Phenotypic evidence of faulty neuronal norepinephrine reuptake in essential hypertension

Previous reports suggest that neuronal norepinephrine (NE) reuptake may be impaired in essential hypertension, perhaps because of dysfunction of the N E transporter, although the evidence is inconclusive. To further test this proposition, we applied phenotypically relevant radiotracer methodology, in fusion of tritiated NE and quantification of NE metabolites, to 34 healthy lean subjects (body mass index <27.0 kg/m(2)), 19 overweight (body mass ind ex >28.0 kg/m(2)) but otherwise healthy normotensive subjects, 13 untreated lean patients with essential hypertension, and 14 obesity-related hyperten sives. Spillover of NE from the heart was increased in lean hypertensives o nly (mean+/-SD 33.4+/-20.6 versus 16.1+/-11.7 ng/min in lean normotensives, P<0.05), but this could have resulted from high cardiac sympathetic nerve firing rates, faulty NE reuptake, or both. The arterial plasma concentratio n of 3-methoxy-4-hydroxylphenylglycol, an extraneuronal metabolite of NE, w as elevated in lean hypertensives only (3942 +/- 1068 versus 3055 +/- 888 p g/mL in healthy subjects, P<0.05). The fractional extraction of plasma trit iated NE in passage through the heart, determined on the basis of neuronal NE uptake, was reduced in lean essential hypertensives (0.65 +/- 0.19 versu s 0.81 +/- 0.11 in healthy subjects, P<0.05). Cardiac release of the tritia ted NE metabolite [H-3]dihydroxylphenylglycol, produced intraneuronally by monoamine oxidase after uptake of [H-3]NE by the transporter, was reduced i n lean hypertensives only (992 +/- 1435 versus 4588 +/- 3189 dpm/min in hea lthy subjects, P<0.01) These findings suggest that neuronal reuptake of NE is impaired in essential hypertension. Through amplification of the neural signal, such a defect could constitute a neurogenic variant of essential hy pertension. In obesity-related hypertension, there was no phenotypic eviden ce of NE transporter dysfunction.