Psychopharmacology(1992) 106:S35-S 36

Psychopharmacology © Springer-Verlag 1992

Mini-Paper Interaction of moclobemide and tricyclic antidepressants with the tyramine pressor effect in rats W. Burkard, F. d'Agostini, R. Kettler, and M. Da Prada Pharmaceutical Research Department, F. Hoffmann-La Roche Ltd, CH-4002 Basel, Switzerland

Abstract. Tyramine at high doses (20 mg/kg) increased arterial blood pressure in freely moving rats. This increase was completely prevented by pretreatment with inhibitors of neuronal membrane carriers for noradrenaline (e.g. desipramine or oxaprotiline). Pretreatment with moclobemide induced a mild potentiation of this tyramine-pressor effect which could also be attenuated dose-dependently by co-administration of oxaprotiline.

tion. Higher doses of tyramine (40 mg/kg) further increased MAP, and the blood pressure remained significantly elevated for more than 20 rain. In these experimental conditions, 15 mg/kg tyramine did not significantly affect MAP (Da Prada et al. 1984).

Key words: Interaction - Blood pressure - M A O - A inhibitors - MAO-B inhibitors

The irreversible, non-selective MAO inhibitor tranylcypromine (6 mg/kg) induced a marked (35 mmHg increase) and prolonged tyramine potentiating effect when administered prior to a sub-threshold dose of tyramine (5 mg/kg). In contrast, the reversible M A O - A selective inhibitors brofaromine (30 mg/kg) and toloxatone induced only a slight and short-lasting tyramine potentiation. In these experimental conditions, moclobemide (30 mg/kg) did not significantly modify MAP (Da Prada et al. 1989).

The generally negative attitude towards the old irreversible inhibitors of monoamine oxidase (MAO) was based, in part, on reports on the "cheese effect", i.e. pronounced enhancement of the pressor effect of tyramine present in food and, especially, in fermented cheese (Nies and Robinson 1982). In contrast, the reversible inhibitors of MAO, in particular moclobemide, have only a moderate tyramine potentiating effect. We discuss below the interaction between antidepressants and orally administered tyramine on blood pressure in freely moving rats.

Tyramine after MAO-A inhibitors

6040-

Materials and methods Mean arterial blood pressure (MAP) was measured directly in conscious, freely moving male SPF rats with indwelling cannulae in the carotid artery, as described by Carruba et al. (1981). All drugs, including tyramine, were administered intragastrically.

E E 2O-

0 .....

-20

Results and discussion

'•

(rng/kg

Tyramine alone

1 h -

Drugs

p.o.)

' • Tyramine 20 m g / k g

~

110

210 minutes

p.o.

Tyramine (20 mg/kg) produced a significant brief increase (about 20 mmHg) in MAP, 5 min after administra-

Fig. 1. Attenuation of the tyramine and moclobemide pressor effect by oxaprotiline. The symbols represent means of 6-10 rats. The predrug baseline values of the MAP ranged between 108 and 127 mmHg. • Tyramine after saline; • tyramine after moclobemide

Offprint requests to: W. Burkard

(30); ~ tyramine after moclobemide (30)+oxaprotiline (1); x tyramine after moclobemide (30)+ oxaprotiline (3)

$36

Tyramine after MAO-B inhibitors Pretreatment (1 h) with irreversible inhibitors of M A O - B of p o o r selectivity, such as M D L 72145, A G N 1135 or selegiline, increased the tyramine pressor effect to a similar degree to that of the reversible inhibitors of M A O - A . The specific M A O - B inhibitor Ro 19-6327, however, even at extremely high doses ( M A O - B inhibition E D s 0 = 0.016 mg/kg p.o., 2 h), did not increase the effect of tyramine on blood pressure (Burkard et al. in preparation).

Tyramine after noradrenaline uptake inhibitors A high dose of tyramine (20 mg/kg) increased blood pressure; this was completely prevented by pretreatment (1 h) with noradrenaline uptake inhibitors, such as desipramine (5 mg/kg) or oxaprotiline (5 mg/kg). Amitriptyline (10 mg/kg), a relatively weak inhibitor of noradrenaline uptake, induced only a small decrease in the tyramine pressor effect (Da Prada et al. 1990).

Tyramine after combination with moclobemide and a noradrenaline uptake inhibitor Pretreatment (1 h) with moclobemide (30 mg/kg) induced a mild potentiation of the pressor effect of a high tyr-

amine dose (20 mg/kg). Oxaprotiline coadministered with moclobemide dose-dependently decreased the tyramine pressor effect (Fig. 1). In conclusion, these experiments demonstrate that tyramine pressor effect can be prevented by inhibiting the noradrenaline transport system.

References Carruba MP, Picotti GB, Miodini P, Lotz W, Da Prada M (1981) Blood sampling by chronic cannulation technique for reliable measurements of catecholamines and other hormones in plasma of conscious rats. J Pharmacol Methods 5:293-303 Da Prada M, Kettler R, Burkard WP, Haefely WE (1984) Moclobemide, an antidepressant with short-lasting MAO-A inhibition: brain catecholamines and tyramine pressor effects in rats. In: Tipton KF, Dostert P, Strolin Benedetti M (eds) Monoamine oxidase and disease. Academic Press, London, pp I37 154 Da Prada M, Keller HH, Kettler R (1989) Vergleich der neuen MAO-A-Hemmer Moclobemid, Brofaromin und Toloxaton mit Tranylcypromin im Tierversuch: Bedeutung fiir die Praxis. Psychiatr Prax 16 : 18-24 Da Prada M, Kettler R, Burkard WP, Lorez HP, Haefely W (1990) Some basic aspects of reversible inhibitors of monoamine oxidase-A. Acta Psychiatr Scand [suppl] 360:7-12 Nies A, Robinson DS (1982) Monoamine oxidase inhibitors. In: Paykel ES (ed) Handbook of affective disorders. Churchill Livingstone, London, pp 24~%261