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

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.pmol) 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 mg kg' (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 10pM 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 (3Mm) 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 (29upM) 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 ECjo and in the maximum response to Ad, whilst clorgyline (10pM) 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.

New actions of an old friend: perivascular adipose tissue's adrenergic mechanisms

“…Elliott et al () investigated amine metabolism in rat isolated mesenteric arteries and found that metabolism of the substrates tyramine and benzylamine was carried out by SSAO and to a lesser extent MAO‐A. Inhibition of both MAO‐A and SSAO (with clorgyline and MDL 72145, respectively) was required to affect contraction of the arteries to tyramine (Elliott et al, ). Studies to assess this effect in arteries with PVAT are needed in addition to studies investigating whether NA is metabolized by SSAO in PVAT.…”

Metabolism of tresperimus by rat aorta semicarbazide‐sensitive amine oxidase (SSAO)

“…SSAO is localized to the outer side of the plasma membrane, allowing it to metabolize circulating amines [28]. Because of the widespread distribution of SSAO in blood vessels other than the aorta [29] and the low plasma SSAO activity, tissue-bound SSAO in vasculature could be hypothesized to be the main site of tresperimus metabolism.…”

Metabolism of amines in the isolated perfused mesenteric arterial bed of the rat

“…Blockade of neuronal uptake with cocaine increased the amount of metabolites formed during Tyr infusion. At the concentration used here, cocaine has been shown to potentiate the effects of directly acting sympathomimetic amines and to inhibit the responses to indirectly acting agents, such as Tyr, in this preparation (George & Leach, 1973;Elliott et al, 1989c) indicating that it effectively blocked neuronal uptake. The fact that this resulted in an increase in metabolites leaving the tissue could indicate that the nerve endings in this tissue represented a significant site of accumulation of Tyr from which deaminated metabolites were not readily released.…”