Interaction of MAO inhibitors and dietary tyramine: A new experimental model in the conscious rat

Abstract

The aim of this study was to assess a new model for tyramine-induced pressor effects in the rat. The predictivity of the test is improved by simulating the real clinical situations where tyramine is ingested with food and beverages containing the amine. The pressor effect was investigated after oral administration of tyramine in a feed preparation or in a water solution by continuously recording blood pressure just above the aorta junction via a left-carotid catheter. The response was quantified by measurement of peak systolic blood pressure and as the percentage of tyramine-sensitive rats (TSR) in which the maximal pressor response to the amine was higher than 30 mm Hg (clinical risk threshold). Tyramine elicited, after oral administration (by gavage), a statistically significant dose-dependent increase in blood pressure from the 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 rats showed a systolic blood pressor increase higher than 30 mm Hg after oral administration of tyramine at a dose of 80 mg kg p.o. in solution (TSR = 96%). Administration of tyramine in food (80 mg kg ) significantly delayed the time of the peak blood pressure (13 ± 2 min instead 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 solution and 67 mg kg p.o. in feed preparation, respectively. Thus, as has been 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 tyramine without significant pressor effect (doses below 40 mg kg p.o. versus doses below 10 mg kg p.o. with tyramine in solution), a necessary condition to study the interaction between MAOI's and oral tyramine. To validate our model, phenelzine (48 mg kg ), a nonselective and irreversible MAO inhibitor, and toloxatone (75 mg kg ), a reversible MAO-A inhibitor, 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 pressor effect that was characterized by a TYR30 dose of 7 mg kg , whereas, as expected, a new generation reversible MAO-A inhibitor, such as toloxatone, induced a much weaker potentiation (TYR30 of 19 mg kg ). It is concluded that the described model provides a sensitive method for the evaluation of the interaction between MAOI's and oral tyramine.