Biomedical subjects
Publications and source records attributed to R A Donald.
Six healthy male subjects were studied to assess how naloxone affects the hypothalamic-pituitary-adrenal (HPA) axis response to the stimulant drug, methylphenidate. It was found that the ACTH response to combined naloxone and methylphenidate was significantly greater than the sum of the ACTH responses to naloxone and methylphenidate individually.
In order to evaluate the effect of alpha-1 adrenoreceptor regulation of ACTH release during insulin-induced hypoglycaemia, we studied the response to hypoglycaemia with and without prazosin premedication in eight normal men. Prazosin pretreatment did not affect basal or peak plasma ACTH, cortisol or GH during hypoglycaemic stress. However basal plasma levels of noradrenaline were increased (P less than 0.02) as were responses of AVP, angiotensin II (P less than 0.05) and noradrenaline (P less than 0.05) to hypoglycaemia after prazosin. Though it is possible that these augmented responses masked an inhibitory effect of prazosin, we were unable to demonstrate a major role for alpha-1 adrenergic receptors in mediating the ACTH response to hypoglycaemic stress in normal man.
Methylphenidate (0.3 mg/kg) was administered intravenously to 20 normal subjects. Behavioral responses varied considerably among individuals. Both cortisol and growth hormone showed significant increases (p less than 0.001). The adrenocorticotrophic hormone (ACTH) response seemed insufficient to explain the increase in cortisol. For men only, the increase in cortisol correlated positively with the increase in epinephrine (r = 0.77, p less than 0.05) and correlated negatively with baseline cortisol (r = -0.70, p less than 0.05), with increase in growth hormone (r = -0.70, p less than 0.05), and with the increase in "energy" (r = -0.83, p less than 0.01). The growth hormone response varied between the sexes, and for men, the growth hormone correlated with both an increase in "energy" (r = 0.70, p less than 0.05) and "friendliness" (r = 0.68, p less than 0.05). For all subjects, baseline heart rate correlated with the increase in "energy" (r = -0.69, p less than 0.002). In a separate study, six male subjects received, on different occasions, saline and a lower dose of methylphenidate. Together, these studies show that the increases in cortisol, growth hormone, and epinephrine, and the decrease in prolactin are dose-dependent.
Six healthy male subjects were studied to determine whether the reduced plasma cortisol response to methylphenidate observed in depressed patients could be reproduced in normal subjects by pretreatment with physostigmine. Indeed, physostigmine was found to mimic this effect. The finding raises the possibility that increased cholinergic rather than decreased adrenergic activity could explain the blunted cortisol response to stimulants reported in depressed patients. Physostigmine also enhanced the growth hormone rise and prolactin decline, and limited the increase in heart rate following methylphenidate administration.
Twenty patients with a major depressive disorder and 20 control subjects were subjected to a 1 mg dexamethasone suppression test (DST) and a challenge with intravenous (IV) methylphenidate (MP)(0.3 mg/kg). None of the controls, but 9 depressives, were DST non-suppressors. Among the depressives there were correlations between DST-cortisol and baseline (4 p.m.) levels of cortisol, growth hormone, prolactin and adrenaline. Compared with the controls the depressives had a decreased cortisol response and an enhanced adrenaline response to the MP challenge. The decreased cortisol response was not related to either DST-cortisol or baseline cortisol, but was correlated with the mood response to MP.
To evaluate the effect of changes in plasma catecholamines on the pituitary-adrenal response to ovine corticotrophin releasing factor (CRF) in normal man, the response to CRF alone (10 subjects) was compared responses after infusions of adrenaline (6 subjects), noradrenaline (6 subjects) and after oral administration of the alpha 2 agonist clonidine (10 subjects). Compared to control levels, plasma adrenaline and noradrenaline concentrations were increased three- and four-fold respectively by exogenous infusions, whereas plasma noradrenaline was significantly lowered by clonidine. Despite these changes in plasma catecholamine levels, the responses of plasma ACTH, cortisol and aldosterone to CRF did not differ significantly from control (CRF alone) in any of the three studies. Neither clonidine pretreatment nor catecholamine infusions altered basal levels of plasma ACTH, cortisol or aldosterone and no effect of CRF or catecholamine manipulations on plasma arginine vasopressin concentration was observed. These results show that modulation of peripheral plasma catecholamine levels within physiological limits does not affect CRF-stimulated release of ACTH or the adrenal response in normal man.
Plasma ACTH, arginine vasopressin (AVP), and catecholamines were measured at 5-min intervals in the pituitary venous effluent of the unanesthetized horse. Pulses of ACTH and AVP were found to be surprisingly brief (usually of less than 10-min duration) and frequent (averaging between 15-25 min). A highly significant relationship in the changes in concentration of these two hormones was demonstrated (P less than 0.0002) both at rest and after a mild hypoglycemic stimulus. Although there was also a significant correlation (P less than 0.005) between simultaneous plasma ACTH and AVP values the pulse amplitude ratio of AVP to ACTH showed a considerable variation. A rise in cortisol appeared to have a greater suppressive effect on the amplitude of ACTH than AVP pulses. The gradient in hormonal concentration between pituitary effluent and jugular plasma was at times over 50-fold for ACTH, and 500-fold for AVP. A gradient was also found for epinephrine, norepinephrine, and dopamine. A highly significant correlation (P less than 0.005) was demonstrated between changes in norepinephrine, ACTH, and AVP concentrations, but no such relationship could be shown for epinephrine and dopamine. It is concluded that there is a close temporal relationship between changes in ACTH, AVP, and norepinephrine concentrations. Pulses of these hormones are greater in amplitude and more frequent than would have been suspected from sampling peripheral plasma. The variability in the pulse amplitude ratio of ACTH and AVP may suggest that other factors are affecting ACTH secretion. The ability to sample frequently for several hormones and to obtain a marked gradient in hormonal secretion between the pituitary venous effluent and jugular plasma suggest that the horse should provide an excellent animal model in which to study the regulation of hypothalamic and pituitary hormone secretion.
In order to assess the physiological importance of endogenous arginine vasopressin (AVP) in augmenting the ACTH response to corticotrophin-releasing factor (CRF), the response to CRF during hypertonic saline infusion in six Coopworth sheep was examined. A 4-h infusion of 5% (w/v) NaCl (3.8 ml/min) resulted in significantly (P less than 0.01) greater rises in ACTH and cortisol, but not aldosterone, than were observed after CRF alone. Infusion of hypertonic saline without CRF resulted in a highly significant (P less than 0.001) rise in plasma osmolality and AVP but no significant change in plasma ACTH, cortisol or aldosterone. It is concluded that a marked but physiological increase in peripheral (and presumably central) levels of AVP does not result in any demonstrable change in plasma ACTH concentration. However, under these conditions, the ACTH and cortisol responses to CRF are considerably augmented.
Explore the source record for details and available documents.
The endocrine function of 59 patients with pituitary tumours who were treated in our unit between 1962 and 1982 is reviewed. There were 20 patients with growth hormone (GH) secreting adenomas, 17 with prolactinomas (1 tumour secreted both GH and prolactin), 14 corticotrophin (ACTH) secreting adenomas and nine non-functioning pituitary adenomas. Patients were treated with pituitary surgery and/or irradiation, with and without the addition of drugs. Patients treated with drugs alone were not included. Following combined surgery, radiotherapy and bromocriptine therapy only two acromegalic patients had persistently raised growth hormone levels and five continued to be hyperprolactinaemic. Pituitary irradiation alone was associated with the development of hypothyroidism in three of eight patients. A delayed but significant fall in free thyroxine index (p less than 0.01) was noted in patients receiving 4500 cGy radiotherapy and surgery. Four patients also developed delayed ACTH deficiency at times varying from one to six years after treatment. It is concluded that patients who have received pituitary surgery or irradiation require regular long-term endocrine assessment.
Explore the source record for details and available documents.
The effect of IV injections of an enkephalin analogue (DAMME) in sheep prior to the administration of CRF has been compared with chlorpromazine-morphine (CPZ-M) injections as well as a chlorpromazine-morphine-nembutal (CPZ-M-N) regime. The results showed that the administration of DAMME 60 minutes prior to CRF injections, gave more consistent and more sustained inhibition of spontaneous plasma ACTH and plasma cortisol secretion than either CPZ-M or CPZ-M-N pre-treatment. Changes in plasma ACTH and plasma cortisol levels were more readily detectable in DAMME-treated sheep as compared with saline controls when 50 micrograms injections of CRF were given into the carotid artery. This suggests that DAMME may inhibit endogenous CRF release by an action at hypothalamic level or above.
The plasma ACTH response to corticotrophin releasing factor (CRF) was studied in seven normal individuals. Five subjects were restudied following 4 d of salt restriction which resulted in raised endogenous plasma angiotensin II secretion. In a third experiment six subjects were given CRF following pre-infusion of hypertonic saline which significantly increased endogenous plasma vasopressin (AVP) levels. We were unable to demonstrate that high endogenous plasma AII levels were associated with a significant change in the plasma ACTH or cortisol responses to CRF. However there was an almost three-fold increase in the ACTH response when endogenous plasma AVP was elevated by hypertonic saline. It is concluded that AVP is likely to be of physiological importance in potentiating the ACTH response to CRF and that AVP and CRF together may provide a better test of pituitary ACTH secretion than either peptide alone.
Acute moderate hemorrhage (15 ml/kg withdrawn over 10 min) was used to study stress hormone changes in blood and cerebrospinal fluid (CSF) of conscious sheep with chronic indwelling intracerebroventricular catheters. Mean plasma arginine vasopressin (AVP) and ACTH rose 150- and 14-fold, respectively, above basal values to peak levels at 20 min after onset of hemorrhage. A smaller (4- to 5-fold) rise occurred in plasma angiotensin II (AII) to peak levels at 10 min. The corticosteroid response (cortisol and aldosterone) occurred later (peak at 45 min) and was consistent with the dependence of these steroids on plasma ACTH and AII changes. Increases in plasma epinephrine and norepinephrine were small and transient. Compared to changes in plasma, changes in CSF hormone levels after hemorrhage were small and independent of plasma concentrations. Mean CSF AVP increased to peak levels at 15 min whereas rises in CSF ACTH, AII-like immunoreactivity, and cortisol were slower and delayed in comparison with the patterns observed in plasma. Despite evidence of increased sympathetic activity, and rise in plasma catecholamines, CSF epinephrine fell after hemorrhage and CSF norepinephrine did not change. These results show that in conscious sheep rapid and major increases in plasma AVP, ACTH, and AII follow acute moderate hemorrhage. Concomitant changes in CSF hormone levels are small and delayed. With the possible exception of AVP it appears unlikely that the acute systemic hormone response to hemorrhage is determined by hormone changes in CSF.
The dynamics of the release of proopiomelanocortin-derived hormones from ovine anterior pituitary cells in response to varying pulse characteristics of ovine corticotropin-releasing factor (CRF) were investigated with an in vitro automated 15-column simultaneous perifusion system. Columns of cells were stimulated continuously or with trains of CRF pulses of varying pulse length (2-16 min), pulse period (20-160 min), and concentration, for 500 min. Ovine ACTH, beta-lipotropin, and beta-endorphin immunoreactivity were measured by unextracted RIA. Each pulse of CRF stimulated clearly defined and highly correlated (r greater than 0.9) pulses of the three pituitary hormones, suggesting similar mechanisms controlling release. In dose-response experiments, the minimum concentration of CRF in a 10-min pulse required to significantly raise the output of ACTH was 200 pM, and initial responses had not attained maximal levels with concentrations of CRF increased to 2 microM. Responses to pulsed CRF stimulation decreased with time with all stimulation patterns selected, although previously unstimulated control columns retained the initial capacity to respond. Multiple linear regression analysis showed that hormone output per pulse of CRF (43 nM) increased with increasing pulse period and pulse length. Output of pituitary hormones per unit of CRF applied decreased with pulse length but increased with pulse period. In summary, the responses of proopiomelanocortin derivatives were shown to be sensitive to abrupt increases in CRF, to reduce output under continued stimulation, and to have an inherent time lag before responding maximally to subsequent pulsed stimulation.
Ovine corticotropin releasing factor (CRF) was administered to six normal men and the plasma ACTH and cortisol responses compared with those following the same dose of CRF (200 micrograms) plus the opiate receptor blocker naloxone (20mg). The addition of naloxone was associated with a significant increase in plasma ACTH, cortisol and aldosterone responses. No change was observed in peripheral plasma levels of epinephrine, norepinephrine, arginine vasopressin, angiotensin II or renin activity in response to CRF plus naloxone. It is concluded that endogenous opioid peptides may inhibit the ACTH response to CRF. However the addition of naloxone does not increase the ACTH response to CRF sufficiently to constitute a useful test of pituitary function.
Explore the source record for details and available documents.
Following an intravenous infusion of methylphenidate (0.3 mg/kg) there were significant increases in plasma epinephrine, heart rate, systolic and diastolic pressure, but there was no change in plasma norepinephrine. This pattern of response differs from that seen with D-amphetamine or caffeine.