COMPARISON OF THE EFFECTS OF DESIPRAMINE ON NORADRENALINE-EVOKED AND METHOXAMINE-EVOKED VENOCONSTRICTION IN MAN

1 The dorsal hand vein compliance technique was used to investigate th e dual effect of tricyclic antidepressants at the noradrenergic synaps e (i.e. noradrenaline uptake blockade leading to potentiation and alph a(1)-adrenoceptor blockade leading to antagonism of the effect of nora drenaline). The effects of a single oral dose (100 mg) of desipramine (DMI) on venoconstrictor responses to locally infused noradrenaline an d methoxamine, a selective alpha(1)-adrenoceptor agonist with little a ffinity for the uptake mechanism, were examined. 2 Eight healthy male volunteers participated in four weekly experimental sessions. Each ses sion was associated with one of the following treatment conditions: no radrenaline/DMI, noradrenaline/placebo, methoxamine/DMI, methoxamine/ placebo. Subjects were allocated randomly to treatments and sessions a ccording to a double-blind balanced design. Noradrenaline acid tartrat e (0.33-33 ng min(-1)) and methoxamine hydrochloride (0.0135-135 mu g min(-1)) were infused into the superficial dorsal hand vein; each dose was infused for 5-7 min with 5 min intervening washout periods. Systo lic and diastolic blood pressure and pulse rate were recorded before t he infusion and immediately after the infusion of the highest dose. Sa livation, an index of anticholinergic activity of the antidepressant, was measured by the dental roll technique. 3 Both noradrenaline and me thoxamine produced dose-dependent venoconstriction: the geometric mean ED(50) for noradrenaline was 4.41 ng min(-1) and for methoxamine was 2558 ng min(-1); the potency ratio (noradrenaline/methoxamine) was 288 4. DMI shifted the dose-response curve for noradrenaline to the left ( ANOVA: P<0.025), resulting in a dose-ratio of 0.26. DMI did not affect the dose-response curve for methoxamine significantly; the dose ratio was 1.24. 4 None of the local infusions and/or systemic treatments ha d any significant effects on supine systolic and diastolic blood press ure and pulse rate. 5 DMI caused a substantial (47.6%) reduction in sa livary output that significantly differed from the slight statisticall y insignificant increase (5.8%) of salivary output recorded after plac ebo. 6 These results show that a single oral dose (100 mg) of DMI caus es significant potentiation of the response to noradrenaline without s ignificantly affecting the response to methoxamine. The potentiation i s likely to be due to uptake blockade since the response to methoxamin e was not affected. Furthermore, the lack of significant antagonism of the response to methoxamine indicates that a single oral dose (100 mg ) of DMI does not cause sufficient a,adrenoceptor blockade to be detec ted as a pharmacodynamic change in our test system.