Plasma dihydroxyphenylglycol and the intraneuronal disposition of norepinephrine in humans

Abstract

We examined plasma levels of the sympathetic neurotransmitter norepinephrine (NE) and its deaminated metabolite dihydroxyphenylglycol (DHPG) during supine rest in healthy human subjects and in sympathectomized patients, during physiological (tilt) or pharmacological (yohimbine, clonidine) manipulations known to affect sympathetically mediated NE release, during blockade of neuronal uptake of NE (uptake-1) using desipramine, and during intravenous infusion of NE. Healthy subjects had a mean arteriovenous increment in plasma DHPG in the arm (10%, P less than 0.05), whereas sympathectomized patients had a mean arteriovenous decrement in DHPG in the affected limb (mean decrease 21%, P less than 0.05 compared with healthy subjects). Tilt and yohimbine, which stimulate, and clonidine, which inhibits, release of endogenous NE, produced highly correlated changes in plasma NE and DHPG (r = 0.94). Pretreatment with desipramine abolished DHPG responses to yohimbine while enhancing NE responses. To attain a given increase in plasma DHPG, about a tenfold larger increment in arterial NE was required during NE infusion than during release of endogenous NE. When plasma NE was markedly suppressed after administration of clonidine, plasma DHPG decreased to a plateau level of 700-800 pg/ml. The results indicate that (i) plasma DHPG in humans is derived mainly from sympathetic nerves; (ii) increments in plasma DHPG during stimulation of NE release result from uptake of NE into sympathetic nerve endings and subsequent intraneuronal conversion to DHPG; (iii) plasma DHPG under basal conditions probably is determined mainly by net leakage of NE into the axonal cytoplasm from storage vesicles; and (iv) increments in NE concentrations at neuronal uptake sites can be estimated by simultaneous measurements of DHPG and NE during NE infusion and NE release. Measurement of NE and DHPG provides unique clinical information about sympathetic function.