Evaluation of Nicorandil in Treatment of induced pulmonary arterial hypertension in male Rats

Authors

  • Taha Hashim Ahmed Department of Pharmacology and Toxicology, College of Pharmacy, Mustansiriyah University, Iraq
  • Israa Burhan Raoof Department of Clinical Laboratories Sciences, College of Pharmacy, Mustansiriyah University, Iraq
  • Bahir Abdul-Razzaq Mshemish Department of Pharmacology and Toxicology, College of Pharmacy, Mustansiriyah University, Iraq

DOI:

https://doi.org/10.32947/ajps.v24i3.1077

Keywords:

Nicorandil, tadalafil, Brain natriuretic peptide, Pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a chronic, rare, and non-treatable disease, resulting in elevated mean arterial pressure (≥25mmHg) during rest and (≥30mmHg) during exercise.

 

 Pulmonary arteries remodeling including endothelial apoptosis, smooth muscle hyperplasia, and endothelial dysfunction are distinct features of PAH. This study aims to evaluate effect of nicorandil as an alternative treatment for PAH in comparison to tadalafil by evaluating its anti-inflammatory effect and histopathological changes. A total of 60 male wistar rats were divided to 6 groups, a control healthy group, and another 5 groups injected with monocrotaline to induce PAH. The induction group was left untreated while the other 4 groups were treated with either nicorandil or tadalafil, with or without treatment blockers (N-Nitroarginine methyl ester and glimepiride), after 21 days they were sacrificed for histopathology and measurement of inflammatory markers. Nicorandil reduced the levels of osteopontin, and cardiac marker brain natriuretic peptide (BNP) significantly (P≤0.05) , also it showed an improved histopathological picture of PAH by reducing smooth muscle proliferation, necrosis, and inflammation in pulmonary arteries. In conclusion, nicorandil in this study showed promising results in reducing inflammation and improving endothelial function.

 

References

- Arnold ND, Pickworth JA, West LE, Dawson S, Carvalho JA, Casbolt H, et al. A therapeutic antibody targeting osteoprotegerin attenuates severe experimental pulmonary arterial hypertension. Nat Commun 2019;10(1).

- Corssac GB, Bonetto JP, Campos-Carraro C, Cechinel LR, Zimmer A, Parmeggiani B, et al. Pulmonary arterial hypertension induces the release of circulating extracellular vesicles with oxidative content and alters redox and mitochondrial homeostasis in the brains of rats. Hypertension Research 2021;44(8).

- Thenappan T, Ormiston ML, Ryan JJ, Archer SL. Pulmonary arterial hypertension: Pathogenesis and clinical management. BMJ (Online)2018;360.

- Zhang X, Yu Q, Yao X, Liu G, Li J, Du L. Effects of nicorandil on all-cause mortality and cardiac events in CAD patients receiving PCI: A systematic review and meta-analysis. Int Heart J 2019;60(4).

- Shi L, Chen L, Qi G, Tian W, Zhao S. Effects of Intracoronary Nicorandil on Myocardial Microcirculation and Clinical Outcomes in Patients with Acute Myocardial Infarction: A Meta-Analysis of Randomized Controlled Trials. American Journal of Cardiovascular Drugs 2020;20(2).

- Le Ribeuz H, Masson B, Dutheil M, Boët A, Beauvais A, Sabourin J, et al. Involvement of SUR2/Kir6.1 channel in the physiopathology of pulmonary arterial hypertension. Front Cardiovasc Med 2023;9.

- Oh JG, Ishikawa K. Experimental models of cardiovascular diseases: Overview. In: Methods in Molecular Biology. 2018.

- Lenz M, Kaun C, Krychtiuk KA, Haider P, Brekalo M, Maier N, et al. Effects of nicorandil on inflammation, apoptosis and atherosclerotic plaque progression. Biomedicines 2021;9(2).

- Leong ZP, Hikasa Y. Effects of masitinib compared with tadalafil for the treatment of monocrotaline-induced pulmonary arterial hypertension in rats. Vascul Pharmacol 2019;122–123.

- Sahara M, Sata M, Morita T, Hirata Y, Nagai R. Nicorandil attenuates monocrotaline-induced vascular endothelial damage and pulmonary arterial hypertension. PLoS One 2012;7(3).

- Dong Y, Chen YT, Yang YX, Shou D, Li CY. Urinary metabolomic profiling in Zucker diabetic fatty rats with type 2 diabetes mellitus treated with glimepiride, metformin, and their combination. Molecules 2016;21(11).

- ’Jawad M, ’Jasim G. Biochemical and Histopathological evaluation of prostatic tissue under effect of Pterostilbene in benign prostatic hyperplasia rat model. Al-Mustansiriyah Journal of Pharmaceutical Sciences (AJPS) 2023;23(2).

- ’Al-Khfajy wrood’, ’Arif I, ’Al-Sudani B. Role of Fasting Mimicking Diet in Farnesoid x Receptor for Suppressing Epithelial-to-Mesenchymal Transition, Cell Cycle Progression, and Viability of Prostate Cancer Cells. raqi J Pharm Sci 2023;32(1).

- Silva IAN, Gvazava N, Bölükbas DA, Stenlo M, Dong J, Hyllen S, et al. A Semi-quantitative Scoring System for Green Histopathological Evaluation of Large Animal Models of Acute Lung Injury. Bio Protoc 2022;12(16).

- Dasgupta A, Wahed A. Cardiac Markers. Clinical Chemistry, Immunology and Laboratory Quality Control 2014;127–44.

- Helgeson S, Imam J, Moss J, Hodge D, Burger C. Comparison of Brain Natriuretic Peptide Levels to Simultaneously Obtained Right Heart Hemodynamics in Stable Outpatients with Pulmonary Arterial Hypertension. Diseases 2018;6(2).

- Rampa DR, Murugesan P, Chao H, Feng H, Dai W, Lee D, et al. Reversal of pulmonary arterial hypertension and neointimal formation by kinin B1 receptor blockade. Respir Res 2021;22(1).

- Klinger J. Brain natriuretic peptide in pulmonary arterial hypertension: biomarker and potential therapeutic agent. Drug Des Devel Ther 2009;

- Zuo X-R WQCQYYZWHBLQ et al. Nicorandil Prevents Right Ventricular Remodeling by Inhibiting Apoptosis and Lowering Pressure Overload in Rats with Pulmonary Arterial Hypertension. PLoS One 2012;

- Nemoto K, Oh-ishi S, Inui T, Nakazawa M, Hyodo K, Nakajima M, et al. Long-term improvement during tadalafil therapy in a patient with pulmonary hypertension secondary to pulmonary Langerhans cell histiocytosis. Respir Med Case Rep 2016;18.

- Jing H, Xie R, Bai Y, Duan Y, Sun C, Wang Y, et al. The Mechanism Actions of Astragaloside IV Prevents the Progression of Hypertensive Heart Disease Based on Network Pharmacology and Experimental Pharmacology. Front Pharmacol 2021;12.

- Bonventre J V., Sabbisetti V. Acute Kidney Injury: Biomarkers from Bench to Bedside. Chronic Kidney Disease, Dialysis, and Transplantation: A Companion to Brenner and Rector’s The Kidney - Expert Consult: Online and Print 2010;668–76.

- Mamazhakypov A, Maripov A, Sarybaev AS, Schermuly RT, Sydykov A. Osteopontin in Pulmonary Hypertension. Biomedicines [Internet] 2023;11(5). Available from: https://www.mdpi.com/2227-9059/11/5/1385

- Wang Y, Han DD, Wang HM, Liu M, Zhang XH, Wang HL. Downregulation of osteopontin is associated with fluoxetine amelioration of monocrotaline-induced pulmonary inflammation and vascular remodelling. Clin Exp Pharmacol Physiol [Internet] 2011;38(6):365–72. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1440-1681.2011.05516.x

- Kim JY, Yang HM, Lee JE, Kim BK, Jin S, Lee J, et al. Activation of Protein Kinase G (PKG) Reduces Neointimal Hyperplasia, Inhibits Platelet Aggregation, and Facilitates Re-endothelialization. Sci Rep 2016;6.

- Dey NB, Boerth NJ, Murphy-Ullrich JE, Chang PL, Prince CW, Lincoln TM. Cyclic GMP-dependent protein kinase inhibits osteopontin and thrombospondin production in rat aortic smooth muscle cells. Circ Res 1998;82(2).

- Akopova O. On the impact of K(ATP) channel opening on mitochondrial reactive oxygen species production. Histology, Cytology and Embryology 2017;1(2).

- Tuder RM, Abman SH, Braun T, Capron F, Stevens T, Thistlethwaite PA, et al. Development and Pathology of Pulmonary Hypertension. J Am Coll Cardiol2009;54(1 SUPPL. 1).

- Rai PR, Cool CD, King JAC, Stevens T, Burns N, Winn RA, et al. The cancer paradigm of severe pulmonary arterial hypertension. Am J Respir Crit Care Med2008;178(6).

- Bogaard HJ, Abe K, Vonk Noordegraaf A, Voelkel NF. The right ventricle under pressure: cellular and molecular mechanisms of right-heart failure in pulmonary hypertension. Chest 2009;135(3).

- Stenmark KR, Meyrick B, Galie N, Mooi WJ, McMurtry IF. Animal models of pulmonary arterial hypertension: The hope for etiological discovery and pharmacological cure. Am J Physiol Lung Cell Mol Physiol2009;297(6).

- Hautbergue T, Antigny F, Boët A, Haddad F, Masson B, Lambert M, et al. Right ventricle remodeling metabolic signature in experimental pulmonary hypertension models of chronic hypoxia and monocrotaline exposure. Cells 2021;10(6).

- McClenaghan C, Woo KV, Nichols CG. Pulmonary Hypertension and ATP-Sensitive Potassium Channels: Paradigms and Paradoxes. Hypertension2019;74(1).

- Egawa M, Ishikura F, Nishikawa R, Ihara M, Takano Y, Kawaguchi N, et al. EFFECTS OF TADALAFIL TO PREVENT THICKENING OF PULMONARY ARTERY IN MONOCROTALINE-INDUCED PULMONARY HYPERTENSION RATS: COMPARED WITH ECHOCARDIOGRAPHIC FINDINGS: PP.13.485. J Hypertens 2010;28.

- Yamamura A, Fujitomi E, Ohara N, Tsukamoto K, Sato M, Yamamura H. Tadalafil induces antiproliferation, apoptosis, and phosphodiesterase type 5 downregulation in idiopathic pulmonary arterial hypertension in vitro. Eur J Pharmacol 2017;810.

- Krick S, Platoshyn O, Sweeney M, McDaniel SS, Zhang S, Rubin LJ, et al. Nitric oxide induces apoptosis by activating K+ channels in pulmonary vascular smooth muscle cells. Am J Physiol Heart Circ Physiol 2002;282(1 51-1).

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Published

2024-07-09

How to Cite

Taha Hashim Ahmed, Israa Burhan Raoof, & Bahir Abdul-Razzaq Mshemish. (2024). Evaluation of Nicorandil in Treatment of induced pulmonary arterial hypertension in male Rats . Al Mustansiriyah Journal of Pharmaceutical Sciences, 24(3), 330–342. https://doi.org/10.32947/ajps.v24i3.1077