The effects of certain anaesthetic and anti-convulsant drugs on the CSF potassium fluxes of the dog.

1 A technique has been developed for open-ended perfusion of the cerebroventricular system of the unanaesthetized dog.2 Perfusion with an artificial CSF solution containing inulin and (42)K allowed the potassium fluxes out of and into the CSF to be monitored over a period of 2 to 3 hours.3 Sodium thiopentone and sodium pentobarbitone, in doses producing light anaesthesia, caused varying degrees of depression (up to 50%) in the CSF potassium fluxes, influx being consistently more affected than efflux. These effects are attributed to a decrease in the potassium exchange between extracellular and intracellular compartments in the brain.4 Diazepam depressed both potassium fluxes by up to 10% while there was some evidence that diphenylhydantoin depressed only potassium influx.5 Paraldehyde, in contrast to the other drugs, when given at a dose level sufficient to produce light anaesthesia, stimulated CSF potassium fluxes, particularly efflux.

The transport of L-tryptophan from cerebrospinal fluid in the dog.

1. Endogenous tryptophan is uniformly distributed in dog cerebrospinal fluid (c.s.f.) and is about one tenth of the normal fasting plasma level.2. Using a recirculatory ventriculo-cisternal perfusion technique in conscious dogs it was found that L-tryptophan was removed from c.s.f. by a non-saturable mechanism in addition to bulk absorption of c.s.f. The clearance of L-tryptophan from c.s.f. was unaffected by thiopentone anaesthesia.3. Dialysis of dog plasma against an artificial c.s.f. solution containing L-tryptophan demonstrated that a large proportion of the tryptophan in dog plasma was protein-bound and that the unbound diffusible proportion would equilibrate with tryptophan concentrations equivalent to those normally found in dog c.s.f.4. Use of an open-circuit ventriculo-cisternal perfusion system in unanaesthetized dogs revealed the presence of a saturable component in the transport of tryptophan from c.s.f.5. As [(14)C]L-tryptophan infused into a recirculatory perfusion system produced no radioactively labelled metabolites, it was concluded that removal of tryptophan from c.s.f. by cerebral metabolism does not contribute substantially to maintaining the low levels of tryptophan in c.s.f. but that brain uptake associated with protein-binding may give rise to a small saturable component. The results indicate that the actual concentration gradient of tryptophan between plasma and c.s.f. is much less than it appears from the total concentration of tryptophan in the two fluids, and that the mechanism by which the c.s.f. - plasma distribution of tryptophan is maintained is mainly attributable to simple diffusion.

Interaction in the cerebral metabolism of the biogenic amines. Effects of phenelzine on the cerebral metabolism of the 5-hydroxyindoles in dog brain.

1. Chronic administration of phenelzine to dogs caused 5-hydroxyindol-3-ylacetic acid (5-HIAA) concentrations in c.s.f. from the lateral ventricle to be maintained at 50% of their normal values, but did not alter the concentrations of 5-HIAA in c.s.f. from the cisterna magna.2. Following 10 days treatment with phenelzine, the active transport of 5-HIAA from c.s.f. which normally occurs in the region of the fourth ventricle, was inhibited. This transport system was also inhibited by the addition of phenylacetic acid, the acid metabolite of phenelzine, to the fluid perfusing the cerebral ventricles.3. After 10-12 days treatment with phenelzine all regions of brain showed concentration increases to approximately 300% for 5-HT and 150% for 5-HIAA, but no alteration in the tryptophan concentration.4. Intravenous administration of tryptophan to dogs pretreated with phenelzine caused large increases in the concentration of tryptophan in brain and body fluids but did not alter either the concentrations of 5-hydroxytryptamine and 5-HIAA in brain or of 5-HIAA in c.s.f.5. A model of the cerebral metabolism of 5-hydroxytryptamine is proposed and the results are interpreted to mean that phenelzine has inhibitory actions, either directly or in some instances indirectly, on intracerebral tryptophan 5-hydroxylase, monoamine oxidase and the transport of 5-HIAA from both brain and c.s.f.

Interaction in the cerebral metabolism of the biogenic amines. Effect of phenelzine on this interaction.

1. Chronic administration of phenelzine to dogs caused the concentrations of homovanillic acid (HVA) in c.s.f. from both the lateral ventricle and cisterna magna to fall to new low levels at which they were maintained.2. After 10-12 days treatment with phenelzine the caudate nucleus had elevated concentrations of dopamine and 3-methoxytyramine and lowered concentrations of 3,4-dihydroxyphenylacetic acid and HVA.3. Intravenous administration of tryptophan to dogs pretreated with phenelzine caused in c.s.f. an increase in the concentrations of HVA and in the caudate nucleus a decrease in dopamine concentration and an increase in the concentrations of its metabolites, 3-methoxytyramine, 3,4-dihydroxyphenylacetic acid and HVA.4. A model is proposed for the cerebral metabolism of dopamine and some of the points at which tryptophan and its metabolites may interact with dopamine metabolism are discussed.

Interaction in the cerebral metabolism of the biogenic amines: effect of intravenous infusion of L-tryptophan on tryptophan and tyrosine in brain and body fluids.

1. The distribution of the amino-acids tryptophan and tyrosine has been determined in plasma ultrafiltrate, whole plasma, erythrocytes, cerebrospinal fluid (c.s.f.) and various regions of the brain in dogs.2. The effect of tryptophan administration on the distribution of both these amino-acids showed that the alterations produced in tryptophan concentration did not appear to change the concentrations of tyrosine from their normal pattern.3. The implications of these results with regard to amino-acid transport systems in man and dog are discussed.

Interaction in the cerebral metabolism of the biogenic amines: effect of intravenous infusion of L-tryptophan on the metabolism of dopamine and 5-hydroxyindoles in brain and cerebrospinal fluid.

1. In dogs, an intravenous injection of L-tryptophan followed by intravenous infusion of L-tryptophan, although unable to maintain stable concentrations of tryptophan in the plasma or cerebrospinal fluid, produced stable, raised concentrations of 5-hydroxyindol-3-ylacetic acid (5-HIAA) in the cerebrospinal fluid (c.s.f.). This indicated that it was possible to raise the concentrations of the 5-hydroxyindoles in brain and to maintain the cerebral metabolism in a new steady state.2. The regional distribution of the total molal concentration of the 5-hydroxyindoles in brain after the administration of tryptophan was similar to the distribution found in control animals, thus suggesting the normal rate limiting step of metabolism, the activity of the enzyme tryptophan 5-hydroxylase, was still the controlling factor.3. Tryptophan administration caused a greater proportionate increase in the concentration of 5-HIAA than in that of 5-hydroxytryptamine (5-HT) in all regions of brain, perhaps indicating that the ;storage' capacity for 5-HT becomes filled under these conditions.4. Administration of tryptophan caused a large rise in the concentration of homovanillic acid in c.s.f. demonstrating that there was an interaction between the cerebral metabolism of tryptophan and dopamine.