Ah. Abdelmawla et al., COMPARISON OF THE EFFECTS OF DESIPRAMINE ON NORADRENALINE-EVOKED AND METHOXAMINE-EVOKED VENOCONSTRICTION IN MAN, British journal of clinical pharmacology, 40(5), 1995, pp. 445-451
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.