Source and physiological significance of plasma 3,4-dihydroxyphenylglycol and 3-methoxy-4-hydroxyphenylglycol.

To elucidate the source and physiological significance of plasma 3,4-dihydroxyphenylglycol (DHPG) and 3-methoxy-4-hydroxyphenylglycol (MHPG) as metabolites of noradrenaline (NA), unlabeled and tritium-labeled NA [( 3H]NA) were infused into conscious rats and the formation of labeled and unlabeled DHPG and MHPG examined. Animals were pretreated with clorgyline to determine the effects of inhibiting monoamine oxidase type A (MAO-A), with desipramine to determine the effects of blockade of NA neuronal uptake, or with reserpine to determine the effects of interference with vesicular translocation of NA. Inhibition of neuronal uptake prevented the formation of DHPG from exogenous NA and halved the formation of MHPG, indicating that DHPG is derived from NA metabolized intraneuronally and that MHPG is derived from NA metabolized extraneuronally and from DHPG produced intraneuronally. Blockade of vesicular translocation of NA with reserpine increased DHPG formation from exogenous NA by 300% and MHPG formation by 70%, consistent with enhanced availability of NA in the neuronal cytoplasm for metabolism by MAO-A. About 74% of NA recaptured by sympathetic nerves was estimated to be sequestered into storage vesicles. Endogenous DHPG and MHPG were derived mainly (60-70%) from leakage of NA from storage vesicles and to a smaller extent (30-40%) from NA recaptured after exocytotic release. An increased plasma DHPG to NA ratio with no change in the MHPG to NA ratio during infusions of physiologically active NA demonstrated that changes in plasma MHPG do not necessarily follow changes in DHPG. Consideration of the intra- and extraneuronal sources of plasma DHPG and MHPG, their main derivation from NA directly released into the neuronal cytoplasm and the influences of neuronal uptake and translocation of NA into storage vesicles is essential for the correct interpretation of plasma concentrations of these metabolites in the evaluation of sympathetic nervous function.