Effect of pantoprazole on I-R -induced myocardial injury in diabetic rats targeting inflammatory cytokine release and oxidative stress

Document Type : Original Article


1 Department of Pharmacology, Amity Institute of Pharmacy, Amity University, Uttar Pradesh-201303, India

2 Cardiovascular Division, Department of Pharmacology, Amity University Haryana, Gurugram-122413, India

3 Rajendra Institute of Technology and Sciences (RITS), Sirsa, Haryana, India

4 Gurukul Kangri Vishvidyalaya Haridwar, Uttarakhand, India


Objective(s): To evaluate the pleiotropic potential and underlying mechanism of pantoprazole (PPZ) (common Proton Pump Inhibitors, PPIs) in type 2 diabetes mellitus (T2DM) -associated ischemia/reperfusion (I-R)-induced myocardial infarction which is still uncharted. Whereas some other PPIs have demonstrated their anti-diabetic, antioxidant, and anti-inflammatory potential.
Materials and Methods: We evaluated the potential of coinciding treatment of PPZ (4 mg/kg/po/day for 8 weeks) in Wistar albino rats against STZ (50 mg/kg/IP) induced T2DM model and I-R provoked cardiac infarction model in diabetic and non-diabetic condition.
Results: PPZ significantly inhibited the perturbed deviations in blood glucose concentration, HbA1c, C-peptide, plasma insulin, and ameliorated the lipid profile (dyslipidemia). PPZ protected myocardial tissue against lipid peroxidation by restoring the levels of serum TBARS and reduced NBT. The significant protective effects of PPZ were evident by ameliorating CKMB, LDH, cTnI, and myocardial oxidative stress in PPZ treated animals. Additionally, PPZ prominently reduced various proinflammatory cytokines release including TGF-β1, TNF-α, and IL-6. PPZ upsurges the bioavailability of nitrite/nitrate concentration which may pacify the impact of myocardial infarction in diabetic I-R injury.
Conclusion: The consequences indicate that PPZ possesses a potent protective effect against diabetic I-R-induced myocardial infarction via suppressing oxidative stress, inflammation, and dyslipidemia-associated tissue damage.


1. Demographic and geographic outline. [cited 2021 Jan 1]. Available from: URL: https://www.diabetesatlas.org/en/sections/demographic-and-geographic-outline.html
2. Goyal SN, Sharma AK, Haiderali S, Reddy M N, Arya DS, Patil CR. Erratum: Prediabetes: grounds of pitfall signalling alteration for cardiovascular disease. RSC Adv 2015; 5:1619-1619.
3. Sharma G, Sahu M, Kumar A, Sharma AK, Aeri V, and Katare DP. Temporal dynamics of pre and post myocardial infarcted tissue with concomitant preconditioning of aerobic exercise in chronic diabetic rats. Life Sci 2019; 225:79–87.
4. Yu XY, Chen HM, Liang JL, Lin QX, Tan HH, Fu YH, et al. Hyperglycemic myocardial damage is mediated by proinflammatory cytokine: Macrophage migration inhibitory factor. PLoS One 2011; 6:e16239.
5. Ghebre Y and Raghu G. Proton pump inhibitors in IPF: Beyond mere suppression of gastric acidity. QJM Oxford University Press; 2016; 109:577–579.
6. Naseri E and Yenisehirli A. Proton pump inhibitors omeprazole and lansoprazole induce relaxation of isolated human arteries. Eur J Pharmacol 2006; 531:226–231.
7. Lin H, Li Y, Zhu H, Wang Q, Chen Z, Chen L, et al. Lansoprazole alleviates pressure overload-induced cardiac hypertrophy and heart failure in mice by blocking the activation of β-catenin. Cardiovasc Res 2020; 116:101-113.
8. Yenisehirli A and Onur R. Positive inotropic and negative chronotropic effects of proton pump inhibitors in isolated rat atrium. Eur J Pharmacol 2005; 519:259–266.
9. Patlolla JMR, Zhang Y, Li Q, Steele VE, and Rao C V. Anti-carcinogenic properties of omeprazole against human colon cancer cells and azoxymethane-induced colonic aberrant crypt foci formation in rats. Int J Oncol 2012; 40:170–175.
10. Yates TA, Tomlinson LA, Bhaskaran K, Langan S, Thomas S, Smeeth L, et al. Lansoprazole use and tuberculosis incidence in the United Kingdom Clinical Practice Research Datalink: A population based cohort. PLoS Med 2017; 14:e1002457.
11. Dias LM. Pantoprazole: A proton pump inhibitor. Clin Drug Investig 2009; 29:3–12.
12. Tabeefar H, Beigmohammadi MT, Javadi MR, Abdollahi M, Mahmoodpoor A, Ahmadi A, et al. Effects of pantoprazole on systemic and gastric pro- and anti-inflammatory cytokines in critically Ill patients. Iran J Pharm Res  2012; 11:1051–1058.
13. Koh JS, Joo MK, Park JJ, Yoo HS, Choi B Il, Lee BJ, et al. Inhibition of STAT3 in gastric cancer: Role of pantoprazole as SHP-1 inducer. Cell Biosci 2018; 8:50.
14. Yan X-X, Zheng A-D, Zhang Z-E, Pan G-C, and Zhou W. Protective effect of pantoprazole against sepsis-induced acute lung and kidney injury in rats. Am J Transl Res 2019; 11:5197–5211.
15. Does pantoprazole protect against reperfusion injury following myocardial ischemia in rats? - PubMed. [cited 2020 Dec 30]. Available from: URL: https://pubmed.ncbi.nlm.nih.gov/23377820/
16. Sharma AK, Kumar A, Sahu M, Sharma G, Datusalia AK, and Rajput SK. Exercise preconditioning and low dose copper nanoparticles exhibits cardioprotection through targeting GSK-3β phosphorylation in ischemia/reperfusion induced myocardial infarction. Microvasc Res 2018; 120:59–66.
17. Sharma AK, Kumar A, Taneja G, Nagaich U, Deep A, Datusalia AK, et al. Combined and individual strategy of exercise generated preconditioning and low dose copper nanoparticles serve as superlative approach to ameliorate ISO-induced myocardial infarction in rats. Pharmacol Reports 2018; 70:789–795.
18. Casciaro M, Navarra M, Inferrera G, Liotta M, Gangemi S, and Minciullo PL. PPI adverse drugs reactions: a retrospective study. Clin Mol Allergy 2019; 17:1-5.
19. Villegas K, Meier JL, Long M, Lopez J, and Swislocki A. The Effect of Proton Pump Inhibitors on Glycemic Control in Patients with Type 2 Diabetes. Metab Syndr Relat Disord 2019; 17:192–196.
20. Lin H-C, Hsiao Y-T, Lin H-L, Uang Y-S, Cheng H-W, Wang Y, et al. The use of proton pump inhibitors decreases the risk of diabetes mellitus in patients with upper gastrointestinal disease: A population-based retrospective cohort study. Medicine (Baltimore) 2016; 95:e4195.
21. Sherwani SI, Khan HA, Ekhzaimy A, Masood A, and Sakharkar MK. Significance of HbA1c Test in Diagnosis and Prognosis of Diabetic Patients. Biomark Insights 2016; 11:95–104.
22. Sharma G, Ashhar MU, Aeri V, and Katare DP. Development and characterization of late-stage diabetes mellitus and -associated vascular complications. Life Sci 2019; 216:295–304.
23. Sharma AK, Kumar A, Taneja G, Nagaich U, Deep A, and Rajput SK. Synthesis and preliminary therapeutic evaluation of copper nanoparticles against diabetes mellitus and -induced micro- (renal) and macro-vascular (vascular endothelial and cardiovascular) abnormalities in rats. RSC Adv 2016; 6:36870–36880.
24. Sharma AK, Taneja G, Khanna D, and Rajput SK. Reactive oxygen species: friend or foe? RSC Adv 2015; 5:57267–57276.
25. Wang Y, Song X, Yue X, Su H, Gu Y, Bowman L, et al. Protection by nitrite against the ischemic effects induced by acute myocardial infarction in mice. Anatol J Cardiol 2017; 18:315–320.
26. Xia M, Liu L, Qiu R, Li M, Huang W, Ren G, et al. Anti-inflammatory and anxiolytic activities of Euphorbia hirta extract in neonatal asthmatic rats. AMB Express 2018; 8:179-192.
27. Kumar S, Malhotra R, and Kumar D. Euphorbia hirta : Its chemistry, traditional and medicinal uses , and pharmacological activities. 2010; 4:58-61.
28. Subramanian SP, Bhuvaneshwari S, and Prasath GS. Antidiabetic and antioxidant potentials of Euphorbia hirta leaves extract studied in streptozotocin-induced experimental diabetes in rats. 2011; 278–285.
29. Sharma AK, Khanna D, and Balakumar P. Low-dose dipyridamole treatment partially prevents diabetes mellitus-induced vascular endothelial and renal abnormalities in rats. Int J Cardiol 2014; 172:530–532.
30. Beysel S, Unsal IO, Kizilgul M, Caliskan M, Ucan B, and Cakal E. The effects of metformin in type 1 diabetes mellitus. BMC Endocr Disord 2018; 18:1-13.