The influence of amine metabolizing enzymes on the pharmacology of tyramine in the isolated perfused mesenteric arterial bed of the rat

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Abstract
1 The pressor response to the infusion of tyramine (Tyr) into the isolated perfused mesenteric arterial bed of the rat has been studied at both a low and a high dose (0.2 and 2.0 μmol) and the effect of monoamine oxidase-A (MAO-A) and semicarbazide-sensitive amine oxidase (SSAO) inhibition was examined. Very little MAO-B activity is found in homogenates of this tissue when Tyr is used as substrate. 2 Inhibition of SSAO by treating rats with 1 mg kg−1 (E)-2-(3′,4′-dimethoxyphenyl)-3-fluoroally lamine (MDL 72145) 1 h before dissection, had no significant effect on the maximum pressure attained or the area under the curve (AUC) of the response to both low and high doses of Tyr. Inhibition of MAO-A, by inclusion of 10 μm clorgyline in the perfusing fluid, resulted in no significant potentiation at both low or high doses of Tyr. The inhibition of both these enzymes together substantially increased the AUC of the pressor response. 3 Cocaine (3 μm) significantly potentiated the responses to adrenaline (Ad). At this dose, cocaine significantly reduced the peak height and the AUC of the responses to both doses of Tyr. 4 Inhibition of extraneuronal uptake mechanisms with corticosterone (29 μm) did not potentiate the response to Ad and did not significantly alter the response to Tyr (low dose). 5 The effects of MDL 72145 and clorgyline on the directly acting amine, Ad, were studied. MDL 72145 caused a small but significant increase in the EC50 and in the maximum response to Ad, whilst clorgyline (10 μm) increased the EC50 value slightly and decreased the maximum response. When the two inhibitors were used in combination, a significant increase in the maximum response but with no change in the EC50 was seen. 6 These data indicate that the action of Tyr in this vascular bed is, at least, partly indirect. Inactivation of Tyr is effected by both MAO-A and SSAO in the blood vessel wall. Inhibition of both enzymes seems to be necessary to achieve a significant potentiation of the pressor response. The effects of these enzyme inhibitors on directly acting amines may mask any potentiation of the response when MAO-A or SSAO alone are inhibited.