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Abstract. CQP 201—403 is a propylergoline derivative with strong dopamine stimulant properties in animals models. It was developed in order to meet the need for a dopamine agonist compound which would offer longer action and improved tolerability. In this study, we tested CQP 201—403 in healthy male volunteers in order to assess its PRL suppression action and other hormonal effects as well as its duration of action and tolerability. Twenty-one volunteers participated in a dose-range study conducted according to a double-blind cross-over design with placebo control. The PRL suppression effect of single oral doses ranging from 0.05 mg to 0.035 mg were investigated. The duration of action of CQP 201—403 was tested in 6 other volunteers receiving a single oral dose of 0.025 mg or placebo. Blood was sampled over 48 h for PRL and GH measurements. An endocrine profile was performed in 6 volunteers receiving either 0.025 mg CQP 201—403 as a single oral dose or placebo. Blood was sampled over 8 h for measuring plasma PRL, GH, LH, FSH, TSH and cortisol. The results show strong dose-dependent PRL suppression (P< 0.001) begining 2 h after ingestion. PRL suppression lasted for more than 24 h and the normal sleep PRL surges were abolished. GH was transiently stimulated during the first few hours; the GH sleep profile was normal. All other hormones were not affected by the administration of CQP 201—403. Tolerability was good and no drug attributable changes in safety measures occurred. This study demonstrated that CQP 201—403 is a potent and long-acting PRL suppression compound in healthy volunteers. Strong PRL suppression and optimal tolerability were achieved with the 0.025 mg dose. This new dopamine agonist promises to be a therapeutically useful dopaminomimetic compound which could probably be prescribed at a once-daily dosage.

ABSTRACT

The effect of acute administration of human growth hormone (HGH) and of alpha-melanocyte stimulating hormone (alpha-MSH) on plasma aldosterone, cortisol, corticosterone and growth hormone has been studied in normal man and in patients with panhypopituitarism. There is no acute effect of exogenous HGH on plasma levels of aldosterone, cortisol and corticosterone in normal man and in patients with panhypopituitarism. The plasma level of immunoreactive HGH measured during acute HGH infusion in man does not seem to be proportional to the doses administered in our study. Alpha-MSH raises the concentration of plasma HGH, but this stimulation is not dose-dependent. Aldosterone, cortisol and corticosterone concentrations are not influenced by the elevation of HGH mediated by alpha-MSH in normal man. Although in some patients with panhypopituitarism an elevation of plasma aldosterone concentration following alpha-MSH infusion is observed, it is unlikely that MSH is directly involved in the acute regulation of aldosterone secretion in healthy subjects.

ABSTRACT

A radioimmunoassay for [8-arginine]-vasopressin (AVP), previously described (Czernichow et al. 1975) has been used for the determination of antidiuretic hormone in a 4 ml urine sample. AVP is extracted from acidified urine with a cation exchanger (Amberlite CG 50) with an overall recovery of 72 %. The blank value measured in extracted samples of urine was 0.29 pg/ml ± 0.21 (sem) and calculated by extrapolation of the regression line of the recovery experiment was 0.49 pg/ml. The coefficient of variation within-assay was 13 % and between-assay 18%. Addition of the amounts of AVP found in each specimen of urine voided gave results nearly identical to those of the amounts found in 24 h pool of urine, indicating that the assay was not affected by changes in concentration of the other urinary components during the day. The daily urinary excretion of AVP measured in 34 subjects was found to be 34 ng in 17 women and 70 ng in 17 men, a significant difference. Urinary concentration and excretion rate of AVP rose during thirst test and during Carter-Robbins test performed in 13 healthy subjects. In the latter test it was observed that the women displayed a strikingly more pronounced AVP elevation after the osmolar stimulus than the men. In both sexes a significant correlation was found between AVP excretion rate and plasma osmolality as well as free water clearance. Three cases of complete or incomplete diabetes insipidus and potomania could be clearly differentiated according to the total output of AVP during the thirst test. Extremely high values of AVP were found in the urine of 5 subjects with Schwartz-Bartter syndrome associated with bronchogenic tumours.

ABSTRACT

The effects on plasma aldosterone levels of combinations of the main factors involved in aldosterone regulation have been studied in normal young male subjects. These factors, namely K, angiotensin II and ACTH were studied using combinations of K⁺ with angiotensin II, K⁺ with ACTH, and angiotensin II with ACTH.

KC1 infused in amounts (5–10 mEq./h) insufficient to increase plasma aldosterone by itself was found to potentiate the aldosterone response to an infusion of angiotensin II (7 ng/kg/min) in 8 out of 13 subjects. The same amount of KCl was also found to increase the rise in plasma aldosterone following an infusion of ACTH (16 ng/kg/min).

When an angiotensin II infusion was superimposed on the last 2 h of a 4-h infusion of ACTH, a striking rise in plasma aldosterone was observed, which exceeded the values obtained by ACTH alone. Conversely, when an ACTH infusion was superimposed on the last 2 h of a 4-h angiotensin II infusion, a further increase of plasma aldosterone was again observed. Our data support the idea that changes in all the known stimuli of aldosterone secretion have to be taken into account when interpreting changes in plasma aldosterone. Thus KCl, infused at rates without effect on aldosterone when given alone, will increase aldosterone during angiotensin II or ACTH infusion. The data also demonstrate that no refractory period is observed when one stimulus is superimposed on a previous one.

Abstract. Both arginine vasopressin (AVP) and angiotensin II (All) potentiate the corticotropin-releasing activity of CRF₄₁ via a potentiation of CRF₄₁-induced cAMP production. In perfused rat anterior pituitary cells, AII (10⁻⁸ mol) showed a transitory 2-fold increase in its ACTH-releasing activity, when tested after application extract of rat stalk median eminence. In order to determine whether this facilitating effect on All corticotropin-releasing activity occurred through cAMP-dependent mechanisms, the ACTH-releasing activity of All was tested after stimulation with CRF₄₁, AVP or forskolin, three secretagogues with known effects on cAMP production. When given 16 min after CRF₄₁, 10 μg/l, All (10⁻⁸ mol) showed a significant increase (210%) in its ACTH-releasing activity, which returned to the normal level when All-stimulation was repeated at 32 min (121%) and 48 min (100%). Similarly, forskolin, 3 × 10⁻⁶ mol, produced a significant transitory increase (208%) in the subsequent All-induced ACTH release whereas AVP, 10 μg/l and 100 μg/l, had no effect on the following ACTH response to All. These results suggest that the All-induced ACTH secretion – which is cAMP independent – nevertheless may be modulated by previously stimulation of the cAMP pathway.

Abstract. Prealbumin, one of the main thyroxine transport proteins, has recently been shown to be a valuable immunohistochemical marker of neuroendocrine tumours. We report the case of a multisecretory pancreatic endocrine tumour whose prealbumin secretion was so high that it produced a peak on routine serum protein electrophoresis and induced a euthyroid hyperthyroxinemia. The maximal binding capacity of prealbumin for thyroxine was indeed markedly increased, whereas its affinity for this hormone was normal. The tumour was associated with gastric hyperacidity and hypergastrinemia thereby evoking a Zollinger-Ellison syndrome. The secretin stimulation test and gastrin tumoural immunohistochemistry were, however, negative. We suggest that the concomitant tumoural production of gastrin-releasing peptide was responsible for the gastric hyperacidity and hypergastrinemia. This hormone probably also accounted for a moderate hypercorticism.

Abstract. The effect of vasopressin released during Finnish sauna on blood pressure, heart rate and skin blood flow was investigated in 12 healthy volunteers. Exposure to the hot air decrease body weight by 0.6 to 1.25 kg (mean = 0.8 kg, P < 0.001). One hour after the end of the sauna sessions, plasma vasopressin was higher (1.7 ± 0.2 pg/ml, P < 0.01 mean ± sem) than before the sauna (1.0 ± 0.1 pg/ml). No simultaneous change in plasma osmolality, plasma renin activity, plasma norepinephrine, epinephrine, cortisol, aldosterone, beta-endorphin and metenkephalin levels was observed. Despite the slight sauna-induced elevation in circulating vasopressin, intravenous injection of the specific vascular vasopressin antagonist d(CH₂)₅Tyr-(Me)AVP (5 μg/kg) 1 h after the sauna had no effect on blood pressure, heart rate or skin blood flow. These data suggest that vasopressin released into the circulation during a sauna session reaches concentrations which are not high enough to interfere directly with vascular tone.

Abstract.

The role of renal prostaglandins (PGE₂ and PGF_2α) and kallikrein in the renal escape from excess mineralocorticoid has been evaluated in 10 normal volunteers on a high sodium diet. Escape from 9-α-fluorohydrocortisone (9-α-FF) administered for 12 days (0.6 mg daily) occurred within 4–5 days when 345 ± 50 mmol sodium had accumulated. Indomethacin, a cyclooxygenase inhibitor, was then administered for 3 days while maintaining 9-α-FF. This was followed by a further cumulative gain of 105 ± 28 mmol sodium after which escape resumed. Potassium balance remained negative throughout the study. Both PGE₂ and PGF_2α excretion increased significantly under 9-α-FF from respective control values of 220 ± 50 and 818 ± 86 ng/24 h, to 610 ± 317 and 1213 ± 132 ng/24 h at the time of escape. Concomitantly urinary kallikrein increased from 1.1 ± 0.2 to 2.5 ± 0.3 units/24 h. Creatinine clearance increased from a mean baseline value of 111 ± 4 to 123 ± 4 ml/min during the same period. Indomethacin produced an inhibition of prostaglandin excretion without significant alteration of kallikrein excretion. Overall these results and particularly the transient sodium retention induced by indomethacin at the time of mineralocorticoid escape, suggest that prostaglandins may contribute to the escape phenomenon, whereas the role of kallikrein does not appear to be determinant.

Abstract.

The influence of acute stimulation by ACTH, upright posture and angiotensin II on plasma aldosterone levels was assessed in human panhypopituitarism.

While stimulation by ACTH in hypopituitary patients induced a plasma aldosterone increase similar to that observed in healthy controls, stimulation by upright posture or by infusion of angiotensin II resulted in a lower plasma aldosterone response than in controls in most of the patients.

These results suggest that the presence of an anterior pituitary hormone, most likely ACTH, directly or indirectly exerts a permissive action on aldosterone secretion in man.