Breathing during exercise in subjects with mild-to-moderate airflow obstruction: effects of physical training.

In this study we explored the effects of physical training on the response of the respiratory system to exercise. Eight subjects with irreversible mild-to-moderate airflow obstruction [forced expiratory volume in 1 s of 85 +/- 14 (SD) % of predicted and ratio of forced expiratory volume in 1 s to forced vital capacity of 68 +/- 5%] and six normal subjects with similar anthropometric characteristics underwent a 2-mo physical training period on a cycle ergometer three times a week for 31 min at an intensity of approximately 80% of maximum heart rate. At this work intensity, tidal expiratory flow exceeded maximal flow at control functional residual capacity [FRC; expiratory flow limitation (EFL)] in the obstructed but not in the normal subjects. An incremental maximum exercise test was performed on a cycle ergometer before and after training. Training improved exercise capacity in all subjects, as documented by a significant increase in maximum work rate in both groups (P < 0.001). In the obstructed subjects at the same level of ventilation at high workloads, FRC was greater after than before training, and this was associated with an increase in breathing frequency and a tendency to decrease tidal volume. In contrast, in the normal subjects at the same level of ventilation at high workloads, FRC was lower after than before training, so that tidal volume increased and breathing frequency decreased. These findings suggest that adaptation to breathing under EFL conditions does not occur during exercise in humans, in that obstructed subjects tend to increase FRC during exercise after experiencing EFL during a 2-mo strenuous physical training period.     

Airway hysteresis in normal subjects and individuals with chronic airflow obstruction

Specific conductance (sGaw) was measured without prior pharmacological induction of bronchoconstriction before and 5-10 s after a total lung capacity (TLC) volume history in normal subjects and in individuals with chronic airflow obstruction (CAO); increased sGaw after inspiration to TLC was considered evidence of airway hysteresis. Lung elastic recoil [Pst(L)] was also measured before and after inspiration to TLC. In the normal subjects 1) prebronchodilator sGaw increased significantly, whereas Pst(L) decreased significantly after inspiration to TLC; 2) modulators of cyclooxygenase activity had no significant effects on sGaw responses to deep inspiration; and 3) airway hysteresis diminished after inhalation of atropine or metaproterenol. In the CAO group 1) prebronchodilator sGaw and Pst(L) decreased significantly after inspiration to TLC, and 2) bronchoconstriction after deep inspiration diminished after inhalation of atropine or metaproterenol. This study demonstrates that normal airways exhibit hysteresis even without alteration of resting airway tone and that airway hysteresis is impaired in CAO.     

Effect of reserpine administered during infancy on brain catecholamines and adult behaviour in the rat

Reserpine (0.1 mg/kg/day) was administered to rats from 11 through 30 days of age. During and after administration of reserpine, concentrations of catecholamines, epinephrine and norepinephrine, in the brain were estimated. Levels of catecholamines were about 30 per cent of normal during the period of reserpine administration. Approximately 3 weeks were required for these levels to return to normal. When animals were 95-100 days of age, they were deprived of food and were trained to press a bar for food. When the rate of responding became stable, the animals were subjected to three successive extinctions at daily intervals and the increase in response rate after the onset of each extinction was determined. This extinction-induced increase in response rate was greater for previously reserpinized animals than controls during the second and third extinctions, but not the first. These findings are interpreted as a decreased ability of the animals, reserpinized during infancy, to learn to respond discriminatively during non-reinforcement (extinction). Thus, an effect of reserpine administration during infancy on a type of behaviour in the adult has been demonstrated. This occurs after the catecholamine-depleting effect of the reserpine has been fully dissipated.     

Evaluation of hypothalamic-pituitary function in a combination of tests with four hypothalamic releasing hormones and L-dopa in normal subjects and in patients with hypothalamic and/or pituitary disorders

Hypothalamic-pituitary function was evaluated in a combination of tests with four hypothalamic releasing hormones (4RHs) and L-dopa in normal subjects and in patients with hypothalamic and/or pituitary disorders. Plasma concentrations of anterior pituitary hormones (GH, ACTH, TSH, PRL, LH and FSH) were measured before and after simultaneous iv administration of GHRH, CRH, TRH and LHRH. In addition, changes in the plasma levels of GHRH and GH were investigated before and after oral administration of L-dopa. Normal subjects showed appreciable responses to both tests. In five patients with hypothalamic disorders, the response of plasma anterior pituitary hormones varied, but plasma GHRH and GH did not respond to L-dopa. Patients with idiopathic and postpartum hypopituitarism showed low response to 4RHs or none at all, but L-dopa evoked a normal GHRH response in 2 of the 4 cases having no GH response. In the patients with hypopituitarism due to resection of a pituitary tumor, the response of anterior pituitary hormones to 4RHs was low, and L-dopa administration induced a normal GHRH and low GH response in 5 out of the 7 cases. After 4RHs administration, the patients with ACTH deficiency syndrome showed different patterns of impaired ACTH secretion, and isolated, combined or limited ACTH reserve. Seven patients with anorexia nervosa showed exaggerated GH, delayed TSH and FSH, low ACTH and LH, that is, normal PRL response to 4RHs, but no response of plasma GHRH or GH to L-dopa, suggesting the presence of hypothalamic dysfunction. These results indicate that the combination of the 4RHs test and L-dopa test is a simple and useful means for evaluating hypothalamic-pituitary function by measuring the response of plasma GHRH and six anterior pituitary hormones in the patients with endocrine disorders.     

Human corticotropin-releasing hormone test in normal subjects and patients with hypothalamic, pituitary or adrenocortical disorders

Human corticotropin-releasing hormone (hCRH) test was performed in 57 normal volunteers and 102 patients with hypothalamic, pituitary and adrenocortical diseases. Intravenous bolus injection of synthetic hCRH, 100 micrograms for adults or 1.5 micrograms/kg for children, increased plasma ACTH and cortisol levels in about 90% of normal subjects. In 47 patients with Cushing's disease, plasma ACTH tended to show an exaggerated response to hCRH and peak ACTH was the most frequent abnormal component among the several reaction parameters. Poor responders among normal subjects and patients with Cushing's disease had significantly higher plasma cortisol levels before CRH administration. Patients with hypothalamic hypopituitarism showed exaggerated response, whereas patients with primary pituitary lesion, isolated ACTH deficiency or adrenal Cushing's syndrome showed no ACTH response. These differences in the response of patients suggest the value of the hCRH test in their differential diagnosis.     

Adrenergic desensitization in leukocytes of normal and asthmatic subjects.

Cyclic AMP was measured in leukocytes of normal and asthmatic subjects before and after one week of treatment with equal amounts of ephedrine. During the control and placebo periods, the measurements of cyclic AMP in leukocytes of asthmatic subjects were similar to those of normal individuals. After one week of treatment with ephedrine, both groups exhibited suppression of the leukocyte cyclic AMP response to adrenergic stimulation in vitro: however, the suppression of response was significantly greater in asthmatic subjects (p less than .u1). Subcutaneous administration of epinephrine was followed by further suppression of the leukocyte cyclic AMP response to in vitro stimulation which was similar in both groups during all treatment periods. The results indicate that in vivo exposure to adrenergic medications is followed by desensitization of the leukocyte responses to subsequent adrenergic stimulation in vitro. After administration of small doses of medication, the severity and/or duration of desensitization is significantly greater in asthmatic leukocytes.     

Provocation of a paradoxical growth hormone response to corticotropin-releasing hormone by pretreatment with metoclopramide in patients with acromegaly and normal subjects

Two of 7 patients with acromegaly and one of 7 normal subjects exhibited a paradoxical rise in growth hormone (GH) to human corticotropin-releasing hormone (CRH) when pretreated with metoclopramide, although CRH alone did not induce an increase in GH. In one of these two patients with acromegaly, the GH increase to metoclopramide alone also reached the criteria of a paradoxical response. These two acromegalic patients showed a GH increase to metoclopramide pretreatment before and up to two months after surgery. In another acromegalic patient, whose GH level remained high 5 months after surgery, metoclopramide induced an increase in GH level, while in a patient who had an above-normal GH level 18 months after surgery, the resumption of physiological GH secretion after surgery was evidenced by a postoperative absence of a GH response to metoclopramide. It is suggested from these results that the GH response to metoclopramide and the metoclopramide-provoked GH response to CRH in patients with acromegaly result from the secretion of GH from nonadenomatous cells of the pituitary.     

Behavior of plasma cortisol in the course of testing with lysine-8-vasopressin and with lysine-8-vasopressin + resperine in normal subjects

Eight normal subjects were tested with LVP before and after treatment with Reserpine. The results show that Reserpine inhibits the cortisolemic response to the LVP test. This effect can most likely be attributed to the depletion of catecholamines induced by these drugs on the CNS and, in particular, in the Hypothalamus.     

Adrenergic response to intense muscular activity in sedentary subjects as a function of emotivity and training]

Seven male sedentary human subjects were studied during intense muscular work (80% of maximal oxygen uptake) performed either for 15 min or until exhaustion (mean duration: 47 +/- 2 min). Plasma catecholamines were estimated before and after the experiment by means of an original fluorimetric assay. Epinephrine or norepinephrine were individually isolated from plasma and assayed in single extracts by a highly sensitive fluorimetric method. Epinephrine and norepinephrine levels as low as 15 ng per liter were detectable by this procedure in human plasma. The adrenergic pattern was found to be greatly different from one subject to another and related to emotivity: the effect of this factor was revealed by the predominance of epinephrine in plasma at rest or under exercise (ratio NA/A less than 1). In nonemotive subjects (ratio NA/A greater than 1 at rest) plasma epinephrine and norepinephrine increased progressively during exercise. Increments after exercise were higher for norepinephrine changes; however, the fact that epinephrine concentrations correlated significantly with norepinephrine suggests a simulataneous and coordinated stimulation of adrenal glands and orthosympathetic nervous system. In emotive subjects (ratio NA/A less than 1 at rest) the apprehension of muscular work promoted a difference in catecholamine responses: norepinephrine release was not affected by subject's anxiety, while epinephrine secretion, already elevated before the test, reached a high degree of magnitude in the first minutes of muscular work, remaining nearly constant until exhaustion. Physical training of nonemotive subjects, during 2 months with two intense exercises by a week, reduced strongly norepinephrine release after exhaustive muscular work. In the same conditions, the adrenal-medullary response was not significantly modified when compared with untrained subjects. Our results suggest that the adrenergic behaviour during exercise is a function of effort intensity to be supplied; catecholamines seem to be important factors in regulating body homeostasy during muscular work in man. In addition, emotive subjects exhibit amplified adrenal-medullary response, which may be related to psychological stimuli.     

Exercise intensity and glucose tolerance in trained and nontrained subjects

The improved glucose tolerance and increased insulin sensitivity associated with regular exercise appear to be the result, in large part, of the residual effects of the last bout of exercise. To determine the effects of exercise intensity on this response, glucose tolerance and the insulin response to a glucose load were determined in seven well-trained male subjects [maximal O2 uptake (VO2max) = 58 ml.kg-1.min-1] and in seven nontrained male subjects (VO2max = 49 ml.kg-1.min-1) in the morning after an overnight fast 1) 40 h after the last training session (control), 2) 14 h after 40 min of exercise on a cycle ergometer at 40% VO2max, and 3) 14 h after 40 min of exercise at 80% VO2max. Subjects replicated their diets for 3 days before each test and ate a standard meal the evening before the oral glucose tolerance test. No differences in the 3-h insulin or glucose response were observed between the control trial and before exercise at either 40 or 80% VO2max in the trained subjects. In the nontrained subjects the plasma insulin response was decreased by 40% after a single bout of exercise at either 40 or 80% VO2max (7.0 X 10(3) vs. 5.0 X 10(3), P less than 0.05; 3.8 X 10(3) microU.ml-1.180 min-1, P less than 0.01). The insulin response after a single bout of exercise in the nontrained subjects was comparable with the insulin responses found in the trained subjects for the control and exercise trials.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of fenfluramine on growth hormone and prolactin secretion in obese subjects

Obese subjects show a subnormal growth hormone (GH) and prolactin (PRL) release in response to a variety of stimuli. Fenfluramine, an anorexiant drug used in obesity therapy, may have some effects on hypothalamic-pituitary function mediated by serotoninergic stimulation. The present investigation in obese subjects was carried out to study the effects of fenfluramine (60 mg orally) on GH and PRL secretion after intravenous arginine infusion. Ten volunteer obese females were studied and compared with 10 volunteer normal weight controls. In the obese group the GH response to arginine was significantly lower than in control group. Fenfluramine administration restored the subnormal GH response to arginine in obese subjects. The PRL response to arginine in obese women was subnormal. Fenfluramine administration restored the response of PRL to arginine infusion to normal. In conclusion, fenfluramine--under acute circumstances--enhances the hypothalamic-pituitary response to arginine in obese subjects. The decreased GH and PRL output in obese subjects is not due to an absolute hormonal deficiency and this effect of fenfluramine on GH secretion may--due to its lipolysis stimulation--be useful in obesity treatment.     

Effect of chloroquine on insulin and glucose homoeostasis in normal subjects and patients with non-insulin-dependent diabetes mellitus.

Plasma glucose, insulin, and C peptide concentrations were determined after an oral glucose load in normal subjects and in a group of patients with non-insulin-dependent diabetes mellitus before and during a short course of treatment with chloroquine. In the control group there was a small but significant reduction in fasting blood glucose concentration but overall glucose tolerance and hormone concentrations were unaffected. In contrast, the patients with non-insulin-dependent diabetes mellitus showed a significant improvement in their glucose tolerance, which paralleled the severity of their diabetes. This response seems to reflect decreased degradation of insulin rather than increased pancreatic output. These observations suggest that treatment with chloroquine or suitable analogues may be a new approach to the management of diabetes.     

Influence of haloperidol on blood cortisol response to lysine-8-vasopressin in normal subjects

The investigations were done on ten normal subjects. The LVP test was performed before and after intravenous-infusion of Haloperidol (Img). The results show that haloperidol eliminates the cortisolemic response during stimulation with LVP; that is most likely, in relation to the specific blocking effect of this drug on dopaminergic receptors in the hypothalamus and on the hypothalamo-diencephalic pathways.     

The influence of plasma triglycerides on human growth hormone response to arginine and insulin: a study in hyperlipemics and normal subjects.

Human growth hormone (HGH) response to arginine (25 gm IV in 30 min) and to insulin (0.1 U/kg B.W.) was studied in 12 male patients (mean age 36 +/- 2 years), with normal glucose tolerance and normal body weight, affected with Fredrickson's Type IV primary hyperlipemia. The patients were examined both when plasma triglycerides (TG) were elevated and following clofibrate (2 gm/die for 30-60 days) induced TG reduction. No variations in glucose or FFA behaviour or in body weight were observed after clofibrate. HGH response to arginine was absent, while that to insulin was only inhibited, when plasma TG were elevated. A significant increase in HGH peaks after arginine (from 1.99 +/- 0.59 to 9.34 +/- 1.58 ng/ml) and a slight increment in HGH peaks after insulin (from 23.09 +/- 7.19 to 31.46 +/- 7.95 ng/ml) were observed following reduction in plasma TG. Arginine test was carried out in 7 normal subjects during saline infusion and at the 3rd hour of lipid infusion (Intralipid 20%). HGH response to arginine was absent in all of the subjects during lipid infusion. The HGH response to insulin test, carried out in 9 other normal subjects during saline infusion and at the 3rd hour of lipid infusion (Lipiphysan 15%) was significantly inhibited during lipid infusion. Since lipid infusion provoked an increment, not only in plasma TG but also in FFA, the inhibition of HGH release could be correlated with the elevated plasma levels of both TG and FFA. The results obtained in both spontaneous and experimental hyperlipemia not only confirm the role played by FFA in the regulation of HGH secretion, but also support the hypothesis that elevated TG levels could inhibit HGH response to some stimuli.     

Dissociated response of thyrotropin and prolactin to dopamine receptor blockade with domperidone in hypothyroid subjects.

To investigate the hypothesis of an altered hypothalamic dopaminergic activity in primary hypothyroidism, eight patients with hypothyroidism and seven normal subjects, all female, were studied. All of them were submitted to two tests: TRH stimulation and after the administration of dopamine receptor-blocking drug, Domperidone. The hypothyroid patients with basal TSH values less than or equal to 60 mU/L (4 cases--group 1) had lower PRL levels than the remaining 4 subjects with TSH greater than 60 mU/L (group 2) (p less than 0.001), despite all patients presenting the PRL levels within the normal range. A significant increase occurred for both TSH and PRL after the administration of TRH and Domperidone in normal as well as in the hypothyroid subjects, except for TSH in group 1 after the administration of Domperidone. The area under the curve for PRL response to THR was not different between the normal subjects and both hypothyroid groups, while that under the curve for TSH was greater in the hypothyroidism as a whole than in the normal subjects (p = 0.006) and between the hypothyroid groups, being greater in group 2 than in 1 (p less than 0.009). In relation to Domperidone, the area under the curve for TSH was significantly higher in group 2 when compared to the normal controls (p less than 0.001), while for PRL it was not different between hypothyroid groups in relation to normal controls and when groups I and II were compared. These results suggest that the hypothalamic dopamine activity is not altered in primary hypothyroidism and favor the small relevance of dopamine on the control of TSH secretion.     

Plasma glucagon response to intravenous alanine in obese and non-obese subjects

To investigate glucagon (IRG) and insulin (IRI) responses to alanine infusion in obesity and to assess the effect of body weight reduction with respect to hormonal balance, we compared six obese subjects with nine normal weight controls. None of the subjects were diabetic by OGTT criteria. Plasma IRI and IRG were measured following IV alanine at a rate of 0.1 g/kg over a period of 2 min. Our obese subjects had an increase in IRG response to alanine, which was due to decreased suppression of alpha-cell function due to insulin resistance. Weight reduction via calorie restriction reduced insulin demand, resulting in reduced plasma IRI by restoring beta-cell function, and the IRG response was paradoxically decreased as compared with that before weight loss. It is conceivable that improvements in insulin sensitivity after body weight reduction may re-establish the normalization of pancreatic beta-cell function and the insulin-induced inhibition of IRG secretion. Our obese subjects were characterized by decreased IRG secretion which was reflected in a change in body weight reduction.     

Apomorphine induced biting and fighting behaviour in reserpinized rats and an approach to the mechanism of action

Various patterns of aggressive behaviour have been induced by drugs. In the present study, the biting and the fighting responses were induced in rats by apomorphine alone, and reserpine plus apomorphine combination respectively, and these could be blocked completely by a dopamine receptor blocking agent. Dopamine, norepinephrine and clonidine given intraperitoneally or intraventricularly failed to induce these responses. Chemical agents known to increase the concentration of dopamine in the brain, induced the biting, but not the fighting response, whereas these behavioural patterns were more intense due to apomorphine in the rats pretreated with reserpine and dopamine or α-methyltyrosine and reserpine combinations. In amphetamine pretreated rats, apomorphine induced intense biting after 10 min and a few bouts of fighting after 30 min. It is suggested that (i) the receptors on which apomorphine acts may be called ‘Apomorphine Receptor’ rather than ‘Dopamine Receptor’, (ii) dopamine incompletely activates these receptors which are sensitised in the absence of catecholamines and induce a higher degree of stereotyped behaviour i.e. fighting, due to apomorphine.     

Head-down bed rest reduces the breathing rate short-term variability in subjects with orthostatic intolerance

Orthostatic intolerance is the most serious symptom of cardiovascular deconditioning induced by microgravity. We have showed that in symptomatic subjects the baroreflex control of sinus node is affected by short term simulated microgravity. At present the influence of the respiration on the cardiovascular system in this condition is not clear. The aim of the present study was to examine the behaviour of the Breathing Rate (BR) in 5 Non-Symptomatic (NS) and 3 Symptomatic (S) subjects before and after 4 hours of head-down bed rest (HD).     

Effects of low dose L-triiodothyronine administration on mental, behavioural and thyroid states in elderly subjects

Decreased serum T3 concentrations in elderly subjects and their possible relationship with the development of dementia have been indicated. To see the effects of a passive increase in the serum T3 concentration, low dose T3 administration was undertaken. Forty-four subjects from 65 to 93 years of age (average 81.0 +/- 7.8) were divided into 2 groups. The grade of dementia was determined by Hasegawa's dementia rating scale (DR score). In 22 subjects, 25 micrograms per day of T3 was administered for 4 W, while the control group was given a placebo. The DR score was measured before and immediately after the study. Changes in behaviour were monitored in a double-blind fashion. The administration of T3 induced a 0.65 nmol/l increase in serum T3 in 2 W and 0.36 nmol/l in 4 W. These T3 increases were not associated with significant changes in the DR score but 7 of 22 subjects showed apparent improvement in behaviour. TSH was suppressed to less than 1 mU/l in 2 W and then slightly increased by the 4th week, but T4, rT3 and fT4 all showed significant and progressive decreases. The DR score after T3 correlated significantly with the rT3/T4 ratio (before T3: -0.55, changes: +0.50) and also with changes in rT3 (r = 0.49). In conclusion, T3 administration to the elderly subjects was associated with behavioural improvement in some individuals, but the intellectual ability as assessed by the DR score in those with low T3 or elevated rT3 were hardly improved by passive T3 elevation.     

Differences in the effects of amphetamine and methylphenidate on brain dopamine turnover and serum prolactin concentration in reserpine-treated rats.

In the present study we compared the ability of amphetamine and methylphenidate to antagonize the elevation of serum prolactin produced by reserpine because of the differences in the actions of amphetamine and methylphenidate on brain dopamine turnover. Groups of male rats were treated with either methylphenidate (10 mg/kg) or amphetamine (5 mg/kg) alone or in combination with reserpine (5 mg/kg). The reserpine treatment was given 4 hours before methylphenidate or amphetamine, and the rats were killed 5 hours after reserpine. Neither amphetamine nor methylphenidate alone was able to suppress serum prolactin. Amphetamine but not methylphenidate was able to block the increase of serum prolactin in response to reserpine. Amphetamine lowered brain DOPAC in control and reserpine-treated rats, but methylphenidate elevated brain DOPAC in control rats and had no effect in reserpine-treated rats. These results indicate that the methylphenidate group of CNS stimulants can be differentiated on the basis of their neuroendocrine effects from the amphetamine group of stimulants.