AIM To investigate the effects of lidocaine on phenylephrine (PE)-induced myocardial cell hypertrophy by regulating the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2 related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway.

METHODS H9C2 rat myocardial cells were divided into six groups: control, PE, lidocaine low concentration, lidocaine high concentration, lidocaine high concentration + pcDNA, and lidocaine high concentration + Keap1 activator (pcDNA-Keap1). Cell viability was assessed using the CCK-8 assay. Lactate dehydrogenase (LDH) release in the cell supernatant was measured using a colorimetric method. Immunofluorescence staining was performed to evaluate the area of H9C2 cells. The mRNA levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and β-myosin heavy chain (β-MHC) were quantified by quantitative real-time PCR (QRT-PCR). The levels of malondialdehyde (MDA), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) in H9C2 cells were detected by the kit. Protein expression of Keap1, Nrf2, and HO-1 was analyzed by Western blot. Additionally, primary cardiomyocytes from neonatal rats were used to validate the findings.

RESULTS Compared to the control group, the PE group exhibited reduced cell viability, GSH-Px, SOD levels, and Nrf2/HO-1 protein expression, while LDH release, H9C2 cell area, ANP, β-MHC, BNP mRNA levels, MDA, and Keap1 protein expression were significantly increased (P<0.05). Compared with the PE group, the H9C2 cell viability, GSH-Px, SOD levels, and Nrf2 and HO-1 proteins were increased in both lidocaine low and high concentration group, while the release of LDH in the supernatant, H9C2 cell area, ANP, β-MHC, BNP mRNA expression, MDA level, and Keap1 protein were reduced (P<0.05). PcDNA Keap1 reversed the effects of lidocaine on PE induced oxidative stress and cell hypertrophy in H9C2 cells. Similarly, lidocaine inhibited oxidative stress and attenuated hypertrophy in neonatal rat cardiomyocytes by downregulating the Keap1-activated Nrf2/HO-1 pathway.

CONCLUSION Lidocaine alleviate PE-induced oxidative stress and myocardial cell hypertrophy by downregulating Keap1 and activating the Nrf2/HO-1 signaling pathway.