The effects of administration of mCPP on psychological, cognitive, cardiovascular, hormonal and MHPG measurements in human volunteers.

m-Chlorophenylpiperazine (mCPP) is a metabolite of the antidepressant trazodone which has been widely used in psychopharmacology research as a probe of serotonin (5-hydroxytryptamine; 5-HT) function. However, in addition to binding at 5-HT receptors it also binds strongly to alpha 2-adrenoceptors, and it is conceivable that some of the physical and psychological symptoms previously reported following mCPP infusion are due to effects upon central noradrenergic neurotransmitter function. In this double-blind placebo-controlled balanced-crossover study in 12 healthy male volunteers we have examined the effects of infusion of mCPP (0.08 mg/kg over 2 min) on symptoms of anxiety, cognitive performance, pulse and blood pressure, and plasma concentrations of adrenocorticotrophic hormone (ACTH), cortisol, prolactin, growth hormone, and the noradrenaline metabolite 3-methoxy-4-hydroxyphenyl glycerol (MHPG). The results confirm previous findings that in humans mCPP causes significant increases in the symptoms of anxiety, and in the plasma concentrations of cortisol, prolactin and growth hormone. In addition, our results demonstrate that mCPP causes no significant changes in cognitive performance, in pulse or systolic blood pressure, or in the plasma concentration of MHPG. Since pulse, systolic blood pressure and MHPG plasma concentrations all to some degree reflect central noradrenergic activity, we believe it unlikely that the psychological and hormonal effects of mCPP are due primarily to effects on noradrenergic neurotransmission. Further studies to address this specific issue are needed, however, before firm conclusions can be reached.

Effects of carbamazepine on 5-hydroxytryptamine function in rodents.

The effects of carbamazepine (CBZ) on brain 5-hydroxytryptamine (5-HT) function were investigated in rodents pretreated with CBZ acutely or for 14 days. In behavioural experiments, mice pretreated with 14 days CBZ showed increased 5-HT2-mediated head twitch behaviour after injection of carbidopa (25 mg/kg) followed by 5-hydroxytryptophan (5-HTP, 100 mg/kg). However, no change in head twitches after 5-methoxy,N,N,-dimethyltryptamine (5MeODMT 5.0 mg/kg), a direct agonist, was observed. Chronic CBZ administration to rats did not alter either the behavioural syndrome induced by 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT, 1.0 mg/kg), an index of postsynaptic 5-HT1A responses, or hypothermia after 8-OH-DPAT (0.5 mg/kg) which is thought to reflect presynaptic 5-HT1A activity. Both hyperactivity and the behavioural syndrome seen after tranylcypromine (20 mg/kg) followed by L-tryptophan (100 mg/kg) were decreased by prior treatment with CBZ (14 days). Accumulation of 5-HTP after administration of the amino acid decarboxylase inhibitor NSD1015 (100 mg/kg) was decreased after acute CBZ (50 mg/kg) in hippocampus. However, after 14 days oral treatment no change in this measure of 5-HT synthesis was seen, in either hippocampus or frontal cortex. CBZ (50 microM) added to superfused brain slices did not affect potassium-stimulated [3H]-5-HT release. However, hippocampal slices from rats pretreated with CBZ (14 days) showed increased potassium-stimulated [3H]-5-HT release. CBZ (14 days) did not alter 5-HT2 binding in rat frontal cortex.(ABSTRACT TRUNCATED AT 250 WORDS)

In vivo cation transport during short-term and long-term digoxin therapy.

We have studied the effects of digoxin on cation transport in vivo by measuring the changes in plasma and red cell rubidium concentrations following an oral load of rubidium chloride. In eight patients who had been taking digoxin for 7 to 10 days (mean plasma digoxin concentration 1.3 ng ml-1) the rise in plasma rubidium concentrations was enhanced and the rise in red cell rubidium concentrations was attenuated following the oral load of rubidium chloride, by comparison with the changes in well-matched controls. In contrast, the disposition of rubidium was not altered in 12 patients who had been taking digoxin for more than 3 months (mean plasma digoxin concentration 1.1 ng ml-1). These results suggest that the inhibitory effects of digoxin on cation transport are detectable in vivo during short-term therapy, but not during long-term therapy, and confirm our previous in vitro findings.

Cation transport abnormalities in vivo in untreated essential hypertension.

In order to study cation transport in vivo we have measured the changes in plasma and intra-erythrocytic rubidium concentrations after the oral administration of rubidium chloride. In this paper we describe our findings in 22 patients with untreated essential hypertension, compared with the findings in 22 carefully matched control subjects. Our findings in patients receiving short-term digoxin therapy and in patients with chronic renal failure are also included for comparison. Whereas the findings in patients receiving digoxin and in patients with chronic renal failure are compatible with a widespread reduction in sodium, potassium-ATPase activity in vivo, the findings in patients with untreated essential hypertension are not. Further analysis of the data and a similar study of the disposition of 42K after the intravenous administration of 42KCl suggest that in vivo net cation transport is enhanced in the erythrocytes of patients with untreated essential hypertension.

A sensitive high-temperature electrothermal atomic absorption analysis for Rb+ in erythrocytes and plasma of normal and hypertensive persons.

This method for determination of Rb+ in human plasma and erythrocytes by graphite-furnace atomic absorption spectrophotometry has a sensitivity of 29 nmol/L for plasma, 12 nmol/L for erythrocytes. The detection limit is 24 nmol/L for plasma, 4.8 nmol/L for erythrocytes. This assay is approximately 30-fold more sensitive than previously reported techniques involving atomic absorption spectrophotometry, enabling use of smaller samples. The rubidium signal is linear with concentration up to 1.2 mumol/L, and addition of other cations to the matrix produces only minor alterations in the Rb+ signal. We measured plasma and erythrocytic Rb+ concentrations in healthy subjects and in patients with untreated essential hypertension. In both, our values are similar to those previously reported for healthy individuals.

An in vivo study of cation transport in essential hypertension.

In order to study cation transport in vivo the changes in plasma and red cell rubidium concentrations were measured following an oral load of rubidium chloride. Eight patients receiving short-term digoxin therapy, 10 patients with chronic renal failure and 22 patients with untreated essential hypertension were studied, and the findings were compared with those in healthy control subjects matched for age, sex, race, obesity index, and plasma and red cell potassium concentrations. In patients receiving short-term digoxin therapy, and in patients with chronic renal failure, the increases in plasma rubidium concentrations after the oral load of rubidium chloride were significantly enhanced and the increases in red cell rubidium concentrations were significantly attenuated. These findings are consistent with a generalized reduction in Na+, K+-ATPase activity in vivo. In contrast, in patients with untreated essential hypertension the increases in both plasma and red cell rubidium concentrations following the oral load were significantly enhanced. These data do not support the hypothesis that essential hypertension is associated with reduced Na+, K+-ATPase activity in vivo, at least in the red cell.

A method for the study of cation transport in vivo: effects of digoxin administration and of chronic renal failure on the disposition of an oral load of rubidium chloride.

In order to study cation transport in vivo we have measured the changes in plasma and intra-erythrocytic rubidium concentrations following an oral load of rubidium chloride. The changes in plasma rubidium concentration are related to the distribution of rubidium to all the body tissues and the changes in intra-erythrocytic rubidium concentrations provide an example of rubidium uptake by one particular tissue. In eight healthy volunteers pretreatment with a loading dose of digoxin (20 micrograms/kg) enhanced the rise in plasma rubidium concentrations and attenuated the rise in intra-erythrocytic rubidium concentrations after the oral load of rubidium chloride. Ten patients with chronic renal failure, compared with a well-matched control group, were found to have changes similar to, but more marked than, those caused by digoxin, i.e. a much greater rise in plasma rubidium concentrations and a much smaller rise in intra-erythrocytic rubidium concentrations, after the oral load of rubidium chloride. These findings are consistent with wide-spread reduction in Na+, K+-ATPase activity in subjects who have taken a loading dose of digoxin and patients with chronic renal failure. They are, therefore, consistent with the findings of previous studies in vitro and show that it is possible to demonstrate changes in cation transport in vivo.

Monitoring digoxin therapy: I. Plasma concentrations and an in vitro assay of tissue response.

1 An in vitro technique is described for measuring the uptake of 86Rb by human erythrocytes. 2 Fifteen patients were treated with digoxin for atrial fibrillation and other fast arrhythmias. 3 86Rb uptake by the patients' own red cells fell from pre-treatment values during digitalization. 4 The therapeutic response of patients with atrial fibrillation correlated better with the changes in 86Rb uptake than with plasma digoxin concentrations.

Manganese metabolism in cows and goats.

When 54MnCl2 was incubated with fresh bovine or caprine serum for 20 h and the serum subjected to electrophoresis at pH 9.5, the 54Mn bound to transferrin and alpha2-macroglobulin in proportions which varied with the temperature of incubation and the temperature of electrophoresis. Between 0 and 37 degrees C, the higher the temperature of incubation the larger the proportion bound to transferrin and the lower the proportion bound to alpha2-macroglobulin. The temperature at which electrophoresis was performed had little effect on the proportion of 54Mn bound to transferrin, but increasing temperature reduced the proportion of 54Mn bound to alpha2-macroglobulin. Mn2+ did not bind to purified transferrin in vitro in the absence of an oxidising agent. In the presence of permanganate, Mn3+ was formed and chelated by transferrin at physiological pH. In fresh serum this oxidation step may be performed by ceruloplasmin or molecular oxygen. Mn2+ was bound reversibly to alpha2-macroglobulin but this protein played no part in the oxidation of divalent manganese and had no effect on the protein binding of trivalent manganese. Manganese in the divalent state, either free as Mn2+ or bound to alpha2-macroglobulin, is removed from blood plasma very efficiently by the liver. However, the manganic-transferrin complex normally found in circulation is not rapidly removed from plasma. The liver can remove large amounts of excess manganous manganese which it presumably excretes; the small essential fraction of the manganese absorbed is oxidised to the trivalent state and bound to transferrin.