Nicorandil mitigates amiodarone‐induced pulmonary toxicity and fibrosis in association with the inhibition of lung TGF‐β1/PI3K/Akt1‐p/mTOR axis in rats

Abstract

The long‐term side effect of the antiarrhythmic drug, amiodarone (AMIO), such as lung toxicity, remains a critical clinical issue. The previous knowledge denotes diverse antioxidant, anti‐inflammatory, and antifibrotic properties of the anti‐anginal drug, nicorandil (NI). Therefore, we aimed to investigate the possible protective effect of NI on pulmonary tissue remodelling following AMIO‐induced lung toxicity. The included rats were assigned into four equal groups (n = 8): (1) control, (2) control group that received NI 10 mg kg−1 day−1, (3) model group that received AMIO in a dose of 60 mg kg−1 day−1, and (4) treated group (AMIO‐NI) that were treated with AMIO plus NI as shown above. Drug administration continued for 10 weeks. AMIO resulted in deteriorated (p < 0.001) pulmonary functions accompanied by respiratory acidosis. AMIO showed an obvious histological injury score with intense collagen deposition, disturbed nitric oxide synthase enzymes (NOS/iNOS), and increased alpha smooth muscle actin expression. Furthermore, AMIO upregulated the transforming growth factor (TGF‐β1)/phosphoinositide‐3 kinase (PI3K)‐Akt1‐p/mammalian target of rapamycin (mTOR) axis, which determined the possible mechanism of AMIO on pulmonary remodelling. NI treatment significantly (p < 0.001) prevented the AMIO‐induced lung toxicity, as well as inhibited the TGF‐β1/PI3K/Akt1‐p/mTOR axis in the lung tissue of rats. The results were confirmed by an in‐vitro study. Conclusion The current results revealed that NI was effective in preserving the lung structure and functions. Amelioration of the oxidative stress and modulation of TGF‐β1/PI3K/Akt1‐p/mTOR have been achieved. This study suggests NI administration as a preventive therapy from the serious pulmonary fibrosis side effect of AMIO.

Inhibitory Effects of Nobiletin on Voltage-Gated Na+ Channel in Rat Ventricular Myocytes Based on Electrophysiological Analysis and Molecular Docking Method

“…The SARS-CoV-2 infection is a high-risk-inducing factor for cardiovascular disease due to severe cytokine storms and systemic inflammatory responses [ 34 , 35 , 36 , 37 , 38 ]. Anti-arrhythmic drugs currently in clinical use, such as amiodarone, which has pulmonary toxicity, and quinidine, which has proven to show a pro-arrhythmia effect, may aggravate the damage to the cardiopulmonary circulatory system [ 39 , 40 , 41 , 42 ]. Therefore, the development of low-toxicity and multi-target cardiovascular drugs is also urgently needed [ 43 ].…”

Nicorandil mitigates arsenic trioxide‐induced lung injury via modulating vital signalling pathways SIRT1/PGC‐1α/TFAM, JAK1/STAT3, and miRNA‐132 expression

“…This action induces relaxation in both arterial and venous vessels while concurrently reducing cardiac workload. Notably, nicorandil prevented the elevation of pulmonary arterial pressure and acted as a prophylactic agent against induced lung injury by restoring redox balance and exerting anti‐inflammatory effects (El‐Kashef, 2018; Harb et al, 2023; Yadav et al, 2005). Given these attributes, nicorandil is a promising candidate for alleviating ATO‐induced pulmonary toxicity.…”