Effects of enalapril on mitochondrial‐mediated apoptosis, inflammation and nitric oxide synthase production in aged rat tibialis anterior muscle

Abstract

The angiotensin converting enzyme inhibitor enalapril decreases skeletal muscle apoptotic DNA fragmentation in aged rats. Apoptosis is triggered through several pathways including TNF-á and NO. A major impact of enalapril is increased NO levels via upregulation of bradykinin. Therefore, we determined enalapril's (20 mg/kg/day) effect alone or in combination with the NOS blocker L-NAME (1 mg/kg) on TNF- á and various NOS isoforms in the TA muscle of aged rats. Rats were assigned to enalapril, enalapril + L-NAME, L-NAME or placebo from 24 to 27 months of age. Enalapril reduced body weight, and increased overall NOS activity in TA; both changes were reversed by L-NAME. Enalapril reduced iNOS, and the combination of enalapril + L-NAME prevented this. Protein levels of eNOS and nNOS were increased by enalapril, with a small decrease when L-NAME was co-administered. TNF-á levels were lowered by enalapril and not reversed by L-NAME. We also investigated parameters of muscular mitochondrial function and biogenesis. Enalapril decreased H2O2 and was not reversed by L-NAME. No treatments affected O2 consumption, susceptibility to opening of the permeability transition pore or gene expression of PCG-1á and T-fam. Our data suggest that enalapril may modulate mitochondrial mediated apoptosis through either NO or TNF-á signaling pathways, in the absence of any other change in mitochondrial function.