Aldose reductase, a key enzyme in the oxidative deamination of norepinephrine in rats

The sympathoneural neurotransmitter norepinephrine (NE) is deaminated to 3, 4-dihydroxymandelaldehyde (DHMAL) and subsequently converted to either 3,4- dihydroxymandelic acid (DHMA) or 3,4- dihydroxyphenylglycol (DHPG). In this study, we investigated the relative importance of aldose reductase versus aldehyde reductase in the formation of DHPG from DHMAL. The in vitro incuba tion of NE with aldose reductase in the presence of monoamine oxidase (MAO) resulted in the formation of DHPG, which was confirmed by mass spectrometr y. Although aldehyde reductase also generated DHPG, its activity was much l ower than that of aldose reductase. With northern blotting, the expression of both aldose reductase and aldehyde reductase was detected in rat superio r cervical ganglia. However, with western blotting, only aldose reductase w as immunologically detectable. Treatment of rats with aldose reductase inhi bitors for 3 days increased the plasma level of DHMA. There was no correlat ion between the selectivity of inhibitors and effects on NE metabolite leve ls. A significant decrease in DHPG, however, was obtained only with an extr emely high dose (9 mg/kg/day) of the nonselective inhibitor AL 1576. The pr esent study confirmed that aldose reductase generates DHPG from NE in the p resence of MAO. In rat sympathetic neurons, aldose reductase appears to be more important than aldehyde reductase for the formation of DHPG. However, when aldose reductase is inhibited, it appears that aldehyde reductase can compensate for the conversion of DHMAL to DHPG, indicating redundancy in th e reduction pathway. (C) 1999 Elsevier Science Inc.