Effect of deltorphin on pituitary-adrenal response to insulin-induced hypoglycemia and ovine corticotropin-releasing hormone in healthy man.

To determine the role of delta-opioid receptors in the modulation of hypothalamic-pituitary-adrenal activity, we studied in normal subjects the effect of the highly selective delta-opioid receptor agonist deltorphin (DT) on the secretion of ACTH, cortisol, and arginine vasopressin in response to insulin-induced hypoglycemia. In an attempt to clarify the site of opiate modulation of ACTH secretion, we also studied in normal subjects the effect of DT on the ACTH response to ovine CRH-41. DT blunted the ACTH, cortisol, and arginine vasopressin responses to insulin-induced hypoglycemia, whereas it had no effect on the ACTH and cortisol responses to CRH. We conclude that DT-induced activation of delta-opioid receptors exerts an inhibitory influence on hypoglycemia-stimulated ACTH secretion. Based on the lack of an effect of DT on the ACTH response to CRH, we postulate that DT may modulate the secretion of ACTH through suprapituitary mechanisms.

Circadian profile of plasma calcitonin gene-related peptide in healthy man.

Calcitonin gene-related peptide (CGRP) is known to exert potent cardiovascular effects and is presumed to participate in the neural control of circulation and blood flow. It has been assayed in many physiological and disease conditions, yet virtually nothing is known of the normal fluctuations in its circulating levels. We have studied the variability throughout a 24-h period of plasma concentrations of CGRP in eight recumbent healthy volunteers (four men and four women, 25-37 yr old), after careful standardization of their daily diet and routine schedules. A correlation with the circadian rhythms of blood pressure (BP), heart rate (HR), and plasma aldosterone (PA), PRA, plasma cortisol (PC), and atrial natriuretic peptide (ANP) was also made. Plasma CGRP concentrations ranged from a mean peak value of 18.1 +/- 1.5 pmol/L to a mean lowest value of 11.7 +/- 0.4 pmol/L (P less than 0.05). The mean circadian acrophase of CGRP (calculated by cosinor analysis to occur at 2314 h) anticipated the corresponding acrophases of the other hormones (0122, 0528, 0809, and 0840 h for ANP, PRA, PA, and PC, respectively). Instead, BP and HR rhythms seemed to be antiphasic with the ANP rhythm (calculated acrophases occurred at 1356, 1339, and 1314 h for systolic BP, diastolic BP, and HR, respectively). Our data demonstrate that, like many other hormones, CGRP circulates in plasma with a circadian rhythm. There seems to be a temporal sequence starting with the nocturnal rise in plasma CGRP concentrations and progressing with the ensuing elevations of ANP, PRA, PA, and PC, whereas BP and HR are kept to their lowest values. These findings are in favor of a physiological role of CGRP in the complex regulation of BP homeostasis.

Responses of plasma renin activity, aldosterone, adrenocorticotropin, and cortisol to dermorphin, a new synthetic potent opiate-like peptide, in man.

This study was designed to investigate the effect of dermorphin (D), a new synthetic potent opiate-like peptide (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2), on PRA, plasma aldosterone (PA), plasma cortisol (PC), and plasma ACTH levels in normal men. D infusion (5.5 micrograms/kg X min for 30 min) significantly increased PRA (P less than 0.01) and decreased PC levels (P less than 0.02). D produced a small decrease in ACTH and a small increase in PA. Pretreatment with the opioid receptor antagonist naloxone (N) blunted the D-induced PRA increase and completely prevented the D-induced PC decrease, but enhanced PC and ACTH levels. These data indicate that the action of D is mediated through opioid receptors, and are consistent with the conclusion that 1) D, a new opioid peptide, increases PRA levels, perhaps via activation of the sympathetic nervous system, providing evidence that opioid peptides may exert an influence on renin secretion; and 2) D suppresses PC levels, perhaps by affecting ACTH secretion, corroborating previous observations that opioid peptides might affect the function of the pituitary-adrenocortical axis.

Prolactin-releasing activity of dermorphin, a new synthetic potent opiate-like peptide, in normal human subjects.

Dermorphins (D) are heptapeptides (H-Tyr-D-Ala-Phe-Gly-Tyr-X-Ser-NH2; X, Pro or Hyp) with powerful central and peripheral opiate-like activity, originally isolated from the skin of South American frogs. To study the effect of a synthetic D on PRL secretion in man, either D (5.5 micrograms/kg . min for 30 min) or D-placebo (0.9% saline) infusion over 30 min was administered iv in random sequence to 11 volunteers (6 women and 5 men). In all the subjects, D induced a significant increase in the levels of PRL, more consistently in women than in men. To investigate whether the increase in PRL was due to the opiate agonist properties of D, the study was repeated in the same subjects during naloxone infusion. The PRL response to D was completely suppressed, suggesting that the peptide exerts its effect on PRL release via an opiate receptor stimulation of the mu-type. These data allow us to conclude that D may affect PRL release in humans; however, further investigation is necessary before any physiological significance might be attributed to D in man.

Circadian rhythm of calcitonin gene-related peptide in uncomplicated essential hypertension.

OBJECTIVE: To assess the existence of an altered circulating pattern of calcitonin gene-related peptide (CGRP) in hypertension. DESIGN: The 24 h variation in plasma CGRP was measured and compared in 10 patients affected by uncomplicated essential hypertension and in nine age- and sex-matched healthy volunteers. The diurnal variations in blood pressure, atrial natriuretic peptide (ANP), plasma renin activity (PRA), plasma aldosterone and plasma cortisol were also assessed. METHODS: Recumbency studies were performed under standardized, drug-free conditions beginning at 0800 h. Venous samples were drawn every 4 h for 24 h and hormone levels were assessed with specific radioimmunoassays. The blood pressure was measured every 15 min with a SpaceLabs 90207 monitor. RESULTS: The mean 24-h plasma CGRP concentrations were significantly lower in the hypertensive group than in the control group. In both groups a circadian rhythm was present with the same pattern, but at a lower level in hypertension. A temporal sequence starting with the nocturnal rise in plasma CGRP concentrations and progressing with the elevations of ANP, PRA, and plasma aldosterone and cortisol was apparent in both groups. The nocturnal rise in the CGRP and ANP concentrations coincided with the blood pressure and the heart rate falls. CONCLUSIONS: Our data show that CGRP is lower than normal but maintains its circadian variability and its relationship with the diurnal variations in blood pressure and other hormones known to be active on the cardiovascular system.

A new, noninvasive method to monitor the aging of bioprosthetic valves in the mitral position.

Bioprosthetic valves undergo a tissue degeneration of unpredictable onset and amount. This process alters the structure and function of the valve and consequently shortens its lifespan. The echocardiographic technique usually used in the follow-up of these patients does not provide accurate information concerning the amount of prosthesis tissue degeneration. A new technique has been developed based on the spectral analysis of the first heart sound, which enables the evaluation of prosthetic leaflet stiffness. The Young's modulus (E) and stress (s) of the valve leaflets were derived as functions of the inner diameter of the heterograft and its primary vibration frequency, which can be obtained from the frequency spectrum of the first heart sound. Thirty-six patients with a mitral bioprosthetic valve were studied. Fifteen had thickening or calcification, or both, of the valvular leaflets at echocardiographic examination. In patients with a normal valve, E and s showed a good correlation with the duration of implantation (r = 0.909, p < 0.001; and r = 0.828, p < 0.001; respectively). Patients with abnormal leaflets had values of E and s that were greater than the theoretical values expected for their duration of implantation. The procedure is sensitive, accurate and easy to perform, and enables monitoring of the aging of the prosthetic valve and early identification of valve tissue degeneration. Together with echocardiography, this procedure yields a more complete evaluation of prosthetic valves for the follow-up of patients.

Stimulation of growth hormone and corticotropin release by angiotensin II in man.

The intravenous (IV) infusion of angiotensin II (AII) was administered to seven healthy male volunteers in a randomized placebo-controlled study. As expected, AII induced a significant increase in blood pressure and plasma aldosterone concentrations. AII caused a significant increase in corticotropin (ACTH) and growth hormone (GH) release, but had no effect on the release of thyrotropin (TSH) and prolactin (PRL). These findings suggest that peripherally circulating AII might influence ACTH and GH secretion in humans.

Prolactin and growth hormone responses to dermorphin in patients with prolactin-secreting pituitary adenoma.

We have recently shown that dermorphin (D), a new potent opioid peptide (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2) stimulates prolactin (PRL) and growth hormone (GH) secretion in humans. In 11 patients with a PRL-secreting pituitary adenoma (eight microprolactinomas and three macroprolactinomas with suprasellar extension), diagnosed by pituitary dynamic function tests, and radiological evidence with confirmation at surgery, the PRL and GH responses to D were studied to evaluate the effect of pathological hyperprolactinemia on the opioid-induced secretion of GH and PRL. No PRL response to D was observed in all 11 patients. Plasma GH increased after D in all patients, except in three patients bearing a macroprolactinoma. This study shows that the effect of D on PRL and GH secretion can be dissociated in patients with PRL-secreting pituitary adenoma, perhaps for a different derangement in the hypothalamic-pituitary mechanism(s) underlying the opioidergic regulation of GH and PRL secretion. In addition our data indicate that D can be employed as a useful opioid probe in humans.

Evaluation of hormonal function in a series of incidentally discovered adrenal masses.

The discovery of an asymptomatic adrenal mass (incidentaloma) during the investigation of an unrelated condition is relatively common. In this study, we report the clinical, radiologic, and endocrine evaluation of 38 patients (22 women and 16 men aged 24 to 84 years) with adrenal incidentaloma (size, 1 to 12 cm). The patients underwent basal and dynamic evaluation of the hypothalamic-pituitary-adrenal (HPA) axis, renin-angiotensin-aldosterone system, and adrenomedullary function. Moreover, computed tomograpy (CT) scan and 131I-6beta-iodomethyl-19-norcholest-5(10)-en-3beta-ol(NP-59) and/or 131I-metaiodobenzylguanidine (MIBG) scintigraphy were performed. The endocrine evaluation indicated two cases of pheochromocytoma and four cases of preclinical Cushing's syndrome, three of which underwent surgery with histologic diagnosis of two adrenocortical adenomas and one carcinoma. Low levels of serum dehydroepiandrosterone sulfate (DHEA-S), associated with a markedly increased 17-hydroxyprogesterone (17-OHP) response to a corticotropin (ACTH) test, were found in patients with incidentaloma. On the basis of endocrine and morphologic data, 13 patients underwent surgical treatment: five adrenocortical adenomas (two functioning), two pheochromocytomas, two ganglioneuromas, one cortisol-secreting adrenal carcinoma, one lymphangiomatous cyst, one myelolipoma, and one hemorrhage were found. Careful diagnostic assessment of incidentally discovered adrenal masses must be performed to exclude the presence of malignant and/or functioning lesions and to verify the possibility that patients with incidentaloma have a genetic or acquired deficit of adrenal steroidogenic activity.

The effects of dermorphin on the endocrine system in man.

This paper summarizes the results of our recent studies in a group of healthy subjects on the endocrine effects of the new potent opioid peptide, dermorphin (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2), originally isolated from amphibian skin. Intravenous infusion (5.5 microgram/kg/min for 30 min) of dermorphin (D) significantly increased plasma levels of prolactin (PRL), growth hormone (GH), thyrotropin (TSH) and renin activity (PRA), but decreased plasma levels of cortisol. D produced a small decrease in ACTH, and a small increase in plasma aldosterone. Pretreatment with the opioid receptor antagonist naloxone (N) suppressed the PRL and TSH response to D, blunted the D-induced GH and PRA increase, and completely prevented the D-induced plasma cortisol decrease, but enhanced plasma cortisol and ACTH levels. These data indicate that the action of D is mediated through opioid receptors, and are consistent with the conclusion that: (1) D, a new opioid peptide, can stimulate PRL, GH and TSH release in humans; (2) D increases PRA levels, perhaps via activation of the sympathetic nervous system, providing evidence that opioid peptides may exert an influence on renin secretion; (3) D suppresses plasma cortisol levels, by affecting ACTH secretion, corroborating previous observations that opioid peptides might affect the function of the pituitary-adrenocortical axis.

Interrelationships between calcitonin gene-related peptide and sympathoadrenomedullary system: effects of administration of epinephrine and norepinephrine in healthy man.

To investigate the influence of the sympathoadrenomedullary system on the modulation of the circulating levels of calcitonin gene-related peptide (CGRP), the effects of epinephrine (E) and norepinephrine (NE) were studied in 8 normal subjects (4 females and 4 males). The mean basal levels of CGRP in normal subjects were 10.2 +/- 1 pmol/l. After the infusion of E (20 ng/kg per min for 30 min), a significant rise (P < 0.005) in plasma CGRP levels was observed with the expected increases in systolic blood pressure (BP), heart rate (HR) and plasma renin activity (PRA), and decrease in diastolic BP, whereas plasma aldosterone (PA) levels did not significantly change. The infusion of NE (40 ng/kg per min for 30 min) induced an increase in systolic and diastolic BPs, whereas it failed to modify CGRP, HR, PA and PRA. Our data demonstrate that the sympathoadrenomedullary system may modulate CGRP release in man perhaps via the beta-adrenergic pathway. It is likely that the modifications of plasma CGRP levels may be part of the acute vasal response to E.

Dermorphin inhibits spinal nociceptive flexion reflex in humans.

Dermorphin (D) is a potent opiate-like peptide isolated from the skin of some species of frogs. Experimental studies in animals indicate that D has a potent antinociceptive effect, while no investigation exists about its analgesic properties in humans. Our study shows that i.v. infusion of 0.16 mg/kg D induces a marked and long-lasting increase in the threshold of nociceptive flexion reflex in healthy volunteers. This effect is also evident in a complete chronic spinal subject, showing that D depresses the nociceptive transmission mainly acting at spinal level. Naloxone, while fully antagonizing the effects of morphine and enkephalin analogue, is able to reverse only partly (ca. 50%) the depressive effect of D on nociceptive spinal reflex. This fact may suggest that D interacts with different spinal opiate receptor populations in inducing analgesia.

[The empty sella syndrome. Clinical, radiological and endocrinologic analysis in 20 cases]. / La sindrome della sella vuota. Analisi clinica, radiologica ed endocrinologica in 20 casi.

Empty sella syndrome is an anatomical entity in which the pituitary fossa is enlarged and partially filled with cerebrospinal fluid owing to the arachnoid herniation, while the pituitary gland is compressed against the posterior rim of the fossa. This condition can be due to an inherent weakness of the diaphragm sella and/or to an increase in intracranial pressure which promote the herniation of the arachnoid membrane into the pituitary fossa (primary empty sella) or it can results following surgery, radiation or vascular and tumorous pituitary diseases (secondary empty sella). Empty sella can be associated with neuroradiological and endocrine symptoms. This study reports the clinical, endocrine, and roentgenographic features in 20 patients with primary empty sella syndrome. Disturbances of hypothalamic-pituitary function were detected in 6 patients (hyperprolactinemia, hypopituitarism, central diabetes insipidus, hypothalamic hypothyroidism). Three patients exhibited hypergonadotropic hypogonadism. This report supports the following conclusions: a) there is no correlation between size of pituitary fossa, type an extension of arachnoid herniation and the degree of hypothalamic-pituitary dysfunction; b) endocrine alterations are frequent in the empty sella syndrome; c) the association of empty sella and primary diabetes insipidus is not a very rare event.

Incidence of complex ventricular arrhythmias in asymptomatic patients with recent myocardial infarction.

The incidence of ventricular extrasystoles (VES) was documented in 50 patients with recent uncomplicated myocardial infarction, with a 72-h two-channel ambulatory electrocardiogram. All patients were free of symptoms of arrhythmias; unstable angina pectoris and heart failure were absent. A total of 82% of the patients had VES: 23/50 patients had multiform or complex VES, 8/50 patients had ventricular tachycardia. VES were independent of heart rate and stable angina pectoris. Thus, frequent and complex VES are common in asymptomatic patients with uncomplicated recent myocardial infarction. Even in the absence of symptoms, ambulatory electrocardiography is useful. The prognostic significance of asymptomatic complex VES in these patients remains unsettled.

An Italian case of nasopharyngeal carcinoma correlated with Epstein-Barr virus specific antigens.

An Italian case of nasopharyngeal carcinoma was studied clinically; the immunologic study showed the correlation with the Epstein-Barr virus specific antigen.

Effect of penbutolol on circadian blood pressure, and renin, aldosterone and cortisol levels in patients with essential hypertension.

We investigated the effect of an orally administered, long-acting, beta-adrenergic blocking agent, penbutolol, on the circadian rhythm of blood pressure (BP) and heart rate (HR), and plasma renin activity (PRA), aldosterone (PA) and cortisol (PC) levels in hospital patients with essential hypertension validated by a chronobiological inferential statistic method. After a wash-out period of three weeks, a group of 8 hypertensive patients (5 women and 3 men, 27 to 41 years old) underwent automatic BP and HR monitoring, and blood sampling for 24 hours in a hospital room before and after 4 weeks of treatment with penbutolol (40-mg tablet once a day at 9 a.m.). In basal conditions, a statistically significant mean circadian rhythm was demonstrated for HR, diastolic BP, PRA, PA, and PC. Systolic and diastolic BP were lowered by penbutolol, with only a minor decrease of HR. The treatment eliminated also the mean circadian rhythm of BP and HR. Penbutolol induced both a remarkable reduction of PRA with disappearance of the related circadian rhythm and a significant decrease in PA levels with maintenance of their circadian rhythmicity. The circadian secretory patterns of PC were similar before and after therapy. In conclusion, long-term treatment with penbutolol appears not only to set BP, PRA and PA values to lower levels, but also to decrease the within-day variation of BP, HR, and PRA. In addition, penbutolol does not influence the 24 h-secretion of PC.

Slow-release nifedipine: effect on the circadian rhythm of blood pressure in essential hypertension.

The aim of this study was to investigate the effect of orally administered, slow-release, nifedipine tablets on the circadian rhythm of blood pressure and heart rate, in hospital patients with clinical diagnosis of hypertension validated by a chronobiologic inferential statistic method. A group of 14 patients (nine women and five men, 47 to 71 years old) with clinical diagnosis of "essential hypertension" underwent automatic blood pressure and heart rate monitoring in a hospital room for 48 hours. Measurements were taken every 15 min by an oscillometric instrument with automatically inflated cuff. The patients received no treatment during the two proceeding weeks and the first day of the study. On the second day, slow-release nifedipine tablets were administered, one at 10 a.m. and one at 10 p.m. A highly significant circadian rhythm was documented for systolic and diastolic blood pressure, mean arterial pressure and heart rate, both in basal conditions and after nifedipine. Blood pressure mesors were higher than reference standards in basal conditions, and were lowered (average decrease = 20 mmHg for systolic and 9 mmHg for diastolic mesor) by nifedipine. A significant, though minor, elevation of heart rate mesor (from 70 to 75 b.p.m.) was also noted during treatment. The circadian amplitudes of blood pressure and heart rate did not differ significantly before and during treatment. In conclusion, the circadian rhythm of blood pressure is still present with the same amplitude after slow-release nifedipine, but is set at a lower pressure level. Heart rate rhythm is also preserved, with only a minor elevation of its mesor.

Observation of tool use and modification for apparent hygiene purposes in a mandrill.

Tool making or modification to produce a tool of apparent improved functionality has rarely been reported in monkeys, especially when tools are used outside the context of food acquisition. We report on an observation of selection, modification and use of splinters for hygiene purposes in a male mandrill. The zoo-housed animal was video-recorded breaking splinters in sequence to use them underneath his toenails. This record brings forward new evidence that the ability to use and modify tools is not limited to apes and some New World monkeys but is also apparent in Old Word monkeys.