to clarify its effects on cardiovascular system function

Keywords

• Diabetic Cardiomyopathy
• Ticagrelor
• P2Y12 Receptor
• ECG
• Contractility

Tip 1 Diyabetli Sıçan Kalbi Elektriksel ve Mekanik Aktivitelerine Antiagregan Ajan Tikagrelorun Etkisinin İncelenmesi

Abstract

Amaç: Günümüze diabetes mellitus (DM) yaygın olarak görülmekte olup kardiyovasküler bozukluklar için önemli bir risk faktörüdür. DM’li hastalarda vasküler bozukluklardan bağımsız olarak gelişen diyabetik kardiyomiyopati yanında, yüksek trombosit-reaktivitesi gelişmektedir. Bu çalışmada, bir P2Y12 reseptör blokörü tikagrelorun (TİKA), DM’li sıçan kalp fonksiyonuna etkisinin incelenmesi hedeflenmiştir. Gereç ve Yöntem: Bu çalışmada ağırlıkları 250-300 gr arasında değişen Wistar türü erkek sıçanlar kullanılarak bir grup sıçana tek doz streptozotosin (STZ; 50 mg/kg) uygulanarak DM (48-saat sonra kan şekeri ölçülerek) oluşturulmuştur. DM olan sıçanların bir grubuna 8 hafta sonra gavaj yoluyla TİKA (150 mg/kg/gün) 4 hafta boyunca uygulanmıştır (DM+TİKA grubu). STZ enjekte edilen ikinci gruba bu süre içinde su uygulanmıştır (DM grubu). Üçüncü grup sıçana aynı süre su uygulanmıştır (Kon grubu). Uygulama sonrasında sıçanlarda hafif anestezi altında in situ elektrokardiyografi (EKG) kaydedilmiş ve kalpler izole edilerek Langendorff-perfüzyon sisteminde kalbin mekanik aktivitesi ölçülmüştür. Bulgular: Hem DM’li hem de DM+TİKA’lı grup sıçanların kilo kaybederek, vücut-ağırlıklarının Kon-grubuna göre önemli derecede azalmış olduğu (p<0,05), ve DM’li gruptaki yaklaşık 4 kat yüksek olan açlık kan şekeri düzeyinin DM+TİKA grubunda da değişmediği gözlenmiştir. DM’li grupta, EKG parametreleri olan QT- ve RR-intervallerindeki uzamaların ve yavaşlamış kalp-atım hızının TİKA uygulanan grupta da benzer olduğu (p>0,05) gözlenmiştir. Ayrıca, DM’li grupta deprese olan sol ventrikül-içi basınç ile ve sol ventrikül-içi diyastol sonu basınç değişimlerinin DM+TİKA’lı grupta da benzer olduğu, buna karşın DM’li grupta uzamış olan gevşeme süresinin bu grupta daha fazla uzamış olduğu gözlenmiştir (p<0,05). Bunlara ek olarak, DM’li grupta azalmış olan β-adrenerjik yanıtların DM+TİKA grubunda daha da azaldığı gözlenmiştir. Sonuç: Tüm veriler değerlendirildiğinde, TİKA uygulamasının DM’li sıçan kalbinin bozulan elektriksel ve mekanik aktiviteleri üzerinde pozitif etkiler oluşturamadığı, bunun yanında bazı negatif etkiler oluşturabildiği gözlenmiştir. Bu çalışmanın sonuçları, TİKA’nın DM’li memelilerde kalp fonksiyonuna olan etkilerini açıklayabilmek için farklı süreler ve farklı dozlarda TİKA uygulamalı incelemelere ihtiyaç olduğunu vurgulamaktadır.

Keywords

• Ticagrelor
• P2Y12 Reseptörü
• EKG
• Kontraktilite

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