Dual facets of hyponatraemia and arginine vasopressin in patients with ACTH deficiency.

OBJECTIVE: Hyponatraemia is often observed in patients with ACTH deficiency who are thought not to suffer from volume depletion. Their high plasma AVP levels relative to plasma osmolality are presumed to be maintained by non-osmotic mechanisms. We attempted to assess volume status from changes in selected clinical measurements related to body fluid balance in the course of i.v. fluid supplementation and following glucocorticoid (GC) replacement in ACTH-deficient patients, and to interpret plasma AVP levels in the context of the estimated volume status. PATIENTS AND DESIGN: This report consists of three parts. First, an ACTH-deficient patient with hyponatraemia and volume depletion who was followed through volume replacement to recovery after GC replacement is described (case report). Secondly, medical records of five ACTH-deficient patients with hypovolaemia and hyponatraemia were surveyed retrospectively to observe changes in serum levels of sodium, uric acid (UA) and haematocrit (Hct) following i.v. fluid supplementation of low sodium content (retrospective study). Thirdly, five ACTH-deficient patients with or without overt dehydration were studied with regard to body weight, blood pressure, serum sodium, total proteins, Hct and blood urea nitrogen before and after GC replacement (prospective study). Plasma AVP levels were measured after i.v. fluid supplementation without GC replacement in the patients of the retrospective study, and before and after GC replacement in the patients of the prospective study. RESULTS: The first patient became more hyponatraemic after i.v. fluid supplementation and recovered ultimately from hyponatraemia after GC replacement. In five patients studied retrospectively, the serum sodium levels fell progressively following i.v. fluid supplementation, concurrent with reduction in UA levels and Hct, which indicated the dilutional nature of the hyponatraemia. In the patients observed prospectively, the accumulation of fluid and sodium was indicated by a rise in body weight, blood pressure and serum sodium levels and a decline in Hct and total proteins after GC replacement. Plasma AVP levels rose similarly in patients with dilutional hyponatraemia and in patients with borderline hyponatraemia before GC replacement. CONCLUSION: Patients with untreated ACTH deficiency may have either of two kinds of hyponatraemia--i.e. borderline hyponatraemia associated with subclinical hypovolaemia, or dilutional hyponatraemia. Similarity of plasma AVP levels in two hyponatraemic states suggests their AVP secretion is regulated by non-osmotic, non-volume mechanisms, possibly released from GC suppression at low plasma osmolality.

Involvement of growth hormone (GH)-releasing factor in GH secretion induced by serotoninergic mechanisms in conscious rats.

A possible role of hypothalamic GH-releasing factor (GRF) in GH secretion induced by serotoninergic stimuli was investigated in conscious freely moving rats with a passive immunization technique. Either iv injection of 5-hydroxy-L-tryptophan (1 mg/100 g BW) or intracerebroventricular injection of serotonin (10 micrograms/rat) caused an increase in plasma GH in rats treated with normal rabbit serum (0.5 ml/rat, iv) 30 min previously. Injection of rabbit antiserum specific for rat GRF (0.5 ml/rat, iv, 30 min previously) blunted the plasma GH increase induced by 5-hydroxy-L-tryptophan or serotonin in these animals. These results suggest that GH secretion induced by serotoninergic mechanisms is mediated, at least in part, by hypothalamic GRF in the rat.

Stimulation by alpha-adrenergic mechanisms of the secretion of growth hormone-releasing factor (GRF) from perifused rat hypothalamus.

The possible involvement of adrenergic mechanisms in regulating the secretion of growth hormone (GH)-releasing factor (GRF) from the rat hypothalamus was examined in vitro with a perifusion system. A high potassium concentration (56 mM) stimulated GRF release from the hypothalamus. The infusion of clonidine (10(-4) M), an alpha 2-adrenergic stimulant, resulted in an increase in the spontaneous release of GRF. In the presence of propranolol (10(-5) M), a beta-adrenergic blocking agent, clonidine (10(-5) and 10(-4) M) stimulated GRF release more prominently in a dose-related manner, whereas propranolol (10(-5) and 10(-4) M) by itself did not affect the spontaneous GRF release. The stimulatory effect of clonidine (10(-4) M) on GRF release in the presence of propranolol was inhibited by yohimbine (10(-4) M), an alpha 2-adrenergic blocking agent. These findings suggest that alpha 2-adrenergic mechanisms play a role in stimulating GRF release from the hypothalamus in rats.

Stimulation by gastrin-releasing peptide, neurotensin and DN1417, a novel TRH analog, of dopamine and norepinephrine release from perifused rat hypothalamic fragments in vitro.

Both dopamine (DA) and norepinephrine (NE) release from perifused rat hypothalamic fragments was increased by depolarizing concentrations of potassium (K+, 20 mM and 56 mM) in a dose-related and Ca2+-dependent manner. DA and NE release induced by high K+ (20 mM) was further enhanced by gastrin-releasing peptide (GRP, 10(-5)-10(-6) M) and DN 1417 (10(-5) M), a thyrotropin-releasing hormone (TRH) analog. GRP (10(-5) M), neurotensin (NT, 10(-5) M) and DN 1417 (10(-5) M) also stimulated spontaneous release of DA and NE from the hypothalamus. These results suggest that GRP, NT and DN 1417 act at the hypothalamic catecholamine nerve terminals and stimulate the release of DA and NE in the rat.

Further evidence that central neurotensin inhibits pituitary prolactin secretion by stimulating dopamine release from the hypothalamus.

Intracerebroventricular (icv) injection of neurotensin (NT) (2 micrograms/rat) suppressed prolactin (PRL) release induced by L-5-hydroxytryptophan (1 mg/100 g body wt, iv), prostaglandin E2(1 microgram/rat, icv), and FK33-824 (10 micrograms/100 g body wt, iv), a Met5-enkephalin analog, in urethane-anesthetized or conscious rats. In contrast, NT did not suppress elevated plasma PRL levels sustained by a large dose of domperidone (10 micrograms/100 g body wt, iv), a peripheral dopamine antagonist. In in vitro experiments, NT (10(-5) M) stimulated dopamine release from perifused rat hypothalamic fragments. These results suggest that central NT inhibits PRL secretion by stimulating dopamine release from the hypothalamus into hypophysical portal blood in the rat.

Involvement of peptide histidine isoleucine (PHI) in prolactin secretion induced by serotonin in rats.

The possible role of hypothalamic peptide histidine isoleucine (PHI) in prolactin (PRL) secretion induced by serotoninergic mechanisms was investigated in male rats using a passive immunization technique. Intracerebroventricular injection of serotonin (5HT, 10 micrograms/rat) raised plasma PRL levels both in urethane-anesthetized rats and in conscious rats pretreated with normal rabbit serum (0.5 ml/rat, iv, 30 min before). Plasma PRL responses to 5HT were blunted in these animals when they were pretreated with rabbit antiserum specific for PHI (0.5 ml/rat, iv, 30 min before) (mean +/- SE peak plasma PRL: anesthetized rats 271.3 +/- 38.3 ng/ml vs 150.0 +/- 12.6 ng/ml, p less than 0.01, conscious rats 54.3 +/- 6.8 ng/ml vs 30.7 +/- 4.1 ng/ml, p less than 0.025). These results suggest that hypothalamic PHI is involved, at least in part, in PRL secretion induced by central serotoninergic stimulation in the rat.

Inhibition by antiserum to vasoactive intestinal polypeptide (VIP) of prolactin secretion induced by serotonin in the rat.

Intraventricular (i.c.v.) injection of serotonin (5HT) or intravenous (i.v.) injection of 5-hydroxytryptophan (5HTP), a precursor of 5HT, raised plasma prolactin (PRL) levels in urethane-anesthetized rats pretreated with normal rabbit serum. When the animals were injected i.c.v. or i.v. with specific anti-VIP rabbit serum, the plasma PRL responses to 5HT and 5HTP were blunted. These findings suggest that hypothalamic VIP is involved, at least in part, in PRL secretion induced by central serotonergic stimulation in the rat.

Involvement of hypothalamic vasoactive intestinal polypeptide (VIP) in prolactin secretion induced by serotonin in rats.

To study the possible involvement of hypothalamic vasoactive intestinal polypeptide (VIP) in regulating the secretion of prolactin (PRL), the effect of anti-VIP rabbit serum on serotonin (5-HT)-induced PRL release was examined in urethane-anesthetized male rats. Anti-VIP serum (AVS) or normal rabbit serum (NRS) was infused into a single hypophysial portal vessel of the rat for 40 min at a rate of 2 microliters/min with the aid of a fine glass cannula and 5-HT was injected into a lateral ventricle 10 min after the start of the infusion. Intraventricular injection of 5-HT (10 micrograms/rat) caused an increase in plasma PRL levels in control animals infused with NRS and 5-HT-induced PRL release was blunted in animals infused with AVS (mean +/- SE peak plasma PRL: 118.9 +/- 19.8 ng/ml vs 54.7 +/- 16.2 ng/ml, p less than 0.05). These findings suggest that the secretion of PRL induced by 5-HT is mediated, at least in part, by hypothalamic VIP release into the hypophysial portal blood in the rat.

Glucagon-induced somatostatin release from perifused rat hypothalamus: calcium dependency and effect of cysteamine treatment.

Somatostatin (SRIF) release from rat hypothalamus was investigated in vitro with a perifusion system. Glucagon (1 microM) and high potassium concentrations (56 mM) stimulated SRIF release in a calcium-dependent manner. Pretreatment of the rat with cysteamine (30 mg/100 g body weight, 7 h earlier) significantly reduced SRIF release from the hypothalamus in glucagon- and high potassium-stimulated states as well as in the basal state. SRIF release from rat hypothalamus was also stimulated by both dibutyryl cyclic AMP (1 mM) and theophylline (3 mM). These results suggest that glucagon, acting in a calcium-dependent manner and possibly through the adenylate cyclase-cyclic AMP system, stimulates SRIF release from rat hypothalamus and that cysteamine treatment reduces releasable SRIF in the hypothalamus.