The adrenergic system is involved in the neural control of GH secretion with both stimulatory and inhibitory influences mainly mediated via GHRH and/or somatostatin modulation. To throw further light on adrenergic neuroregulation of somatotrophic function in man, the effect of various catecholamine agonists and antagonists on basal or GHRH-stimulated GH secretion was studied. Twenty-one adult males aged 20-30 years underwent the following studies: 1. clonidine (CLON), alpha 2-agonist, (15 micrograms/min infused i.v. from 0 to +10 min) alone and preceded by yohimbine (YOH), alpha 2-antagonist, (30 mg orally at -50 min); 2. GHRH (GHRH 44, 1 microgram/kg i.v. bolus at 0 min) alone and preceded by YOH; 3. CLON alone and combined with methoxamine (METHOX), alpha 1-agonist, (1 mg/min infused i.v. from -10 to +10 min); 4. GHRH alone and combined with i.v. infusion of phentolamine (PHEN), alpha 1/alpha 2-antagonist, (0.5 mg/min from -60 to +30 min); 5. GHRH alone and combined with i.v. infusion of salbutamol (SAL), beta 2-agonist, (10 micrograms/min from -5 to +15 min). The GH response to CLON was inhibited by YOH (area under the response curve, mean +/- S.E.: 672.6 +/- 143.0 vs. 219.6 +/- 16.7 micrograms/l/h, P less than 0.05) but was not modified by METHOX (278.4 +/- 94.1 vs. 216.7 +/- 115.5 micrograms/l/h). On the other hand, YOH was unable to affect the GH response to GHRH (339.3 +/- 19.1 vs. 518 +/- 172.8 micrograms/l/h).(ABSTRACT TRUNCATED AT 250 WORDS)
Atrial natriuretic factor (ANF) is widely distributed in the preoptic area and the hypothalamus, it is present there both in cell bodies and nerve terminals. Effect of experimental alterations in the salt and water balance was examined on preoptic-hypothalamic ANF levels measured in ten microdissected nuclei. Immunohistochemical analysis was also performed to confirm radioimmunological results. Following interventions were performed in adult male rats: adrenalectomy (5 days), daily 0.9% NaCl, aldosterone (5 micrograms/100 g) and dexamethasone (2 micrograms/ml drinking water) treatments in both intact and adrenalectomized groups, and in rats with diabetes insipidus (Brattleboro rats) and DOC-salt hypertension. Although no appreciable alterations were observed in the intensity of ANF-like immunoreactivity in sections of the preoptic-hypothalamic region, ANF levels altered markedly in the periventricular structures (organum vasculosum laminae terminalis, preoptic and periventricular nuclei). Little or no changes were measured in ANF levels of other hypothalamic nuclei (except the perifornical nucleus). Adrenalectomy depleted ANF levels which were restored by NaCl drinking. Aldosterone elevated ANF concentrations both in intact and adrenalectomized animals while dexamethasone treatment was without any significant effect on ANF levels in the periventricular preoptic nucleus. Diabetes insipidus or DOC-salt hypertension had little or no effect on ANF levels in this brain area. Unchanged ANF concentrations were also measured in the vasopressin-containing supraoptic nucleus following adrenalectomy or in diabetes insipidus rats.
A long-lasting decrease of the basal and stress-induced arterial blood pressure was obtained in rats with inherited emotional stress-induced hypertension by means of injections of the dopamine precursor L-DOPA during early postnatal ontogeny (21-25 days of the life). "Permanent" hypotensive effect of L-DOPA was caused by the elevation of the brain but not peripheral catecholamine levels and was not related to a stimulation of the hypothalamic-pituitary-adrenocortical system in response to administration of the dopamine precursor. The restoring effect of L-DOPA was produced through enhancement of synthesis of the brain noradrenaline and, perhaps, adrenaline. The effect was associated with a normalization of the response of the brain adrenergic system to noradrenaline.
The effects of thymic hormone thymosin (fraction 5) and tactivin on the adrenal glucocorticoid function were compared in BALB/c mice. An elevation in plasma corticosterone level was found 3 h after i.p. injection of thymosin (1 microgram/mouse) which was possibly caused by an activation of neuroendocrine structures. This appeared plausible because the pretreatment with dexamethasone (10 micrograms/mouse) abolished the effect of thymosin. In contrast, tactivin produced a decrease in plasma corticosterone if administered to mice with high basal level of the hormone. Tactivin added at doses from 0.00064-2 micrograms/ml together with ACTH (1.6 microIU/ml) to isolated adrenal cells hindered the stimulatory influence of ACTH on the production of corticosterone by the adrenal cells. Thus, the thymic hormone thymosin and tactivin showed opposite influences on the adrenal glucocorticoid function which appeared to be mediated through different mechanisms.
Our experiments showed that a continuous chronic administration of norepinephrine (NE) to rats for 20 h by means of subcutaneously implantable retard tablets, led to a highly significant epinephrine(E) depletion of the adrenal medulla during normoglycemia. The rise of free plasma NE was accompanied by increased free plasma E values at 12 hours. At this time the liver contents of glycogen and free intracellular glucose showed their most pronounced decrease. At 12 and 20 hours both liver glycogen and medullar E values were very low. To check a possible causal relationship between those two events another experiment was performed in which the breakdown of liver glycogen should be inhibited. NE treated rats were force fed with 50% glucose solution 9 h after tablet implantation. This resulted in only mild glycogen depletion, which was no more able to trigger E liberation from the medulla. Therefore we conclude that pronounced liver glycogen depletion possesses a triggering ability for medullar E output by which hypoglycemia could be prevented.
Studies were undertaken to compare and contrast the effects of the vasoactive peptides, angiotensins II and III, bradykinin and endothelin, on mobilization of intracellular calcium in isolated, cultured bovine adrenal medullary (chromaffin) cells. Calcium mobilization was studied using the Fura-2 technique. The potency for elevating intracellular calcium, compared on a molar basis, was bradykinin greater than angiotensin III greater than angiotensin II much greater than endothelin. When nicotine and angiotensin II were added together, a synergism was evident with prolonged elevation of intracellular calcium. However, concomitant addition of angiotensin II and endothelin was barely additive. Yet, combined addition of endothelin and depolarizing potassium chloride yielded a very marked synergism in calcium mobilization. We conclude that the multiplicity of vasoactive peptide receptors on chromaffin cells exert interactive modulation on calcium mobilization in these cells and this property may have functional significance.
Hormonal parameters (see below) were determined in 78 male acne patients of both sexes (mean age 21.2 +/- 3.8 years; (mean +/- S.D.) and compared with 63 controls (25.0 +/- 4.2 years). In a female group consisting of 60 patients acne (23.2 +/- 5.0 years) and 28 controls (26.1 +/- 5.7 years) of age, blood sampling was performed in the luteal phase of the menstrual cycle. Testosterone (T), dehydroepiandrosterone-sulfate (DHEAS), androstenedione (A), free testosterone (FT) and 17-hydroxy-progesterone (17-OHP) were determined by standard radioimmunoassay methods. In addition, sex hormone binding globulin (SHBG), follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), 17 beta-estradiol (E2) and cortisol (F) were evaluated. Moreover, the counts of acne lesions in the face were performed in 34 males and females patients in order to investigate possible correlations between hormones and acne lesions. The results in the male group revealed a significant elevation only for F but not for the other hormones. However, the female acne group significantly elevated levels of T, DHEA and F and a decrease of E became apparent. In addition, the correlation between both free and total T and acne lesions were found in the total of males and females. In the female group, free T and total A were found to correlate with acne lesions. The evaluation of these results indicates that androgens play a more important role in female than in male acne at the hormonal and at the peripheral level in skin. Another interesting finding was the significant increase of F in both male and female acne subjects, thus stressing the role of suprarenal involvement.
In a trial with 50 fattening pigs (20 kg initial body weight), the effect of untreated rapeseed meal (RSM) (148 mmol glucosinolates and aglucones per kg dry matter) on the thyroid was compared with RSM treated with Cu2+ (9.5 mmol glucosinolates and aglucones per kg dry matter) and soybean meal (SBM). The diets containing 8% RSM were supplemented with 0.0625-1.0 and the SBM diet (control) with 0.125 mg iodine kg-1 (I). In comparison with SBM fed control, RSM treatment with Cu2+ resulted in a complete normalization of feed intake and growth. Only untreated RSM without I supplementation depressed performance and resulted in symptoms of I deficiency, but the thyroid and liver weight were also increased and the serum T4 content was significantly reduced in animals which were given RSM not supplemented with I, but treated with Cu2+. In young pigs (4 weeks) a plateau of the serum T4 content was achieved from 0.5 mg I kg-1 of the RSM diet onwards. In contrast, when the concentration of goitrogens was reduced by the treatment with Cu2+, the serum T4 level was increased significantly in groups fed with 0.125 mg I kg-1 diet and more. In older pigs (15 weeks) neither the content of goitrogens nor the I dosage affected the serum T4 level. On the other hand, the I content in the thyroid was a good indicator of the different goitrogenicity of the diet in the case of a low I supply. The present investigations show that pig diets with RSM (greater than 10 mmol glucosinolates and aglucones kg-1) should contain at least 0.5 mg I kg-1, but 0.1 mg supplementary I per kg is sufficient in diets without or with a low content (less than 1 mmol glucosinolates and aglucones per kg-1) of antithyroid compounds.
Inhibitory effect of anterior pituitary tissue implanted into the brain on trophic hormone secretion was studied under resting conditions and after adrenalectomy or ether stress. The weight of pituitary gland in rats bearing anterior pituitary graft in the third ventricle was decreased and the body weight gain was retarded. The levels of ACTH, PRL and GH, but not those of FSH and LH in plasma were significantly lower as compared with all control groups. There was a pituitary ACTH, PRL and GH response to adrenalectomy and ether stress in these rats. Besides supporting literary data on the inhibitory effect of additional pituitary grafts on the adenohypophysis, these findings indicate that pituitary implants did not cause any appreciable alteration of pituitary responsiveness, at least to adrenalectomy or ether stress.
Uptake by the isolated perfused sheep choroid plexus of labelled naturally occurring amino acids, and the analogue MeAIB (methyl amino isobutyric acid) was measured using the single-pass, indicator dilution method. The uptake (Umax) of natural amino acids at the blood face of the choroid plexus, relative to the extracellular marker mannitol, ranged between 26 and 47% when using a saline perfusate. However, when the perfusion fluid was changes to one containing whole blood, uptake of the leucine, phenylalanine, proline, aspartate glutamate and lysine were significantly reduced with Umax now between -1.6 and 19.5%. In contrast the uptake of alanine, glutamine and glycine remained high despite the change in perfusion fluid. All amino acids, which showed uptake from the blood, also demonstrated self-inhibition when an additional 1 mM of the same unlabelled amino acid was added to the perfusion fluid. This indicates saturation of a carrier-mediate uptake process. There was no detectable uptake of the amino acid analogue, MeAIB during perfusion with either medium, confirming the absence of the "A" type amino acid carrier system for which this analogue is specific.
We performed 113 new treatments in 98 patients (pts) (69 females and 27 males), 41 with macroprolactinoma, 26 with microprolactinoma, 5 with empty sella and 26 with idiopathic hyperprolactinemia. Parlodel LA was administered in 31/113, Parlodel LAR in 51/113, Parlodel SRO in 24/113 and Cabergoline in 8/113. In each pt the clinical effect, PRL plasma level CT-scan and visual field examination were monitored. PRL plasma levels normalized in 84/98 pts. In 13/41 macroadenoma pts a complete disappearance of the adenomatous mass was observed at CT-scan after 0.5-3 years' oral bromocriptine or Parlodel LAR therapy. The clinical features normalized in most of the pts. In conclusion, the new long acting dopamine agonists may represent the future of the management of hyperprolactinemic states because of their effectiveness, tolerability and good compliance.
Concentrations of atrial natriuretic factor (ANF) were measured in discrete brain nuclei by radioimmunoassay in rats. Alterations in the salt and fluid homeostasis and aldosterone treatment resulted in marked changes of ANF levels in the preoptic-hypothalamic periventricular structures including the organum vasculosum laminae terminalis, in the subfornical organ and the perifornical nucleus. Furthermore, marked changes were observed in ANF levels of these nuclei in various types of renal hypertensions. Altered ANF levels were found in several brain nuclei (locus coeruleus, dorsal raphe nucleus, tegmentum pontis, nucleus of the solitary tract) of animals with diabetes insipidus or spontaneous hypertension.
A long-lasting decrease of the basal and stress-induced arterial blood pressure was obtained in rats with inherited emotional stress-induced hypertension by means of injections of the dopamine precursor L-DOPA during early postnatal ontogeny (21-25 days of the life). "Permanent" hypotensive effect of L-DOPA was caused by the elevation of the brain but not peripheral catecholamine levels and was not related to a stimulation of the hypothalamic-pituitary-adrenocortical system in response to administration of the dopamine precursor. The restoring effect of L-DOPA was produced through enhancement of synthesis of the brain noradrenaline and, perhaps, adrenaline. The effect was associated with a normalization of the response of the brain adrenergic system to noradrenaline.
Continuous exposure to foster pups elicits specific behavioural patterns in adult naive female or male rats. The first exposure induces active avoidance of young. By day 2 or 3 adults show neutral behaviour. Next day complete maternal behaviour begins to develop; e.g. retrieving of pups, nursing and crouching. The avoidance reaction activates stress mechanisms, and the developed maternal behaviour is associated with moderate prolactin release. The question is raised whether pup-induced catecholamine and prolactin release is able to alter enzyme activity in T-cells. Using Arg-Pro-; Leu-Pro; and Pro-Pro-4-nitroanilide as substrates the activity of a marker enzyme dipeptidyl peptidase IV, DP IV, EC. 3.4.14.5., was measured in T-cell suspension prepared from the thymi of adrenalectomized female and male Wistar rats. We found that changes of DP IV activity during the pup-induced avoidance phase could be prevented by propranolol pretreatment indicating the role of catecholamines in this phenomenon. Prolactin released during artificial maternal behaviour in female rats resulted in an elevation of DP IV activity which failed to develop, if they were given daily injections of bromocriptine or apomorphine. It is concluded that pup-exposure is the most physiological way to influence hormonal mechanisms and immune functions, which are highly responsive to sensory stimuli.
The effect of chronic administration of SMS 201-995, a long acting analogue of somatostatin, has been studied in 30 acromegalic patients (pts). CT-scan showed pituitary adenoma in 20/30 pts, empty sella in 9/30 pts and no sign of pituitary tumor in one case. SMS 201-995 was administered subcutaneously every 8 hours at the daily dose of 150-900 micrograms. Blood samples for GH, insulin and blood glucose were taken hourly from 04:00 to 20:00 h before treatment, after 15 days and then monthly or fortnightly. IGF-I plasma levels were assayed at 08:00 h in the same day as GH determinations. CT-scan controls were carried out after 12-24 months of treatment in 16/20 pts. GH plasma levels were normalized in 16/30 pts after 0.5-9 months of SMS treatment, whereas in 14/30 pts they were reduced by about 50%. In 10/16 pts the CT-scan examination showed a shrinkage of the tumor size of 20-55%, while no variation of the tumor mass was observed in the 2 pts. In conclusion our data show that SMS 201-995 is a very effective medical treatment in acromegalic patients.
The binding parameters of muscarinic antagonists in intact rat thymocytes were determined from competitive binding experiments with 3H-N-methylscopolamine (3H-NMS). The muscarinic antagonists inhibited binding of 3H-NMS in a dose-dependent manner. Non-linear regression analysis of the displacement curves indicated the presence of two affinity states for the muscarinic compounds. The beta-blocking agents R-propranolol, S-propranolol and alprenolol inhibited the binding of 3H-NMS to one, low affinity binding site on rat thymic lymphocytes. The ganglionic blocking substance hexamethonium did not affect the binding of 3H-NMS. The results indicate the presence of two binding sites for the radioligand on rat thymocytes, of which only one is specific for muscarinic receptor antagonists.
Putative sleep substances were infused either singly or in combination into the third ventricle of freely behaving male rats for 10 h nocturnal period. The nocturnal amount of slow wave sleep (SWS) and paradoxical sleep (PS), and the number and duration of their episodes were compared to those of the previous night under saline infusion. The single administration revealed that each substance elicited partially differential and partially common sleep-modulatory activity. SWS was enhanced by the d-type of di-1-methylheptyl-2,5-dioxocyclohexane-1,4-dicarboxylate (d-DOC, 2.3 nmol), delta-sleep-inducing peptide (DSIP 2.5 nmol), deoxyuridine (0.1 nmol), muramyl dipeptide (MDP, 2.0 nmol), and prostaglandin D2 (PGD2, 0.36 nmol). Cytidine (10 pmol) increased the number of SWS episodes and reduced their duration, whereas deoxyguanosine (10 pmol) prolonged the duration. Deoxycytidine (10 pmol) and the 1-type of DOC (0.25 nmol) enhanced PS. Uridine (10 pmol) enhanced both SWS and PS. The simultaneous or sequential administration of DSIP, MDP and uridine resulted in a combination-dependent or sequence-dependent change in sleep-waking dynamics, which was quite different from the time-course sleep-modulation induced by the single administration of each substance. The results suggest that co-circulating sleep substances might interact at least in part, either synergistically or antagonistically, on the sleep-regulatory mechanism.
Changes in peripheral clinico-chemical parameters (packed cell volume (PCV), hemoglobin (HGB), serum glucose, carbamide nitrogen (CN), sodium, uric acid and creatinine) were investigated in mice during the development of acute morphine tolerance. Acute morphine treatment (in drug-naive organism) altered the PCV, HGB, serum glucose and CN levels in a naloxone-reversible manner. Acute tolerance developed in PVC, HGB, sodium and CN values. The data raise the possibility of a relationship between clinico-chemical and pharmacological tolerance.
The effects of the classical benzodiazepine (BDZ) anxiolytic drug chlordiazepoxide (CDP) and the non-BDZ anxiolytic agent buspirone (BUSP) on basal and stress-induced plasma noradrenaline (NA), adrenaline (A) and corticosterone (CS) release were investigated. Male Wistar rats provided with a permanent heart catheter and a permanent stomach catheter were used. Placement of rats into an unfamiliar cage (novel environment stress; NES), that elevated CS, NA and A, was used as a stressor. Acute administration of CDP (1-27 mg/kg) produced dose-related increases in basal plasma CS secretion but was without effect on basal NA content. The largest dose of CDP caused a slight short-term A elevation. The CDP effect on basal CS secretion tolerated with repeated drug treatment and was completely blocked after acute pretreatment with the BDZ receptor antagonist flumazenil. Acute treatment with BUSP (2-20 mg/kg) caused a marked and dose dependent increase in the plasma levels of A, NA and CS. A medium dose of CDP (9 mg/kg) attenuated the NES-induced CS and A elevations. A high dose of CDP (27 mg/kg), that elevated basal CS release, prevented a further CS increase by NES and inhibited the NA and A response to NES. BUSP (2 or 20 mg/kg) was not effective in attenuating the NES-elicited rise of CS, NA and A. However, the 20 mg/kg dose of BUSP actually enhanced the NES-induced A response. In conclusion, BUSP did not show the BDZ-like property to inhibit stress-induced elevations in CS, NA and A. Furthermore, the findings suggest that CDP and BUSP differentially affect the mechanisms controlling CS, NA and A release during basal and stress conditions.
Protein formation in the anterior pituitary was investigated in vitro in thyroidectomized (TX) and/or adrenalectomited (AX) rats treated with a single dose of 100 micrograms/100 g of 3,5,3'-triiodothyronine (T3) and/or with a single dose of 10 micrograms/100 g of dexamethazone (DEX) 12 h before sacrifice. Male Wistar rats of a specific pathogen free colony 6 weeks after TX and/or AX receiving 1% calcium chloride and/or saline after surgery were used in the experiments. Non-pooled anterior pituitaries (in acellular condition) complemented with all essential amino acids, CPK, creatine phosphate in a HEPES buffer containing potassium acetate, magnesium acetate and dithiothreitol, were incubated with 35S-methionine at 28 degrees C for 10 or 40 min. The reaction was stopped by EDTA followed by RNAase plus DNAase treatment and the samples were analyzed for total 35S-methionine incorporation or by SDS 12.5% polyacrylamide gel slab electrophoresis (PAGE). As compared to intact rats (100%), TX and/or AX caused a significant diminution of the total 35S-methionine incorporation into protein ranging from 33% to 68% that may be easily restored to 107% by T3 plus DEX treatment. PAGE analysis reflects an appreciable relation between T3 administration and 21.5 kDa protein (growth hormone) formation in the anterior pituitary. In addition, the effect 5,5'-diphenylhydantoine (DPH) on 35S-methionine incorporation in relation to T3 nuclear specific binding was investigated. The data suggest that the decreased protein synthesis de novo is due to a significant diminution of T3 specific binding to nuclear receptors in the anterior pituitary.
