Background-To assess the sensitivity of biochemical, physiological, and pharmacological markers of peripheral norepinephrine (NE) transporter (NET) function, we chronically antagonized NET by a range of doses of duloxetine [(ϩ)-N-methyl-3-(1-naphthalenyloxy)-2 thiophenepropanamine], which blocks the NE reuptake process. Methods and Results-Duloxetine was administered in a randomized, placebo-controlled study in 15 healthy volunteers.Plasma from duloxetine-treated subjects (ex vivo effect) dose-dependently decreased radioligand binding to human NET (maximum inhibition was 60%) (Pϭ0.02). The dose of intravenous tyramine required to raise systolic blood pressure by 30 mm Hg (PD 30 ) increased dose-dependently with duloxetine and was significant at the end of the 120-mg/d dosage (PϽ0.001). The plasma dihydoxyphenylglycol to NE (DHPG/NE) ratio was reduced significantly at 2 weeks of treatment with 80 mg/d duloxetine (11.3 at baseline, 3.4 at 240 mg/d, PϽ0.001). Plasma NE was significantly increased starting at 120 mg/d duloxetine. Urine results (corrected for 24-hour creatinine excretion) showed a dose-dependent change from the baseline urinary excretion for NE, DHPG, and the DHPG/NE ratio. The most sensitive measure, the DHPG/NE ratio, was significant at the 80-mg dose. Urinary NE excretion was significantly raised after 2 weeks of treatment with 80 mg/d duloxetine (PϽ0.001), the lowest dose used in the study. Conclusions-These findings suggest that the degree of NET blockade can be assessed with the plasma or urine DHPG/NE ratio and the pressor effect of tyramine. Also, the DHPG/NE ratio is more sensitive at the lower end of NET inhibition, whereas tyramine exhibits a linear relation, with NET inhibition commencing at a higher dose.

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Background-Despite the widespread use of tyramine as a pharmacological tool to assess the effects of norepinephrine release from sympathetic nerve terminals, its vascular effects are not adequately characterized. In particular, previous results indicate that intravenous tyramine produces little if any systemic vasoconstriction, suggesting that tyramine does not cause significant norepinephrine release from sympathetic nerves innervating peripheral vascular beds. To test this hypothesis, we determined the effects of intravenous tyramine on local forearm norepinephrine spillover and vascular resistance. Methods and Results-Seven healthy subjects were studied with systemic and local forearm norepinephrine spillover and forearm blood flow at baseline, during systemic tyramine infusion, and after sympathetic stimulation induced by the cold pressor test. Tyramine infusion caused a significant increase in systemic and forearm norepinephrine spillover. The amount of norepinephrine released into the forearm by tyramine was similar to that caused by cold pressor stimulation, 0.15Ϯ0.05 versus 0.18Ϯ0.05 ng · dL Ϫ1 · min Ϫ1 . As expected, forearm vascular resistance increased during the cold pressor test, but tyramine produced forearm vasodilation (4.5Ϯ1 versus Ϫ5Ϯ1 mm Hg · dL Ϫ1 · min

Target-controlled propofol infusion (0.8-0.9 microg mL(-1)) following hydroxyzine premedication is a safe and effective technique for sedation when combined with interscalene brachial plexus block during shoulder surgery in the sitting position.