Comparison of the effects of desipramine on noradrenaline- and methoxamine-evoked venoconstriction in man

Abstract

1. The dorsal hand vein compliance technique was used to investigate the dual effect of tricyclic antidepressants at the noradrenergic synapse (i.e. noradrenaline uptake blockade leading to potentiation and alpha 1-adrenoceptor blockade leading to antagonism of the effect of noradrenaline). The effects of a single oral dose (100 mg) of desipramine (DMI) on venoconstrictor responses to locally infused noradrenaline and methoxamine, a selective alpha 1-adrenoceptor agonist with little affinity for the uptake mechanism, were examined. 2. Eight healthy male volunteers participated in four weekly experimental sessions. Each session was associated with one of the following treatment conditions: noradrenaline/DMI, noradrenaline/placebo, methoxamine/DMI, methoxamine/placebo. Subjects were allocated randomly to treatments and sessions according to a double-blind balanced design. Noradrenaline acid tartrate (0.33-33 ng min-1) and methoxamine hydrochloride (0.0135-135 micrograms min-1) were infused into the superficial dorsal hand vein; each dose was infused for 5-7 min with 5 min intervening washout periods. Systolic and diastolic blood pressure and pulse rate were recorded before the infusion and immediately after the infusion of the highest dose. Salivation, an index of anticholinergic activity of the antidepressant, was measured by the dental roll technique. 3. Both noradrenaline and methoxamine produced dose-dependent venoconstriction: the geometric mean ED50 for noradrenaline was 4.41 ng min-1 and for methoxamine was 2558 ng min-1; the potency ratio (noradrenaline/methoxamine) was 2884. 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 had any significant effects on supine systolic and diastolic blood pressure and pulse rate. 5. DMI caused a substantial (47.6%) reduction in salivary output that significantly differed from the slight statistically insignificant increase (5.8%) of salivary output recorded after placebo. 6. These results show that a single oral dose (100 mg) of DMI causes significant potentiation of the response to noradrenaline without significantly affecting the response to methoxamine. The potentiation is likely to be due to uptake blockade since the response to methoxamine 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 alpha 1-adrenoceptor blockade to be detected as a pharmacodynamic change in our test system.