S. L. Lightman

CLIMACTERIC FLUSHING: CLINICAL AND ENDOCRINE RESPONSE TO INFUSION OF NALOXONE

Six postmenopausal women with frequent attacks of flushing were studied by measuring plasma luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin and noradrenaline concentrations at regular and frequent intervals and at the time of each of 82 flushes. The hormone measurements were made on a control day and on the second day during infusion of either naloxone (22 μg/min) or saline. The perception of a flush was associated with a significant increase of plasma LH concentrations. There were no significant changes in plasma FSH, prolactin or noradrenaline concentrations. Naloxone infusion resulted in a highly significant reduction in the frequency of flushes and in the number of LH pulses. We conclude that flushing and its neuro‐endocrine correlates are related to activation of opiate receptors. Naloxone may provide the basis for a non‐steroidal treatment of climacteric flushing attacks.

EVIDENCE FOR DOPAMINE AS AN INHIBITOR OF VASOPROTEIN RELEASE IN MAN

The effect of dopamine on vasopressin release was studied by the infusion of L‐Dopa, a dopamine precursor that crosses the blood‐brain barrier. L‐Dopa suppressed resting levels of vasopressin and inhibited the rise of vasopressin produced by head‐up tilt. Carbidopa, a decarboxylase inhibitor that does not cross the blood‐brain barrier blocked the action of L‐Dopa. These results suggest that dopamine inhibits the release of vasopressin, either by an action at pituitary level or at the median eminence of the hypothalamus.

STUDIES OF DIURNAL CHANGES IN PLASMA RENIN ACTIVITY, AND PLASMA NORADRENALINE, ALDOSTERONE AND CORTISOL CONCENTRATIONS IN MAN

Diurnal studies were performed on ten normal volunteers taking a normal sodium diet. Half‐hourly blood samples were taken throughout 25 h and assayed for plasma renin activity (PRA) and the plasma concentrations of noradrenaline, aldosterone and cortisol. Sleep was recorded polygraphically and scored by standard criteria. Circadian rhythms were demonstrated for plasma cortisol, aldosterone and noradrenaline concentrations, but not for plasma renin activity. The nadir of the rhythm for the noradrenaline concentration appeared to be related to sleep itself rather than to any chronological index. Only PRA was effected by the stage of sleep, falling sharply during periods of REM sleep. Plasma cortisol and aldosterone concentrations showed a positive correlation over the 24 h. There was, however, no correlation between PRA and plasma aldosterone concentrations, except when the subjects arose after their nights recumbency. Plasma noradrenaline concentration did not correlate with the concentration of any of the other hormones measured.

Rhythms of plasma noradrenaline in man

Abstract Fluctuations in plasma noradrenaline were investigated in normal volunteers sampled over 24 hr. A significant circadian rhythm was demonstrable, with a trough occurring during the nocturnal period in those subjects on a normal sleep-wake cycle. Spectral analysis failed to provide any evidence for significant ultradian rhythms in plasma noradrenaline.

Down-regulation of gonadotrophin secretion in postmenopausal women by a superactive LHRH analogue: lack of effect on menopausal flushing

Summary. The effect of the LHRH analogue D‐Ser (TBU)6‐EA10‐LRH (Hoe 766) on the response of plasma gonadotrophins and the frequency of climacteric flushing was studied in five postmenopausal women. Following an initial stimulatory effect on gonadotrophin secretion plasma gondotrophins returned to near baseline concentrations with loss of their pattern of pulsatile release and of their sensitivity to exogenous LHRH. The frequency of flushing was unaltered during the treatment period.

NALOXONE INCREASES THE NICOTINE‐STIMULATED RISE OF VASOPRESSIN SECRETION IN MAN

Intravenous nicotine was administered to a group of six subjects during the concurrent intravenous infusion of either the opiate antagonist naloxone, or of saline. Nicotine stimulated vasopressin secretion in all subjects. Naloxone infusion increased both the plasma vasopressin response to nicotine and the resulting rise in urine osmolality.

A reaction of acetaldehyde with enkephalins and related peptides.

Abstract The naturally-occurring opioid peptides methionine-enkephalin (Tyr-Gly-Gly-Phe-Met-OH) and leucine-enkephalin (Tyr-Gly-Gly-Phe-Leu-OH), and related peptides with the same N-terminal amino acid sequence react with acetaldehyde in water to form the N-terminal ring-closed imidazolidinone derivative. Experimental evidence for the proposed structure is based on a comparison of the rates of change of the Chromatographic, chemical properties and opiate activity of the enkephalins in the presence of acetaldehyde; methionine-enkephalin exhibits a half-time for reaction of about 14 min in aqueous phosphate buffer, pH 7.0 at 25°. Additional studies indicate that the properties of the acetaldehyde-enkephalin reaction are also shared by the larger opioid peptides. In particular, the pituitary opioid, β-endorphin loses opiate activity on exposure to acetaldehyde at a rate comparable to that observed with the enkephalins.

Distribution of β‐endorphin in normal and schizophrenic human brains

Abstract. β‐Endorphin was measured by radioimmunoassay in post‐mortem human brains. Samples of brain were taken from five discrete areas, both from control brains and brains of schizophrenic patients. No difference in β‐endorphin levels was found in these two groups of brains. β‐Endorphin was confirmed to be widely distributed in the brain, but there were considerable differences in the concentrations in different areas.

STUDIES ON THE RESPONSES OF PLASMA RENIN ACTIVITY AND ALDOSTERONE AND CORTISOL LEVELS TO DOPAMINERGIC AND OPIATE STIMULI IN MAN

Evidence for a role of dopamine and endogenous opioids in the control of the secretion of renin and adrenal steroids was sought in man. The effects of l‐dopa, l‐dopa plus carbidopa, dopamine, domperidone and naloxone were studied on the renin and aldosterone responses to head‐up tilt. l‐dopa diminished the rise in renin following tilt and this effect of l‐dopa was abolished by carbidopa. Aldosterone was not significantly affected by any of the compounds. Cortisol secretion was stimulated by carbidopa plus l‐dopa more than l‐dopa alone, and was also increased by both dopamine and naloxone. The significance of these findings is discussed.

Vasoactive intestinal polypeptide stimulation of prolactin release and renin activity in normal man and patients with hyperprolactinaemia: effects of pretreatment with bromocriptine and dexamethazone

Abstract. Vasoactive intestinal polypeptide (VIP) was infused into normal volunteers and patients with hyperprolactinaemia. Heart rate increased from 62 pL 3 to 75 pL 3 beats min‐1 (P= 0·001) in controls and from 70 pL 2 to 78 pL 3 beats min‐1 (P= 0·001) in hyperprolactinaemics. Similarly, haematocrit increased from 38 pL 2 to 44 pL 1% (P= 0·001) and from 40 pL 1 to 43 pL 2% (P= 0·002) and plasma renin activity from 910 pL 59 to a peak of 3344 pL 282 pg ml‐1 h‐1 (P= 0·001) and from 1577 pL 671 to a peak of 4954 pL 1364 pg ml‐1 h‐1 (P= 0·001) in the two groups, respectively. Prolactin concentrations rose in the control group only, from 134 pL 11 to a peak of 377 pL 35 mU l‐1 (P= 0·001), whilst in the hyperprolactinaemics little change occurred from the pre‐infusion concentration of 3873 pL 2179 reaching a peak of 3998 pL 2347 mU l‐1 (P > 0·07).