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.