Effect of halothane on metabolism of 5-hydroxytryptamine by rat lungs perfused in situ

Abstract

The effect of halothane (2-bromo-2-chloro-1,1,1-trifluoroethane) on the uptake of 14C-labelled 5-hydroxytryptamine (5-HT) and its metabolism to 5-hydroxyindol-3-ylacetic acid (5-HIAA) was investigated in rat lungs perfused in situ. The rate of accumulation of 14C-labelled 5-HIAA in the tissue, monitored as an index of 5-HT metabolism, was linear with time, displayed saturation kinetics and remained stable for at least 180 min of perfusion. Exposure of the lungs to halothane (4%) for 60 min reversibly reduced production of 5-HIAA through an increase in the apparent Km for metabolism of the amine from 1.45 to 3.52 microM (P less than 0.001); the anaesthetic had no effect on the Vmax. of the process. The magnitude of the inhibition increased with time of exposure to the anaesthetic. Halothane exposure did not alter the distribution of [3H]sorbitol or [14C]5-HT, pulmonary vascular resistance, levels of ATP or the kinetics of amino acid transport in the tissue. Inhibition of protein synthesis by cycloheximide did not mimic the effect of the anaesthetic. These observations, together with those made in lungs exposed to inhibitors of 5-HT uptake and metabolism, were consistent with a halothane-mediated inhibition of 5-HT uptake, which did not appear to involve non-specific changes in membrane permeability.

Reversible inhibition of protein synthesis in lung by halothane

“…The role of tryptophan availability in limiting synthesis of lung proteins is controversial (Gacad et al, 1972;Rannels et al, 1979). In addition, halothane inhibits the uptake of 5-hydroxytryptamine by the intact lung by increasing the apparent Km of the transport system for this amine (Watkins et al, 1983), which is structurally similar to tryptophan. However, the inhibitory effect of halothane on protein synthesis was observed under conditions where the extracellular tryptophan concentration was raised sufficiently to enlarge the size of the intracellular pool of the amino acid well beyond that present in control lungs.…”

“…Several studies reported inhibitory effects of halothane on uptake and metabolism of amines from the pulmonary circulation. Clinical doses of halothane decreased the uptake of circulating noradrenaline by lungs of intact dogs (Bakhle & Block, 1976) and by perfused rabbit lungs (Naito & Gillis, 1973), and decreased uptake of 5-hydroxytryptamine by perfused rat lungs (Watkins et al, 1983). Effects of the anaesthetic on carbohydrate or lipid metabolism have not been studied in lung tissue.…”

Protein Synthesis in Perfused Rat Lungs: Determinations Based on Incorporation of Radioactive Proline

“…As compared to earlier studies using tissue fragments [7, 8 , 9 ] , this model provides the advantages of an intact tissue structure and pulmonary circulation [ 10,111 , metabolic stability over the interval required for these investigations [ 121 , and hormone responsiveness [ 131 . In addition, the perfusate composition can be altered in a systematic and controlled fashion, as can perfusion pressures and ventilatory parameters.…”

Trichloroethylene Inhibits Uptake of 3H‐5‐Hydroxytryptamine but not Uptake of 3H‐Zimeldine or 3H‐Propranolol in Isolated Perfused Rat Lungs

“…This would show up as a change in for example extracellular volume of distribution, and therefore, a change in tissue uptake. It has been demonstrated, however, that even a very high concentration of halothane (4%) not was able to alter the distribution of sorbitol in ventilated rat lungs (Watkins et al 1983). Another possible alternative mechanism for the inhibitory effect of trichloroethylene on pulmonary 5-HT uptake, is that the solvent might interact with the uptake carrier in some way.…”

“…The halogenated hydrocarbons trichloroethylene and halothane have also been shown to inhibit the pulmonary uptake of 5-HT in isolated perfused rat lung (Hede & Post 1982). Watkins et al (1983) have also observed an inhibitory effect of halothane (4%) on 5-HT uptake in ventilated rat lungs in situ. The kinetic data showed that the K, for clearance of 5-HT increased from 1.45 to 3.52 pM, whereas V, , was unchanged by halothane exposure.…”