Lack of evidence for improved β-adrenoceptor-mediated papillary muscle contraction by low-dose empagliflozin treatment in a rat model of streptozotocin-induced diabetes

Zeynep Elif Yeşilyurt Dirican; İrem Karaömerlioğlu; Betül Rabia Erdoğan; Gaye Öztürk; Martin Christian Michel; Ebru Arıoğlu İnan

doi:10.12991/jrespharm.1844982

Lack of evidence for improved β-adrenoceptor-mediated papillary muscle contraction by low-dose empagliflozin treatment in a rat model of streptozotocin-induced diabetes

Abstract

Diabetes mellitus leads to cardiovascular complications including impaired cardiac β-adrenoceptor (β-AR) function. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, such as empagliflozin (EMPA), improve outcomes in heart failure patients and animal models. Therefore, we have investigated the effects of EMPA on in vivo cardiac function and β-AR mediated contractile responses in streptozotocin (STZ)-induced diabetes in a design reflecting late-onset of treatment. Male Sprague Dawley rats were divided into 4 groups (control, EMPA-treated control, diabetic, and EMPA- treated diabetic). Diabetes was induced by STZ injection (40 mg/kg). 13-16 weeks after STZ injection, a low dose of EMPA (10 mg/kg/day, daily oral gavage) or vehicle was administered for another 8 weeks. At the end of the treatment period, in vivo cardiac function was evaluated by pressure-volume (PV) loop analysis and β-AR mediated contractile response was determined by isoprenaline on isolated papillary strips. The blood glucose-lowering effect of low-dose EMPA was confirmed. EMPA did not change cardiac function in control rats. Diabetic rats had a reduced heart rate, cardiac output, stroke work, rate of contraction and rate of relaxation and increased isovolumic relaxation, whereas in vitro responses were not markedly attenuated. Treatment with EMPA showed a trend for improvement of some (e.g., stroke volume, ejection fraction, cardiac index) but not all parameters. Our results indicate that low-dose EMPA treatment had limited effects on cardiac impairment despite reducing blood glucose when initiated after diabetes has manifested. Future studies using a preventive rather than therapeutic approach could help to clarify the possible benefits of EMPA on the diabetic heart.

Keywords

References

Pennig J, Scherrer P, Gissler MC, Anto-Michel N, Hoppe N, Füner L, Härdtner C, Stachon P, Wolf D, Hilgendorf I, Mullick A, Bode C, Zirlik A, Goldberg IJ, Willecke F. Glucose lowering by SGLT2-inhibitor empagliflozin accelerates atherosclerosis regression in hyperglycemic STZ-diabetic mice. Sci Rep. 2019; 9(1):17937. https://doi.org/10.1038/s41598-019-54224-9
Cho NH, Shaw JE, Karuranga S, Huang Y, da Rocha Fernandes JD, Ohlrogge AW, Malanda B. IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract. 2018; 138:271-281. https://doi.org/10.1016/j.diabres.2018.02.023
Lee TI, Chen YC, Lin YK, Chung CC, Lu YY, Kao YH, Chen YJ. Empagliflozin Attenuates Myocardial Sodium and Calcium Dysregulation and Reverses Cardiac Remodeling in Streptozotocin-Induced Diabetic Rats. Int J Mol Sci. 2019 Apr 4;20(7):1680. https://doi.org/10.3390/ijms20071680
Action to Control Cardiovascular Risk in Diabetes Study Group; Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH Jr, Probstfield JL, Simons-Morton DG, Friedewald WT. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24):2545-2559. https://doi.org/10.1056/NEJMoa0802743
ADVANCE Collaborative Group; Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560-2572. http://dx.doi.org/10.1056/NEJMoa0802987
Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve FJ, Marks J, Davis SN, Hayward R, Warren SR, Goldman S, McCarren M, Vitek ME, Henderson WG, Huang GD; VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360(2):129-139. doi: 10.1056/NEJMoa0808431. Epub 2008 Dec 17. Erratum in: N Engl J Med. 2009;361(10):1028. Erratum in: N Engl J Med. 2009;361(10):1024-1025. https://doi.org/10.1056/NEJMoa0808431
Michel MC, Mayoux E, Vallon V. A comprehensive review of the pharmacodynamics of the SGLT2 inhibitor empagliflozin in animals and humans. Naunyn Schmiedebergs Arch Pharmacol. 2015; 388(8):801-816. https://doi.org/10.1007/s00210-015-1134-1
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015; 373(22):2117-2128. https://doi.org/10.1056/NEJMoa1504720

Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR; CANVAS Program Collaborative Group. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017; 377(7):644-657. https://doi.org/10.1056/NEJMoa1611925
Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Zelniker TA, Kuder JF, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Ruff CT, Gause-Nilsson IAM, Fredriksson M, Johansson PA, Langkilde AM, Sabatine MS; DECLARE–TIMI 58 Investigators. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2019; 380(4):347-357. https://doi.org/10.1056/NEJMoa1812389
Cannon CP, Pratley R, Dagogo-Jack S, Mancuso J, Huyck S, Masiukiewicz U, Charbonnel B, Frederich R, Gallo S, Cosentino F, Shih WJ, Gantz I, Terra SG, Cherney DZI, McGuire DK; VERTIS CV Investigators.Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med. 2020; 383(15):1425- 1435. https://doi.org/10.1056/NEJMoa2004967
McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Bělohlávek J, Böhm M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukát A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CEA, Merkely B, Nicolau JC, O'Meara E, Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O, Sjöstrand M, Langkilde AM; DAPA-HF Trial Committees and Investigators. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019;381(21):1995-2008. https://doi.org/10.1056/NEJMoa1911303
Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, Januzzi J, Verma S, Tsutsui H, Brueckmann M, Jamal W, Kimura K, Schnee J, Zeller C, Cotton D, Bocchi E, Böhm M, Choi DJ, Chopra V, Chuquiure E, Giannetti N, Janssens S, Zhang J, Gonzalez Juanatey JR, Kaul S, Brunner-La Rocca HP, Merkely B, Nicholls SJ, Perrone S, Pina I, Ponikowski P, Sattar N, Senni M, Seronde MF, Spinar J, Squire I, Taddei S, Wanner C, Zannad F; EMPEROR-Reduced Trial Investigators. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020;383(15):1413-1424. https://doi.org/10.1056/NEJMoa2022190
Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Böhm M, Brunner-La Rocca HP, Choi DJ, Chopra V, Chuquiure-Valenzuela E, Giannetti N, Gomez-Mesa JE, Janssens S, Januzzi JL, Gonzalez-Juanatey JR, Merkely B, Nicholls SJ, Perrone SV, Piña IL, Ponikowski P, Senni M, Sim D, Spinar J, Squire I, Taddei S, Tsutsui H, Verma S, Vinereanu D, Zhang J, Carson P, Lam CSP, Marx N, Zeller C, Sattar N, Jamal W, Schnaidt S, Schnee JM, Brueckmann M, Pocock SJ, Zannad F, Packer M; EMPEROR-Preserved Trial Investigators. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med. 2021;385(16):1451- 1461.https://doi.org/10.1056/NEJMoa2107038
Solomon SD, McMurray JJV, Claggett B, de Boer RA, DeMets D, Hernandez AF, Inzucchi SE, Kosiborod MN, Lam CSP, Martinez F, Shah SJ, Desai AS, Jhund PS, Belohlavek J, Chiang CE, Borleffs CJW, Comin-Colet J, Dobreanu D, Drozdz J, Fang JC, Alcocer-Gamba MA, Al Habeeb W, Han Y, Cabrera Honorio JW, Janssens SP, Katova T, Kitakaze M, Merkely B, O'Meara E, Saraiva JFK, Tereshchenko SN, Thierer J, Vaduganathan M, Vardeny O, Verma S, Pham VN, Wilderäng U, Zaozerska N, Bachus E, Lindholm D, Petersson M, Langkilde AM; DELIVER Trial Committees and Investigators. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med. 2022;387(12):1089-1098. https://doi.org/10.1056/NEJMoa2206286
McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, Burri H, Butler J, Čelutkienė J, Chioncel O, Cleland JGF, Coats AJS, Crespo-Leiro MG, Farmakis D, Gilard M, Heymans S, Hoes AW, Jaarsma T, Jankowska EA, Lainscak M, Lam CSP, Lyon AR, McMurray JJV, Mebazaa A, Mindham R, Muneretto C, Francesco Piepoli M, Price S, Rosano GMC, Ruschitzka F, Kathrine Skibelund A; ESC Scientific Document Group. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42(36):3599-3726. doi: 10.1093/eurheartj/ehab368. Erratum in: Eur Heart J. 2021;42(48):4901. https://doi.org/10.1093/eurheartj/ehab368
Writing Committee; Maddox TM, Januzzi JL Jr, Allen LA, Breathett K, Butler J, Davis LL, Fonarow GC, Ibrahim NE, Lindenfeld J, Masoudi FA, Motiwala SR, Oliveros E, Patterson JH, Walsh MN, Wasserman A, Yancy CW, Youmans QR. 2021 Update to the 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2021;77(6):772- 810. https://doi.org/10.1016/j.jacc.2020.11.022
Ye Y, Bajaj M, Yang HC, Perez-Polo JR, Birnbaum Y. SGLT-2 inhibition with dapagliflozin reduces the activation of the Nlrp3/ASC inflammasome and attenuates the development of diabetic cardiomyopathy in mice with type 2 diabetes. Further augmentation of the effects with saxagliptin, a DPP4 inhibitor. Cardiovasc Drugs Ther. 2017; 31(2):119-132. https://doi.org/10.1007/s10557-017-6725-2
Hammoudi N, Jeong D, Singh R, Farhat A, Komajda M, Mayoux E, Hajjar R, Lebeche D. Empagliflozin Improves Left Ventricular Diastolic Dysfunction in a Genetic Model of Type 2 Diabetes. Cardiovasc Drugs Ther. 2017;31(3):233-246. https://doi.org/10.1007/s10557-017-6734-1
Arow M, Waldman M, Yadin D, Nudelman V, Shainberg A, Abraham NG, Freimark D, Kornowski R, Aravot D, Hochhauser E, Arad M. Sodium-glucose cotransporter 2 inhibitor Dapagliflozin attenuates diabetic cardiomyopathy. Cardiovasc Diabetol. 2020;19(1):7. https://doi.org/10.1186/s12933-019-0980-4
Habibi J, Aroor AR, Sowers JR, Jia G, Hayden MR, Garro M, Barron B, Mayoux E, Rector RS, Whaley-Connell A, DeMarco VG. Sodium glucose transporter 2 (SGLT2) inhibition with empagliflozin improves cardiac diastolic function in a female rodent model of diabetes. Cardiovasc Diabetol. 2017;16(1):9. https://doi.org/10.1186/s12933-016-0489-z
Liu L, Luo H, Liang Y, Tang J, Shu Y. Dapagliflozin ameliorates STZ-induced cardiac hypertrophy in type 2 diabetic rats by inhibiting the calpain-1 expression and nuclear transfer of NF-κB. Comput Math Methods Med. 2022; 2022:3293054. https://doi.org/10.1155/2022/3293054
Tian J, Zhang M, Suo M, Liu D, Wang X, Liu M, Pan J, Jin T, An F. Dapagliflozin alleviates cardiac fibrosis through suppressing EndMT and fibroblast activation via AMPKα/TGF-β/Smad signalling in type 2 diabetic rats. J Cell Mol Med. 2021;25(16):7642-7659. https://doi.org/10.1111/jcmm.16601
El-Sayed N, Mostafa YM, AboGresha NM, Ahmed AAM, Mahmoud IZ, El-Sayed NM. Dapagliflozin attenuates diabetic cardiomyopathy through erythropoietin up-regulation of AKT/JAK/MAPK pathways in streptozotocin-induced diabetic rats. Chem Biol Interact. 2021; 347:109617. https://doi.org/10.1016/j.cbi.2021.109617
Sun P, Wang Y, Ding Y, Luo J, Zhong J, Xu N, Zhang Y, Xie W. Canagliflozin attenuates lipotoxicity in cardiomyocytes and protects diabetic mouse hearts by inhibiting the mTOR/HIF-1α pathway. iScience. 2021;24(6):102521. https://doi.org/10.1016/j.isci.2021.102521
Lim VG, Bell RM, Arjun S, Kolatsi-Joannou M, Long DA, Yellon DM. SGLT2 inhibitor, canagliflozin, attenuates myocardial infarction in the diabetic and nondiabetic heart. ACC Basic Transl Sci. 2019; 4(1):15-26. https://doi.org/10.1016/j.jacbts.2018.10.002
Joubert M, Jagu B, Montaigne D, Marechal X, Tesse A, Ayer A, Dollet L, Le May C, Toumaniantz G, Manrique A, Charpentier F, Staels B, Magré J, Cariou B, Prieur X. The Sodium-Glucose Cotransporter 2 Inhibitor Dapagliflozin Prevents Cardiomyopathy in a Diabetic Lipodystrophic Mouse Model. Diabetes. 2017;66(4):1030- 1040. https://doi.org/10.2337/db16-0733
Kräker K, Herse F, Golic M, Reichhart N, Crespo-Garcia S, Strauß O, Grune J, Kintscher U, Ebrahim M, Bader M, Alenina N, Heuser A, Luft FC, Müller DN, Dechend R, Haase N. Effects of empagliflozin and target-organ damage in a novel rodent model of heart failure induced by combined hypertension and diabetes. Sci Rep. 2020;10(1):14061. https://doi.org/10.1038/s41598-020-70708-5
Ma S, He LL, Zhang GR, Zuo QJ, Wang ZL, Zhai JL, Zhang TT, Wang Y, Ma HJ, Guo YF. Canagliflozin mitigates ferroptosis and ameliorates heart failure in rats with preserved ejection fraction. Naunyn Schmiedebergs Arch Pharmacol. 2022;395(8):945-962. https://doi.org/10.1007/s00210-022-02243-1
Ideishi A, Suematsu Y, Tashiro K, Morita H, Kuwano T, Tomita S, Nakai K, Miura SI. Combination of Linagliptin and Empagliflozin Preserves Cardiac Systolic Function in an Ischemia-Reperfusion Injury Mice With Diabetes Mellitus. Cardiol Res. 2021;12(2):91-97. https://doi.org/10.14740/cr1194
Trang NN, Chung CC, Lee TW, Cheng WL, Kao YH, Huang SY, Lee TI, Chen YJ. Empagliflozin and Liraglutide Differentially Modulate Cardiac Metabolism in Diabetic Cardiomyopathy in Rats. Int J Mol Sci. 2021;22(3):1177. https://doi.org/10.3390/ijms22031177
Xing YJ, Liu BH, Wan SJ, Cheng Y, Zhou SM, Sun Y, Yao XM, Hua Q, Meng XJ, Cheng JH, Zhong M, Zhang Y, Lv K, Kong X. A SGLT2 Inhibitor Dapagliflozin Alleviates Diabetic Cardiomyopathy by Suppressing High Glucose-Induced Oxidative Stress in vivo and in vitro. Front Pharmacol. 2021 ;12:708177. https://doi.org/10.3389/fphar.2021.708177
Hodrea J, Saeed A, Molnar A, Fintha A, Barczi A, Wagner LJ, Szabo AJ, Fekete A, Balogh DB. SGLT2 inhibitor dapagliflozin prevents atherosclerotic and cardiac complications in experimental type 1 diabetes. PLoS One. 2022;17(2):e0263285.https://doi.org/10.1371/journal.pone.0263285
Zhou Y, Wu W. The sodium-glucose co-transporter 2 inhibitor, empagliflozin, protects against diabetic cardiomyopathy by inhibition of the endoplasmic reticulum stress pathway. Cell Physiol Biochem. 2017; 41(6):2503-2512. https://doi.org/10.1159/000475942
El-Shafey M, El-Agawy MSE, Eldosoky M, Ebrahim HA, Elsherbini DMA, El-Sherbiny M, Asseri SM, Elsherbiny NM. Role of Dapagliflozin and Liraglutide on Diabetes-Induced Cardiomyopathy in Rats: Implication of Oxidative Stress, Inflammation, and Apoptosis. Front Endocrinol (Lausanne). 2022;13:862394. https://doi.org/10.3389/fendo.2022.862394
Hasan R, Lasker S, Hasan A, Zerin F, Zamila M, Chowdhury FI, Nayan SI, Rahman MM, Khan F, Subhan N, Alam MA. Canagliflozin attenuates isoprenaline-induced cardiac oxidative stress by stimulating multiple antioxidant and anti-inflammatory signaling pathways. Sci Rep. 2020 ;10(1):14459. https://doi.org/10.1038/s41598-020-71449-1
National Institute for Health and Care Excellence. Type 2 diabetes in adults: management 2019 https://www.nice.org.uk/guidance/ng28 (accessed December 2019).
Harding SE, Brown LA, Wynne DG, Davies CH, Poole-Wilson PA. Mechanisms of ß adrenoceptor desensitisation in the failing human heart. Cardiovasc Res. 1994; 28:1451-1460. https://doi.org/10.1093/cvr/28.10.1451.
Brodde OE, Michel MC. Adrenergic and muscarinic receptors in the human heart. Pharmacol. Rev. 1999; 51(4):651-689. https://doi.org/10.1016/S0031-6997(24)01425-X
Brodde OE, Bruck H, Leineweber K. Cardiac adrenoceptors: physiological and pathophysiological relevance. J Pharmacol Sci. 2006; 100(5):323-337. https://doi.org/10.1254/jphs.CRJ06001X
Lohse MJ, Engelhardt S, Eschenhagen T. What is the role of beta-adrenergic signaling in heart failure? Circ Res. 2003; 93(10):896-906. https://doi.org/10.1161/01.RES.0000102042.83024.CA
Arioglu-Inan E, Kaykı-Mutlu G, Michel MC. Cardiac β3-adrenoceptors - a role in human pathophysiology? Br J Pharmacol. 2019; 176(14):2482-2495. https://doi.org/10.1111/bph.14635
Erdogan BR, Michel MC, Arioglu-Inan E. Expression and signaling of β-adrenoceptor subtypes in the diabetic heart. Cells. 2020;9(12):2548. https://doi.org/10.3390/cells9122548
Dinçer ÜD, Onay A, Arı N, Özçelikay AT, Altan VM. The effects of diabetes on b-adrenoceptor mediated responsiveness of human and rat atria. Diabetes Res Clin Pract. 1998; 40(2):113-122. https://doi.org/10.1016/S0168-8227(98)00034-5
Dinçer ÜD, Bidasee KR, Güner Ş, Tay A, Özçelikay AT, Altan VM. The effect of diabetes on expression of β1-,β2-, and β3-adrenoreceptors in rat hearts. Diabetes. 2001;50(2):455-461. https://doi.org/10.2337/diabetes.50.2.455
Jiang C, Carillion A, Na N, De Jong A, Feldman S, Lacorte JM, Bonnefont-Rousselot D, Riou B, Amour J. Modification of the β-Adrenoceptor Stimulation Pathway in Zucker Obese and Obese Diabetic Rat Myocardium. Crit Care Med. 2015;43(7):e241-9. https://doi.org/10.1097/CCM.0000000000000999
Oelze M, Kröller-Schön S, Welschof P, Jansen T, Hausding M, Mikhed Y, Stamm P, Mader M, Zinßius E, Agdauletova S, Gottschlich A, Steven S, Schulz E, Bottari SP, Mayoux E, Münzel T, Daiber A. The sodium- glucose co-transporter 2 inhibitor empagliflozin improves diabetes-induced vascular dysfunction in the streptozotocin diabetes rat model by interfering with oxidative stress and glucotoxicity. PLoS One. 2014 ;9(11):e112394. https://doi.org/10.1371/journal.pone.0112394
Steven S, Oelze M, Hanf A, Kröller-Schön S, Kashani F, Roohani S, Welschof P, Kopp M, Gödtel-Armbrust U, Xia N, Li H, Schulz E, Lackner KJ, Wojnowski L, Bottari SP, Wenzel P, Mayoux E, Münzel T, Daiber A. The SGLT2 inhibitor empagliflozin improves the primary diabetic complications in ZDF rats. Redox Biol. 2017;13:370-385. https://doi.org/10.1016/j.redox.2017.06.009
Wentworth JM, Fourlanos S, Colman PG, Harrison LC. A pilot study of the feasibility of empagliflozin in recent-onset type 1 diabetes. Metabol Open. 2020; 100021. https://doi.org/10.1016/j.metop.2020.100021
Rosenstock J, Marquard J, Laffel LM, Neubacher D, Kaspers S, Cherney DZ, Zinman B, Skyler JS, George J, Soleymanlou N, Perkins BA. Empagliflozin as Adjunctive to Insulin Therapy in Type 1 Diabetes: The EASE Trials. Diabetes Care. 2018 ;41(12):2560-2569. https://doi.org/10.2337/dc18-1749
Garg SK, Henry RR, Banks P, Buse JB, Davies MJ, Fulcher GR, Pozzilli P, Gesty-Palmer D, Lapuerta P, Simó R, Danne T, McGuire DK, Kushner JA, Peters A, Strumph P. Effects of Sotagliflozin Added to Insulin in Patients with Type 1 Diabetes. N Engl J Med. 2017;377(24):2337-2348. https://doi.org/10.1056/NEJMoa1708337
Arioglu Inan E, Ellenbroek JH, Michel MC. A systematic review of urinary bladder hypertrophy in experimental diabetes: part I. streptozotocin-induced rat models. Neurourol Urodyn. 2018; 37(4):1212-1219. https://doi.org/10.1002/nau.23490
Onay-Besikci A, Guner S, Arioglu E, Ozakca I, Ozcelikay AT, Altan VM. The effects of chronic trimetazidine treatment on mechanical function and fatty acid oxidation in diabetic rat hearts. Can J Physiol Pharmacol. 2007;85(5):527-535. https://doi.org/10.1139/y07-036
Hafez G, Gonulalan U, Kosan M, Arioglu E, Ozturk B, Cetinkaya M, Gur S. Acetylsalicylic acid protects erectile function in diabetic rats. Andrologia. 2014;46(9):997-1003. https://doi.org/10.1111/and.12187
Gonulalan U, Kosan M, Hafez G, Arioglu E, Akdemir O, Ozturk B, Gur S, Cetinkaya M. The effect of diabetes mellitus on alpha1-adrenergic receptor subtypes in the bladder of rats. Urology. 2012;80(4):951 e9-16. https://doi.org/10.1016/j.urology.2012.06.019
Arioglu-Inan E, Ozakca I, Kayki-Mutlu G, Sepici-Dincel A, Altan VM. The role of insulin-thyroid hormone interaction on beta-adrenoceptor-mediated cardiac responses. Eur J Pharmacol. 2013; 718(1-3):533-543. https://doi.org/10.1016/j.ejphar.2013.06.021
Ozakca I, Arioglu E, Guner S, Altan VM, Ozcelikay AT. Role of beta-3-adrenoceptor in catecholamine-induced relaxations in gastric fundus from control and diabetic rats. Pharmacology. 2007;80(4):227-238. https://doi.org/10.1159/000104876
Kayki-Mutlu G, Karaomerlioglu I, Arioglu-Inan E. The effect of nitric oxide synthase on beta 3 adrenoceptor mediated relaxation in STZ diabetic rat heart. J Fac Pharm Ankara. 2019; 43(1):64-71. https://doi.org/10.33483/jfpau.519948
Kayki-Mutlu G, Arioglu-Inan E, Ozakca I, Ozcelikay AT, Altan VM. beta3-Adrenoceptor-mediated responses in diabetic rat heart. Gen Physiol Biophys. 2014; 33(1):99-109. https://doi.org/10.4149/gpb_2013065
Mostafavinia A, Amini A, Ghorishi SK, Pouriran R, Bayat M. The effects of dosage and the routes of administrations of streptozotocin and alloxan on induction rate of type1 diabetes mellitus and mortality rate in rats. Lab Anim Res. 2016; 32(3):160-165. https://doi.org/10.5625/lar.2016.32.3.160
Zannad F, Ferreira JP, Pocock SJ, Anker SD, Butler J, Filippatos G, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet. 2020;396(10254):819-829. https://doi.org/10.1016/s0140-6736(20)31824-9
Yesilyurt ZE, Erdogan BR, Karaomerlioglu I, Muderrisoglu AE, Michel MC, Arioglu-Inan E. Urinary Bladder Weight and Function in a Rat Model of Mild Hyperglycemia and Its Treatment With Dapagliflozin. Front Pharmacol. 2019; 10:911. https://doi.org/10.3389/fphar.2019.00911
Yesilyurt ZE, Ertürk BM, Erdogan BR, Arioglu Inan E, Michel MC. Effects of the sodium-glucose transporter 2 inhibitor empagliflozin on bladder sie, contraction and ralexation in a rat model of type 1 diabetes. Neurourol Urodyn. 2021; 42 Suppl 2:S141-S2. https://doi.org/10.1002/nau.24746
Michel MC, Yesilyurt ZE, Öztürk G, Arioglu Inan E. Empagliflozin and linagliptin do not affect urinary bladder enlargement in a rat model of type 1 diabetes. Br J Pharmacol. 2021; 178:4977-4978. https://doi.org/10.1111/bph.15648
Kim DH, Kim YJ, Kim HK, Chang SA, Kim MS, Sohn DW, Oh BH, Park YB. Usefulness of mitral annulus velocity for the early detection of left ventricular dysfunction in a rat model of diabetic cardiomyopathy. J Cardiovasc Ultrasound. 2010;18(1):6-11. https://doi.org/10.4250/jcu.2010.18.1.6
Gauthier C, Tavernier G, Charpentier F, Langin D, Le Marec H. Functional beta3-adrenoceptor in the human heart. J Clin Invest. 1996; 98(2):556-562. https://doi.org/10.1172/JCI118823
Michel MC, Murphy TJ, Motulsky HJ. New Author Guidelines for Displaying Data and Reporting Data Analysis and Statistical Methods in Experimental Biology. Mol Pharmacol. 2020; 97(1):49-60. https://doi.org/10.1124/mol.119.118927
Erdogan BR, Vollert J, Michel MC. Choice of y-axis can mislead readers. Naunyn Schmiedebergs Arch Pharmacol. 2020; 393(9):1769-1772. https://doi.org/10.1007/s00210-020-01926-x
Amrhein V, Greenland S, McShane B. Scientists rise up against statistical significance. Nature. 2019;567(7748):305-307. https://doi.org/10.1038/d41586-019-00857-9
Michel MC, Murphy TJ, Motulsky HJ. New Author Guidelines for Displaying Data and Reporting Data Analysis and Statistical Methods in Experimental Biology. J Pharmacol Exp Ther. 2020; 372(1):136-147. https://doi.org/10.1124/jpet.119.264143

Details

Primary Language

English

Subjects

Medical Pharmacology

Journal Section

Research Article

Authors

Zeynep Elif Yeşilyurt Dirican
0000-0001-5659-8839
Türkiye

İrem Karaömerlioğlu
0000-0001-6851-8226
Türkiye

Betül Rabia Erdoğan
0000-0001-7377-4777
Türkiye

Gaye Öztürk
0000-0002-2073-7865
Türkiye

Martin Christian Michel This is me
0000-0003-4161-8467
Germany

Ebru Arıoğlu İnan ^*
0000-0002-0860-0815
Türkiye

Publication Date

January 11, 2026

Submission Date

November 19, 2024

Acceptance Date

March 23, 2025

Published in Issue

Year 2026 Volume: 30 Number: 1

DOI

https://doi.org/10.12991/jrespharm.1844982

IZ

https://izlik.org/JA47EK76YB

Cite

RIS / Bibtex

APA

Yeşilyurt Dirican, Z. E., Karaömerlioğlu, İ., Erdoğan, B. R., Öztürk, G., Michel, M. C., & Arıoğlu İnan, E. (2026). Lack of evidence for improved β-adrenoceptor-mediated papillary muscle contraction by low-dose empagliflozin treatment in a rat model of streptozotocin-induced diabetes. Journal of Research in Pharmacy, 30(1), 60-71. https://doi.org/10.12991/jrespharm.1844982

AMA

1.Yeşilyurt Dirican ZE, Karaömerlioğlu İ, Erdoğan BR, Öztürk G, Michel MC, Arıoğlu İnan E. Lack of evidence for improved β-adrenoceptor-mediated papillary muscle contraction by low-dose empagliflozin treatment in a rat model of streptozotocin-induced diabetes. J. Res. Pharm. 2026;30(1):60-71. doi:10.12991/jrespharm.1844982

Chicago

Yeşilyurt Dirican, Zeynep Elif, İrem Karaömerlioğlu, Betül Rabia Erdoğan, Gaye Öztürk, Martin Christian Michel, and Ebru Arıoğlu İnan. 2026. “Lack of Evidence for Improved β-Adrenoceptor-Mediated Papillary Muscle Contraction by Low-Dose Empagliflozin Treatment in a Rat Model of Streptozotocin-Induced Diabetes”. Journal of Research in Pharmacy 30 (1): 60-71. https://doi.org/10.12991/jrespharm.1844982.

EndNote

Yeşilyurt Dirican ZE, Karaömerlioğlu İ, Erdoğan BR, Öztürk G, Michel MC, Arıoğlu İnan E (January 1, 2026) Lack of evidence for improved β-adrenoceptor-mediated papillary muscle contraction by low-dose empagliflozin treatment in a rat model of streptozotocin-induced diabetes. Journal of Research in Pharmacy 30 1 60–71.

IEEE

[1]Z. E. Yeşilyurt Dirican, İ. Karaömerlioğlu, B. R. Erdoğan, G. Öztürk, M. C. Michel, and E. Arıoğlu İnan, “Lack of evidence for improved β-adrenoceptor-mediated papillary muscle contraction by low-dose empagliflozin treatment in a rat model of streptozotocin-induced diabetes”, J. Res. Pharm., vol. 30, no. 1, pp. 60–71, Jan. 2026, doi: 10.12991/jrespharm.1844982.

ISNAD

Yeşilyurt Dirican, Zeynep Elif - Karaömerlioğlu, İrem - Erdoğan, Betül Rabia - Öztürk, Gaye - Michel, Martin Christian - Arıoğlu İnan, Ebru. “Lack of Evidence for Improved β-Adrenoceptor-Mediated Papillary Muscle Contraction by Low-Dose Empagliflozin Treatment in a Rat Model of Streptozotocin-Induced Diabetes”. Journal of Research in Pharmacy 30/1 (January 1, 2026): 60-71. https://doi.org/10.12991/jrespharm.1844982.

JAMA

1.Yeşilyurt Dirican ZE, Karaömerlioğlu İ, Erdoğan BR, Öztürk G, Michel MC, Arıoğlu İnan E. Lack of evidence for improved β-adrenoceptor-mediated papillary muscle contraction by low-dose empagliflozin treatment in a rat model of streptozotocin-induced diabetes. J. Res. Pharm. 2026;30:60–71.

MLA

Yeşilyurt Dirican, Zeynep Elif, et al. “Lack of Evidence for Improved β-Adrenoceptor-Mediated Papillary Muscle Contraction by Low-Dose Empagliflozin Treatment in a Rat Model of Streptozotocin-Induced Diabetes”. Journal of Research in Pharmacy, vol. 30, no. 1, Jan. 2026, pp. 60-71, doi:10.12991/jrespharm.1844982.

Vancouver

1.Zeynep Elif Yeşilyurt Dirican, İrem Karaömerlioğlu, Betül Rabia Erdoğan, Gaye Öztürk, Martin Christian Michel, Ebru Arıoğlu İnan. Lack of evidence for improved β-adrenoceptor-mediated papillary muscle contraction by low-dose empagliflozin treatment in a rat model of streptozotocin-induced diabetes. J. Res. Pharm. 2026 Jan. 1;30(1):60-71. doi:10.12991/jrespharm.1844982