Role of lipid peroxidation and the glutathione‐dependent antioxidant system in the impairment of endothelium‐dependent relaxations with age

Publisher Website
Google Scholar
Abstract
Age‐related changes in the blood prooxidant‐antioxidant state, as well as its influence on the relaxant responses to acetylcholine (ACh) were studied in the tail artery from 6‐, 24‐ and 30‐month‐old Sprague‐Dawley (SD) rats. Malondialdehyde (MDA) plasma levels increased 2 and 3 times in 24‐ and 30‐month‐old rats, respectively, when compared with 6‐month‐old rats (0.43±0.09 μM). This increase was accompanied by an induction of 6‐phosphogluconate dehydrogenase (6PG‐DH) and glutathione reductase (GR) activities in red blood cells from 24‐month‐old rats. In 30‐month‐old rats, a further induction of these enzymatic activities, as well as glucose‐6‐phosphate dehydrogenase (G6P‐DH) and glutathione peroxidase (GPx) activities was observed. No differences with age were found in the concentration‐response curves to ACh in isolated tail artery segments from 6‐ and 24‐month‐old rats precontracted with 0.3 μM noradrenaline (NA). However, a decrease in sensitivity to ACh‐induced relaxation was observed in 30‐month‐old rats; EC30 values were 3.5 (1.3–8.0)×10−7 M and 18.1 (8.9–30.1)×10−7 M for 6‐ and 30‐month‐old rats, respectively. Moreover, a decrease in maximum ACh relaxation (10 μM) was found in 30‐month‐old rats in comparison with that obtained in 6‐month‐old rats (58.5±3.9% and 42.5±3.4% of previous NA contraction, respectively). Incubation of tail artery segments with MDA (0.5, 1 or 10 μM) caused a reduction of ACh‐induced relaxations that was different in the three ages. Thus, the reduction of ACh‐induced relaxations became significant with 0.5 μM MDA in 6‐, with 1 μM MDA in 24‐, and with 10 μM MDA in 30‐month‐old rats. In addition, MDA did not cause a shift in the concentration‐response curve to ACh, but a decrease in the maximum response. Superoxide dismutase (SOD; 150 u ml−1, a superoxide anion scavenger) reversed the inhibitory effect of MDA on ACh‐induced relaxations at all ages studied. We conclude that: (1) ageing produces an increase in lipid peroxidation process, as indicated by the increase in MDA plasma levels, that is accompanied by an induction of lipid peroxide detoxification enzymes; (2) the changes in prooxidant‐antioxidant equilibrium with age contribute, at least partially, to the impairment of the relaxant responses evoked by ACh; and (3) the effect of MDA appears to be mediated by superoxide anion at all ages studied. British Journal of Pharmacology (1998) 123, 113–121; doi:10.1038/sj.bjp.0701595