C. Fankhauser et al., INTERACTION OF MAO INHIBITORS AND DIETARY TYRAMINE - A NEW EXPERIMENTAL-MODEL IN THE CONSCIOUS RAT, Journal of pharmacological and toxicological methods, 32(4), 1994, pp. 219-224
The aim of this study was to assess a new model for tyramine-induced p
resser effects in the rat. The predictivity of the test is improved by
simulating the real clinical situations where tyramine is ingested wi
th food and beverages containing the amine. The presser effect was inv
estigated after oral administration of tyramine in a feed preparation
or in a water solution by continuously recording blood pressure just a
bove the aorta junction via a left-carotid catheter. The response was
quantified by measurement of peak systolic blood pressure and as the p
ercentage of tyramine-sensitive rats (TSR) in which the maximal presse
r response to the amine was higher than 30 mm Hg (clinical risk thresh
old). Tyramine elicited, after oral administration (by gavage), a stat
istically significant dose-dependent increase in blood pressure from t
he dose of 10 mg/kg in solution (i.e., 23 +/- 3 mm Hg, N = 36) and 40
mg/kg in feed preparation (i.e., 20 +/- 2 mm Hg, N = 26). Almost all r
ats showed a systolic blood presser increase higher than 30 mm Hg afte
r oral administration of tyramine at a dose of 80 mg/kg p.o. in soluti
on (TSR = 96%). Administration of tyramine in food (80 mg/kg) signific
antly delayed the time of the peak blood pressure (13 +/- 2 min instea
d of 7 +/- 0.5 min in solution, p < .001). Under these conditions, the
tyramine threshold dose of TYR 30 (dose inducing an average response
equivalent to the clinical risk threshold) was 14 mg/kg p.o. in soluti
on and 67 mg/kg p.o. in feed preparation, respectively. Thus, as has b
een observed in man, the dose-effect curve for tyramine is shifted to
the right when given mixed with food to the rat. The efficacy ratio of
the two tyramine vehicles defined on the basis of the TYR30 ratio is
4.8. Then, this methodology supplies a higher range of doses of tyrami
ne without significant presser effect (doses below 40 mg/kg p.o, versu
s doses below 10 mg/kg p.o. with tyramine in solution), a necessary co
ndition to study the interaction between MAOI's and oral tyramine. To
validate our model, phenelzine (48 mg/kg), a nonselective and irrevers
ible MAO inhibitor, and toloxatone (75 mg/kg), a reversible MAO-A inhi
bitor, were administered orally 60 and 30 minutes respectively before
the dietary tyramine (4-32 mg/kg). Under these conditions, phenelzine
produced a very marked potentiation of the tyramine presser effect tha
t was characterized by a TYR30 dose of 7 mg/kg, whereas, as expected,
a new generation. reversible MAO-A inhibitor, such as toloxatone, indu
ced a much weaker potentiation (TYR30 of 19 mg/kg). It is concluded th
at the described model provides a sensitive method for the evaluation
of the interaction between MAOI's and oral tyramine.