Ivor H. Mills

Opiate receptors on lymphocytes and platelets in man

Receptors for opiates, opiate-like substances, and their antagonists, such as naloxone (a close chemical and conformational congener of morphine), on brain cell homogenates and neuroblastoma X glioma hybrid cells in tissue culture have been reported. The present study on the binding of [3H]naloxone to lymphocytes and platelets freshly isolated from the peripheral blood of 39 healthy adult human volunteers showed that (1) [3H]naloxone bound to lymphocytes and platelets at 4 degrees C, reaching equilibrium in 30 min, and was not removed by washing (three times) with the suspending medium; (2) the binding of [3H]naloxone to cells decreased in the presence of increasing amounts of unlabeled naloxone, approaching a plateau; (3) significant amounts of the radioligand remained bound in the presence of micromolar quantities of the unlabeled ligand; and (4) in the absence of Na+ ions, 1 to 10 nmol of morphine hydrochloride for 10(6) lymphocytes, and 1 to 25 nmol of morphine hydrochloride for 10(8) platelets, decreased the binding of [3H]naloxone by 43 to 57%. It is concluded that at least some of the [3H]naloxone binding sites on human lymphocytes and platelets are specific opioid receptor sites of the mu type (Enkephalins define the delta sites.) The observations on the binding of naloxone to cells do not appear to be artifacts. Opioid receptor sites on lymphocyte and platelet membranes may have properties similar to those on nerve cell membranes.

Naloxone in the treatment of anorexia nervosa: effect on weight gain and lipolysis.

The effects of a constant intravenous infusion of naloxone in doses ranging from 3.2 to 6.4 mg/day were studied in a group of patients with anorexia nervosa. Patients showed a significantly greater weight gain during the infusion compared with the periods before and after naloxone. Plasma fJ-hydroxybutyrate and non-esterified fatty acid levels fell during the infusion. It is suggested that, in man, naloxone has an antilipolytic effect in vivo.

Kallikrein, Kininogen and Kinins in Control of Blood Pressure

Plasma kallikrein releases bradykinin when activated by gram-negative septicemia or irreversible hemorrhagic shock. Pancreatitis releases glandular kallikrein causing hypotension and increased vascular permeability. Bradykinin in the brain produces hypertension. Renal kallikrein is released by high arterial pressure, vasodilators, low doses of noradrenaline, angiotensin II, mineralocorticoids and rapid volume expansion. It has a biphasic relation to sodium excretion. In essential hypertension, kallikrein release into the blood and urine is low and facilitates hypertension. High renin in Bartters syndrome is balanced by high PGE and kallikrein without hypertension.

THYROIDAL HORMONE METABOLISM IN OBESITY DURING SEMI‐STARVATION

Six obese subjects were studied over a period of 12 weeks whilst on a 1260 kJ (300 kcal) formula diet. Weight loss was initially rapid, but later slowed markedly despite good patient compliance. The basal metabolic rate (BMR) fell in all patients during the study. Plasma triiodothyronine fell in all patients, whilst the plasma half‐life of thyroxine increased. Plasma thyroxine, reverse triiodothyronine (reverse T3) and the serum prolactin and thyrotropin response to thyroliberin all showed no significant change.

SERUM T3 AND T4 LEVELS IN PATIENTS WITH ANOREXIA NERVOSA SHOWING TRANSIENT HYPERTHYROIDISM DURING WEIGHT GAIN

Serum thyroxine (T4) and triiodothyronine (T3) levels were measured in a group of thirty‐three patients with anorexia nervosa (AN) and compared with twenty‐five control women presenting with hirsutism and twenty‐one patients with primary myxoedema. T3 levels in the AN patients were significantly lower than in the control subjects and in the patients with myxoedema while T4 levels were significantly higher than in the patients with hypothyroidism but significantly lower than in the control group. Seventeen anorexia patients had further T3 and T4 levels measured following an arbitrary 25% weight gain and both levels had increased significantly. For individual patients, the absolute rise in T3 levels was significantly correlated with the rate of weight gain. Thirteen patients had serial T3 and T4 levels measured during their periods of weight gain. Eight of these subjects showed a gradual rise in T3 levels from subnormal or low normal levels to values in the upper normal range. Four subjects showed a distinct and self limiting overshoot of T3 levels and, associated with this, the patients had clinical features of mild hyperthyroidism.

The neuronal basis of compulsive behaviour in anorexia nervosa

The relationship between arousal and efficiency of the brain is shown by the inverted U of the Yerkes-Dodson curve. Measuring arousal has been difficult because the three types of arousal (EEG, behaviour and autonomic) do not change in unison. From Magouns work, arousal can be stimulated via the reticular formation or from parts of the cortex. Kyotorphin (Tyr-Arg) causes widespread excitation when applied to the cortex and may represent this mechanism: it is then inhibited only by noradrenaline. The hippocampus causes stimulation of arousal to persist after the exciting stimulus stops and can itself be stimulated into long term potentiation. The latter may be related to the onset of compulsive behaviour which appears to occur only with excessive stimulation of arousal. The opioid dynorphin is the main stimulator of the hippocampus and can cause long term potentiation. Inhibition of opioid activity by continuous naloxone infusion facilitates weight gain in anorexia and in some will abolish the compulsive drive. Other opioid antagonists need to be found for the more severe compulsive behaviour patients.

Stimulation of the Renal Kallikrein-Kinin System by Vasoactive Substances and Its Relationship to the Excretion of Salt and Water1

Large doses of angiotensin when infused intravenously or into the renal artery cause natriuresis. The initial effect is release of prostaglandin (probably PGE) and this leads to release of kallikrein. This latter step can be inhibited by noradrenaline. Activation of the kallikrein/kinin system is followed by release of a large molecular weight natriuretic hormone which is absent in glomerulonephritis. A small molecular weight hormone follows the large one and probably effects natriuresis by inhibition of renal Na/K ATPase. This inhibition is reversed by noradrenalint or renal nerve stimulation. Natriuresis is the result of a chain reaction and not a single specific natriuretic hormone.

CORTICOSTERONE‐SECRETING TUMOURS: WITH AND WITHOUT RENAL ARTERY STENOSIS

Two cases of corticosterone‐secreting adrenal adenomata are reported. Both patients were middle‐aged females in whom the clinical course spanned several years before the diagnosis was made. Severe hypertension and recurrent hypo‐kalaemia refractory to standard treatments were outstanding features. The importance of measuring the production rates of all mineralocorticoids when a tumour is suspected is emphasized by Case 1 where the production rate of corticosterone alone was elevated. Bilateral renal artery stenosis was responsible for unsuppressed plasma renin activity in Case 2.

THE NEURONAL BASIS OF COMPULSIVE BEHAVIOUR IN ANOREXIA NERVOSA

The relationship between arousal and efficiency of the brain is shown by the inverted U of the Yerkes-Dodson curve. Measuring arousal has been difficult because the three types of arousal (EEG, behaviour and autonomic) do not change in unison. From Magouns work, arousal can be stimulated via the reticular formation or from parts of the cortex. Kyotorphin (Tyr-Arg) causes widespread excitation when applied to the cortex and may represent this mechanism: it is then inhibited only by noradrenaline. The hippocampus causes stimulation of arousal to persist after the exciting stimulus stops and can itself be stimulated into long term potentiation. The latter may be related to the onset of compulsive behaviour which appears to occur only with excessive stimulation of arousal. The opioid dynorphin is the main stimulator of the hippocampus and can cause long term potentiation. Inhibition of opioid activity by continuous naloxone infusion facilitates weight gain in anorexia and in some will abolish the compulsive drive. Other opioid antagonists need to be found for the more severe compulsive behaviour patients.

Urinary kallikrein in the rat: stimulation with angiotensin infusion but depression with increasing sodium concentration.

1. The kallikrein response to angiotensin II infusion in the conscious rat was studied to compare it with the response in the dog. 2. Active kallikrein was measured by the aprotinin‐suppressible esterase technique in 20 min periods. Angiotensin (5 x 10(‐9) to 5 x 10(‐2) micrograms min‐1) was infused in 10 mM saline in period 10 (group A), or in 90 mM saline in periods 10‐12 (group B). 3. In group A, no dose of angiotensin was antinatriuretic. Natriuresis and urinary sodium concentration were dose dependent. 4. Kallikrein excretion was dose dependent with angiotensin (P < 0.0001) and inversely correlated with urinary sodium concentration (P = 0.011). In natriuretic and non‐natriuretic rats, kallikrein excretion after angiotensin was inversely correlated with urinary sodium concentration in the preceding period. 5. In group B, natriuresis and urinary sodium concentration were dose dependent. Kallikrein excretion in periods 10‐13 was inversely correlated with urinary sodium concentration in the preceding period (P = 0.0001) and inversely correlated with urinary osmolality in periods 9‐13. 6. Infusion of angiotensin II at 5 x 10(‐6) micrograms min‐1 led to antinatriuresis. 7. Formulae were derived which enabled the opposing effects of angiotensin and urinary sodium concentration on kallikrein excretion to be separated. In group A both these effects were statistically significant only in the natriuretic rats (natriuresis > 20 mumols per period). In group B the formulae showed a dose‐dependent rise in kallikrein excretion, which was counteracted by the decrease in kallikrein excretion associated with the increasing urinary sodium concentration. 8. With infusions of 0.9% saline, kallikrein excretion in periods 10‐13 was inversely correlated with urinary sodium concentration in the preceding period (P = 0.001). 9. The overall effect in the rat differs from that in the dog, where kallikrein increases with angiotensin natriuresis and dilution of the urine occurs.