Sitagliptin does not improve isoprenaline-induced cardiac contractility in streptozotocin-induced diabetic rats

Year 2024, Volume: 54 Issue: 3, 359 - 367, 30.12.2024

Ceren Uyar Boztas , Betül Rabia Erdoğan , Ayhanım Elif Müderrisoğlu , Gizem Kaykı Mutlu , Zeynep Elif Yeşilyurt Dirican , İrem Karaömerlioğlu , Vecdi Melih Altan , Ebru Arıoğlu İnan

https://doi.org/10.26650/IstanbulJPharm.2024.1431797

Abstract

Background and Aims: Sitagliptin, a dipeptidyl peptidase IV (DPP-IV) inhibitor, has been shown to have beneficial effects on the diabetic heart. Beta-adrenoceptor (β-AR)-mediated responses are impaired in diabetes. Our aim was to investigate the impact of sitagliptin on the diabetic rat heart in terms of β-AR-mediated responsiveness. In addition, we examined the expression of proteins associated with diastolic dysfunction and endoplasmic reticulum (ER) stress, as well as proteins involved in the β-AR signalling pathway.
Methods: Eight-week-old Sprague-Dawley rats were divided into control, diabetic, and sitagliptin-treated (10 mg/kg/day for 4 weeks) diabetic groups. Type 1 diabetes was induced by intraperitoneal injection of streptozotocin (STZ). Throughout the treatment period, the rats received sitagliptin orally. Cardiac β-AR responsiveness was assessed using in vitro papillary muscle experiments with a nonselective β-AR agonist, isoprenaline, and in vitro Langendorff heart preparation experiments with a β3-AR selective agonist CL 316,243. Western blot experiments were conducted to assess the protein expression of SERCA2a, GRP78, β3-AR, eNOS, and p-eNOS.
Results: Sitagliptin did not reduce blood glucose levels or reverse weight loss in diabetic rats. However, it improved the heart weight to body weight ratio, indicating a reduction in cardiac hypertrophy. Sitagliptin did not correct the isoprenaline-induced contractile response in the diabetic group, nor did it alter the β3-AR mediated relaxation. Sitagliptin treatment also did not improve the downregulation of SERCA2a or the upregulation of GRP78. However, it reduced the upregulation of β3-AR. The protein expression of eNOS and the ratio of p-eNOS to eNOS were similar among the groups.
Conclusion: This study indicates that sitagliptin treatment did not improve isoprenaline-mediated contractile responses or affect β3-AR-mediated relaxation in the diabetic heart. However, the observed increase in β3-AR protein expression in the diabetic heart treated with sitagliptin indicated a potential differential effect of the drug on this pathway compared to the β1-AR signalling pathway. Further studies are needed to elucidate the precise mechanisms by which sitagliptin influences β3-AR-mediated pathways.

Keywords

Beta adrenoceptor, Diabetes, Heart, Isoprenaline, Sitagliptin

Ethical Statement

The study was approved by the local ethical committee of Ankara University (2014-24-161), and animal experiments were performed in accordance with the NIH Guidelines for Care and Use of Laboratory Animals.

Project Number

This study was supported partly by Ankara University Scientific Research Projects Coordination Unit (BAP-15L0237005) and The Scientific and Technological Research Council of Turkiye (SBAG-115S564).

References

• Ahmed, Y., Ali, Z. Y., Mohamed, M. A., Rashed, L. A., & Mohamed, E. K. (2021). Impact of combined therapy of mesenchymal stem cells and sitagliptin on a metabolic syndrome rat model. Journal of Diabetes & Metabolic Disorders, 20, 551-560. doi:https://doi. org/10.1007/s40200-021-00778-3 google scholar
• Amour, J., Loyer, X., Le Guen, M., Mabrouk, N., David, J.-S., Camors, E., . . . Heymes, C. (2007). Altered contractile response due to in-creased ^3-adrenoceptor stimulation in diabetic cardiomyopathy: The role of nitric oxide synthase 1-derived nitric oxide. Anes-thesiology, 107(3), 452-460. doi:https://doi.org/10.1097/01.anes. 0000278909.40408.24 google scholar
• Arioglu-Inan, E., Ozakca, I., Kayki-Mutlu, G., Sepici-Dincel, A., & Altan, V. M. (2013). The role of insulin-thyroid hormone in-teraction on ^-adrenoceptor-mediated cardiac responses. Euro-pean Journal of Pharmacology, 718(1-3), 533-543. doi:https: //doi.org/10.1016/j.ejphar.2013.06.021 google scholar
• Aroor, A. R., Sowers, J. R., Bender, S. B., Nistala, R., Garro, M., Mugerfeld, I., . . . Whaley-Connell, A. (2013). Dipeptidylpepti-dase inhibition is associated with improvement in blood pressure and diastolic function in insulin-resistant male Zucker obese rats. Endocrinology, 154(7), 2501-2513. doi:https://doi.org/10.1210/ en.2013-1096 google scholar
• Brodde, O.-E., Michel, M. C., & Zerkowski, H.-R. (1995). Sig-nal transduction mechanisms controlling cardiac contractil-ity and their alterations in chronic heart failure. Cardiovas-cular Research (30(4)), 570-584. doi:https://doi.org/10.1016/ S0008-6363(95)00152-2 google scholar
• Cao, Q., Xu, D., Chen, Y., Long, Y., Dai, F., Gui, L., & Lu, Y. (2021). Sitagliptin reduces endothelial dysfunction and apoptosis induced by high-fat diet and palmitate in thoracic aortas and endothelial cells via ROS-ER stress-CHOP pathway. Frontiers in Pharmacol-ogy, 12, 670389. doi:https://doi.org/10.3389/fphar.2021.670389 google scholar
• Connelly, K. A., Zhang, Y., Advani, A., Advani, S. L., Thai, K., Yuen, D. A., & Gilbert, R. E. (2013). DPP-4 inhibition attenuates cardiac dysfunction and adverse remodeling following myocardial infarc-tion in rats with experimental diabetes. Cardiovascular Thera-peutics, 31(5), 259-267. doi:https://doi.org/10.1111/1755-5922. 12005 google scholar
• Dincer, U. D., Bidasee, K. R., Guner, S. a., Tay, A., Ozcelikay, A. T., & Altan, V. M. (2001). The effect of diabetes on expression of j81-, jS2-, and ^3-adrenoreceptors in rat hearts. Diabetes, 50(2), 455-461. doi:https://doi.org/10.2337/diabetes.50.2.455 google scholar
• Erdogan, B. R., Michel, M. C., & Arioglu-Inan, E. (2020). Expression and signaling of ^-adrenoceptor subtypes in the diabetic heart. Cells, 9(12), 2548. doi:https://doi.org/10.3390/cells9122548 google scholar
• Esposito, G., Cappetta, D., Russo, R., Rivellino, A., Ciuffreda, L. P., Roviezzo, F., . . . De Angelis, A. (2017). Sitagliptin reduces inflammation, fibrosis and preserves diastolic function in a rat model of heart failure with preserved ejection fraction. British Journal of Pharmacology, 174(22), 4070-4086. doi:https://doi. org/10.1111/bph.13686 google scholar
• Gauthier, C., Leblais, V., Kobzik, L., Trochu, J.-N., Khandoudi, N., Bril, A., . . . Le Marec, H. (1998). The negative inotropic effect of beta3-adrenoceptor stimulation is mediated by activation of a nitric oxide synthase pathway in human ventricle. The Journal of Clinical Investigation, 102(7), 1377-1384. doi:https://doi.org/10. 1172/JCI2191 google scholar
• Gauthier, C., Tavernier, G., Charpentier, F., Langin, D., & Le Marec, H. (1996). Functional beta3-adrenoceptor in the human heart. The Journal of Clinical Investigation, 98(2), 556-562. doi:https: //doi.org/10.1172/JCI118823 google scholar
• Gopal, K., Chahade, J. J., Kim, R., & Ussher, J. R. (2020). The Impact of Antidiabetic Therapies on Diastolic Dysfunction and Diabetic Cardiomyopathy. Frontiers in Physiology, 11, 603247. doi:10.3389/fphys.2020.603247 google scholar
• Haley, J. M., Thackeray, J. T., Kolajova, M., Thorn, S. L., & DaSilva, J. N. (2015). Insulin therapy normalizes reduced myocardial 0-adrenoceptors at both the onset and after sustained hyperglycemia in diabetic rats. Life Sciences 132, 101-107. doi:https://doi.org/ 10.1016/j.lfs.2015.03.024 google scholar
• Hamdani, N., Hervent, A.-S., Vandekerckhove, L., Matheeussen, V., Demolder, M., Baerts, L., . . . De Keulenaer, G. W. (2014). Left ventricular diastolic dysfunction and myocardial stiffness in diabetic mice is attenuated by inhibition of dipeptidyl pep-tidase 4. Cardiovascular Research, 104(3), 423-431. doi:https: //doi.org/10.1093/cvr/cvu223 google scholar
• Ibrahim, M. A., Geddawy, A., & Abdel-Wahab, S. (2018). Sitagliptin prevents isoproterenol-induced myocardial infarction in rats by modulating nitric oxide synthase enzymes. European Journal of Pharmacology, 829, 63-69. doi:https://doi.org/10.1016/j.ejphar. 2018.04.005 google scholar
• Jiang, C., Carillion, A., Na, N., De Jong, A., Feldman, S., La-corte, J.-M., . . . Amour, J. (2015). Modification of the 0-adrenoceptor stimulation pathway in Zucker obese and obese dia-betic rat myocardium. Critical Care Medicine, 43(7), e241-e249. doi:https://doi.org/10.1097/CCM.0000000000000999 google scholar
• Kayki-Mutlu, G., Arioglu-Inan, E., Ozakca, I., Ozcelikay, A., & Al-tan, V. (2014). 03-Adrenoceptor-mediated responses in diabetic rat heart. General Physiology and Biophysics, 33(1), 99-109. doi:https://doi.org/10.4149/gpb_2013065 google scholar
• Khodeer, D. M., Bilasy, S. E., Farag, N. E., Mehana, A. E., & Elbaz, A. A. (2019). Sitagliptin protects diabetic rats with acute myocar-dial infarction through induction of angiogenesis: role of IGF-1 and VEGF. Canadian Journal of Physiology and Pharmacology 97(11), 1053-1063. doi:https://doi.org/10.1139/cjpp-2018-0670 google scholar
• Kizilay, G., Ersoy, O., Cerkezkayabekir, A., & Topcu-Tarladacalisir, Y. (2021). Sitagliptin and fucoidan prevent apoptosis and reduc-ing ER stress in diabetic rat testes. Andrologia, 53(3), e13858. doi:https://doi.org/10.1111/and.13858 google scholar
• Kranias, E. G., & Hajjar, R. J. (2012). Modulation of car-diac contractility by the phopholamban/SERCA2a reg-ulatome. Circulation Research, 110(12), 1646-1660. doi:https://doi.org/10.1161/CIRCRESAHA.111.259754https: //doi.org/10.1161/CIRCRESAHA.111.259754 google scholar
• Lee, T., Kao, Y., Chen, Y., Huang, J., Hsu, M., & Chen, Y. (2013). The dipeptidyl peptidase-4 inhibitor-sitagliptin modulates cal-cium dysregulation, inflammation, and PPARs in hypertensive car-diomyocytes. International Journal of Cardiology, 168(6), 53905395. doi:https://doi.org/10.1016/j.ijcard.2013.08.051 google scholar
• Lee, T.-M., Chen, W.-T., & Chang, N.-C. (2016). Sitagliptin de-creases ventricular arrhythmias by attenuated glucose-dependent insulinotropic polypeptide (GIP)-dependent resistin signalling in infarcted rats. Bioscience Reports, 36(2), e00307. doi:https: //doi.org/10.1042/BSR20150139 google scholar
• Lyseng-Williamson, K. A. (2007). Sitagliptin. Drugs, 67, 587-597. doi:https://doi.org/10.2165/00003495-200767040-00007 google scholar
• Marques, C., Goncalves, A., Pereira, P. M. R., Almeida, D., Martins, B., Fontes-Ribeiro, C., . . . Fernandes, R. (2019). The dipep-tidyl peptidase 4 inhibitor sitagliptin improves oxidative stress and ameliorates glomerular lesions in a rat model of type 1 di-abetes. Life Sciences, 234, 116738. doi:https://doi.org/10.1016/j. lfs.2019.116738 google scholar
• Moniotte, S., & Balligand, J.-L. (2003). The 0 3-adrenoceptor and its regulation in cardiac tissue. Intensivmedizin und Notfallmedizin, 40, 484-493. doi:https://doi.org/10.1007/s00390-003-0317-z google scholar
• Nakajima, Y., Ito, S., Asakura, M., Min, K.-D., Fu, H. Y., Imazu, M., . . . Fukuda, H. (2019). A dipeptidyl peptidase-IV inhibitor improves diastolic dysfunction in Dahl salt-sensitive rats. Journal of Molecular and Cellular Cardiology, 129, 257-265. doi:https: //doi.org/10.1016/j.yjmcc.2019.03.009 google scholar
• Ramirez, E., Picatoste, B., Gonzalez-Bris, A., Oteo, M., Cruz, F., Caro-Vadillo, A., . . . Lorenzo, O. (2018). Sitagliptin improved glucose assimilation in detriment of fatty-acid utilization in ex-perimental type-II diabetes: role of GLP-1 isoforms in Glut4 receptor trafficking. Cardiovascular Diabetology, 17(1), 1-13. doi:https://doi.org/10.1186/s12933-017-0643-2 google scholar
• Reimer, R. A., Grover, G. J., Koetzner, L., Gahler, R. J., Juneja, P., Lyon, M. R., & Wood, S. (2012). Sitagliptin reduces hyper-glycemia and increases satiety hormone secretion more effec-tively when used with a novel polysaccharide in obese Zucker rats. The Journal of Nutrition, 142(10), 1812-1820. doi:https: //doi.org/10.3945/jn.112.163204 google scholar
• Rozec, B., Noireaud, J., Trochu, J., & Gauthier, C. (2003). Place of beta 3-adrenoceptors among other beta-adrenoceptor subtypes in the regulation of the cardiovascular system. Archives Des Maladies Du Coeur Et Des Vaisseaux, 96(9), 905-913. google scholar
• Scheen, A. J. (2018). Cardiovascular effects of new oral glucose-lowering agents: DPP-4 and SGLT-2 inhibitors. Circula-tion Research, 122(10), 1439-1459. doi:https://doi.org/10.1161/ CIRCRESAHA.117.311588 google scholar
• Takada, A., Miki, T., Kuno, A., Kouzu, H., Sunaga, D., Itoh, T., . . . Ishikawa, S. (2012). Role of ER stress in ventricular contractile dysfunction in type 2 diabetes. PloS One, 7(6), e39893. doi:https: //doi.org/10.1371/journal.pone.0039893 google scholar
• Wolska, B., Stojanovic, M., Luo, W., Kranias, E., & Solaro, R. (1996). Effect of ablation of phospholamban on dynamics of cardiac myocyte contraction and intracellular Ca2+. American Journal of Physiology, 271(1), C391-C397. doi:https://doi.org/10.1152/ ajpcell.1996.271.1.C391 google scholar
• Wu, Y., Xu, M., Zhang, J.-H., & Bao, H. (2019). Sitagliptin inhibits EndMT in vitro and improves cardiac function of diabetic rats through the SDF-1a/PKApathway. European Review for Medical and Pharmacological Sciences, 23(2), 841-848. doi:https://doi. org/10.26355/eurrev_201901_16899 google scholar
• Yamaguchi, T., Watanabe, A., Tanaka, M., Shiota, M., Osada-Oka, M., Sano, S., . . . Matsunaga, S. (2019). A dipeptidyl peptidase-4 (DPP-4) inhibitor, linagliptin, attenuates cardiac dysfunction after myocardial infarction independently of DPP-4. Journal of Pharmacological Sciences, 139(2), 112-119. doi:https://doi.org/ 10.1016/j.jphs.2018.12.004 google scholar
• Zhou, Y., Wang, H., Man, F., Guo, Z., Xu, J., Yan, W., . . . Wang, W. (2018). Sitagliptin protects cardiac function by reducing nitrox-idative stress and promoting autophagy in Zucker diabetic fatty (ZDF) rats. Cardiovascular Drugs and Therapy, 32, 541-552. doi:https://doi.org/10.1007/s10557-018-6831-9 google scholar