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Biomedical subjects

R A Donald

Publications and source records attributed to R A Donald.

At least 19 recordsLinked to original sources
PubMed2001

Reduction in basal afternoon plasma ACTH during early treatment of depression with fluoxetine.

RATIONALE: Subjects with depression may exhibit activation of the hypothalamic-pituitary-adrenal (HPA) axis, but little is known about the response of basal hormone levels to antidepressant therapy. OBJECTIVES: To determine whether treatment of depression with standard antidepressant medications resulted in reductions in basal activity of afternoon cortisol, ACTH and AVP. A secondary aim was to examine whether there was any difference in hormonal response between an SSRI (fluoxetine) and a tricyclic antidepressant (nortriptyline). METHODS: Forty-three subjects with a DSM-IV diagnosis of depression (Hamilton score 18.9+/-0.6 at baseline) had five basal venous blood samples drawn at 15-min intervals between 1400 and 1500 hours for cortisol, ACTH and AVP, before and 6 weeks after randomisation to treatment with fluoxetine (n=27) or nortriptyline (n=16). RESULTS: Both medications resulted in a similar improvement in depression as determined by Hamilton score. In the group as a whole, ACTH levels showed a significant decrease over the 6 weeks (4.1+/-0.4 pmol/l at baseline versus 3.3+/-0.3 at 6 weeks, P<0.05), while cortisol and AVP levels were unchanged. Further analysis revealed that the fall in plasma ACTH occurred predominantly in the subgroup treated with fluoxetine (drug x time interaction by ANOVA, P=0.035). There was a significant relationship between cortisol and ACTH at baseline (r=0.48, P=0.002), that weakened considerably after treatment (r=0.22, P=0.16). The subgroup with baseline hypercortisolemia [mean cortisol >276 nmol/l (10 microg/dl), n=18] demonstrated a reduction in both cortisol and ACTH following treatment, but also showed a loss of the relationship between the two. CONCLUSIONS: It is postulated that the initial recovery of the HPA axis during the treatment of depression with fluoxetine is mediated via restoration of glucocorticoid negative feedback on ACTH levels.

Adolescent↗
PubMed2001

The utility of plasma CRH as a predictor of preterm delivery.

It has been suggested that CRH is a placental clock that controls the duration of pregnancy and that the timing of the rise in CRH may permit prediction of the onset of labor. We have performed a prospective longitudinal study, in 297 women, to examine the utility of a single second-trimester plasma CRH measurement to predict preterm delivery. Venous blood samples were taken at 4-weekly intervals, beginning at 16-20 wk gestation, until delivery for CRH and its binding protein. A time point at which a single plasma CRH test might give optimal data to predict preterm delivery was determined. Thirty-one subjects delivered prematurely (10.4%). Sampling for plasma CRH at 26 wk gestation seemed the optimal time point to maximize sensitivity and specificity of the test. The mean (+/- SD) plasma CRH in women at this gestation who eventually delivered after spontaneous labor within 1 wk of their due date (39-41 wk, n = 127) was 34.7 +/- 27.0 pM. A plasma CRH of more than 90 pM at 26 wk gestation had a sensitivity of 45% and a specificity of 94% for prediction of preterm delivery. The positive predictive value was 46.7%. Calculation of free CRH did not improve these figures. In conclusion, a single measurement of plasma CRH, toward the end of the second trimester, may identify a group at risk for preterm delivery, but over 50% of such deliveries will be unpredicted. These data do not support the routine clinical use of plasma CRH as a predictor of preterm labor.

Corticotropin-Releasing Hormone↗
PubMed2000

Interleukin-1 potentiates basal and AVP-stimulated ACTH secretion in vitro--the role of CRH pre-incubation.

The acute-phase cytokine interleukin-1 (IL-1) is known to activate the hypothalamic pituitary adrenal axis, primarily via corticotropin releasing hormone (CRH). The aim of this study was to determine whether IL-1beta could directly stimulate ACTH secretion from perifused equine anterior pituitary cells, and whether CRH pre-incubation affected corticotroph responsiveness. Isolated equine anterior pituitary cells were pre-incubated with media containing 10 nM CRH or vehicle for 20 hours before being loaded onto columns and perifused with 0.02 nM CRH and 100 nM cortisol. Columns were given a 5-minute pulse of arginine vasopressin (AVP, 10 nM), perifused for 4 hours with 0 (control) or 1 nM IL-1beta, then given a further 5-minute pulse of AVP (10nM). ACTH was measured in 5 minute fractions. In the setting of CRH pre-incubation, cells perifused with IL-1beta for 4 hours showed increased basal ACTH secretion compared to control (114 +/- 6 pM vs. 86 +/- 4 pM [means +/- S.E.M.], p < 0.001) and a significantly greater ACTH response to the final AVP pulse (240 +/- 32% vs. 96 +/- 30%, p = 0.009, expressed as % of ACTH response to the initial AVP pulse). The potentiation of AVP-stimulated ACTH release by IL-1 was not observed in cells pre-incubated with vehicle alone. In conclusion, IL-1 increases ACTH release in equine corticotroph cells pre-incubated with CRH and potentiates responsivity to AVP.

Adrenocorticotropic Hormone↗
PubMed2000

Interactions of CRH, AVP and cortisol in the secretion of ACTH from perifused equine anterior pituitary cells: "permissive" roles for cortisol and CRH.

To further elucidate the interaction of CRH, AVP and cortisol in the control of ACTH secretion, we used an in vitro perifusion model with dispersed equine anterior pituitary cells. To approximate the in vivo milieu in the horse, CRH was perifused continuously (at 0, 2 and 20 pmol/L) and 5-min pulses of AVP (0, 1, 3 and 10 nmol/L) were given every 30 min in the presence of 0 or 100 nmol/L cortisol. Total (baseline + incremental) ACTH secretion increased as both the CRH (p<0.001) and the AVP (p<0.001) concentration increased and interaction between CRH and AVP was significant (p=0.042). Cortisol reduced total ACTH secretion in the presence of 2 pmol CRH/L (p=0.001) but not 0 or 20 pmol CRH/L. For incremental ACTH there was interaction between CRH and AVP (p<0.0001), with increased secretion at higher concentrations, and no significant main effect of cortisol. There was significant (p=0.001) interaction between cortisol and CRH, with cortisol attenuating ACTH release at 0 pmol CRH/L (p=0.008), having no effect at 2 pmol CRH/L and potentiating it at 20 pmol CRH/L (p=0.026). We conclude that (1) CRH at high physiological levels has a "permissive" role in preventing the cortisol inhibition of the ACTH response to AVP, and (2) basal cortisol levels have a "permissive" action in priming the HPA axis for maximal responsiveness to stimulated levels of CRH and AVP.

Adrenocorticotropic Hormone↗
PubMed1999

Growth hormone binding protein correlates strongly with leptin and percentage body fat in GH-deficient adults, is increased by GH replacement but does not predict IGF-I response.

GH-binding protein (GHBP) corresponds to the extracellular domain of the GH receptor (GHR) and has been shown to be closely related to body fat. This study aimed to examine the inter-relationship between GHBP, leptin and body fat, and to test the hypothesis that GHBP is modified by GH replacement in GH-deficient adults and predicts IGF-I response. Twenty adults, mean age 47 years (range 20-69) with proven GH deficiency were randomly allocated to either GH (up to 0.25 U/kg/week in daily doses) or placebo for 3 months before cross-over to the opposite treatment. Plasma GHBP and leptin were measured at baseline and 2, 4, 8 and 12 weeks after each treatment. Whole body composition was measured at baseline by dual-energy X-ray absorptiometry (DEXA). There was a strong correlation between baseline leptin and GHBP (r = 0.88, P < 0.0001) and between baseline GHBP and percentage body fat, (r = 0.83, P < 0.0001). Mean GHBP levels were higher on GH compared with placebo, 1.53 +/- 0.28 vs 1.41 +/- 0.25nM, P = 0.049. There was no correlation between baseline IGF-I and GHBP (r = -0.049, P = 0.84), and GHBP did not predict IGF-I response to GH replacement. The close inter-relationship between GHBP, leptin and body fat suggests a possible role for GHBP in the regulation of body composition. GHBP is increased by GH replacement in GH-deficient adults, but does not predict biochemical response to GH replacement.

Absorptiometry, Photon↗
PubMed1998

Growth hormone replacement does not improve psychological well-being in adult hypopituitarism: a randomized crossover trial.

In order to examine the effect of growth hormone (GH) on psychological parameters in adult hypopituitarism, 20 adults were studied, mean age 47 years (range 20-69) with hypopituitarism and confirmed GH deficiency (GH < 3 micrograms/l following clonidine 0.15 mg/m2). Subjects were randomly allocated to either GH-up to 0.25 U/kg per week in daily doses) or placebo for 3 months before crossover to the opposite treatment arm. Psychological parameters were assessed by self-reported questionnaires (Disease Specific Questionnaire (DSQ), the Symptom Checklist-90 (SCL-90), and the Social Adjustment Scale (SAS)) at baseline and monthly intervals to the end of the trial. Both SAS and SCL-90 total scores showed a significant decline with respect to time (p = .03 and .013 respectively), although this was not a function of active treatment. DSQ showed a trend to decline (p = .06), but no effect of active treatment. None of the subscale components of the SCL-90 showed any significant change on active treatment. Improvement in psychological parameters occurs as a function of enrolment to a clinical trial, rather than active GH replacement in adult hypopituitarism.

Adult↗
PubMed1998

Hormone responses to stress in patients with major burns.

The responses of the plasma stress hormones corticotrophin (ACTH), vasopressin (AVP), cortisol and corticotrophin releasing hormone (CRH) have been studied in seven consecutive patients aged between 15 and 65 years who suffered from burns of 15-95% total body surface area. There was a distinct peak in AVP (up to 100 pmol/l) and ACTH levels well above the upper limit of normal in all except one patient within 24 h of burn injury. Following the initial rise, AVP and ACTH tended to fall. Plasma CRH with one exception remained within the normal range. Concurrent measurement of plasma renin activity (PRA), haemoglobin (Hb), haematocrit (Hct) and plasma sodium (Na), to assess hydration, showed that PRA was increased in all except one patient during the first 4 days of hospital admission. The correlation between ACTH and cortisol was highly significant (P < 0.001), as was the correlation between ACTH and AVP, AVP and Na, PRA and Hb, and Hct and Na. Other significant correlations were ACTH and Hct (P = 0.023), ACTH and Na (P = 0.017), AVP and Hct (P = 0.029), CRH (P = 0.018), CRH and Hb (P = 0.001). No significant correlation could be demonstrated between CRH and ACTH or AVP. Our findings suggest that AVP plays a role in the hypercortisolaemia which accompanies major burns. The possible detrimental effect of very high levels of AVP leading to progression of burn depth and reduction of skin graft take by its potent vasoconstrictive action and water retention effect (resulting in oedema) deserves further study. As AVP has the potential to reduce tissue perfusion, the possible use of antagonists in major burns merits further consideration. Persistently raised PRA levels, despite normal biochemical and haematological parameters, may indicate that volume expansion therapy may not be adequate, and that both hypovolaemia and stress may contribute to the AVP response. Stress hormone monitoring may lead to better treatment and a reduction in burn stress.

Adolescent↗
PubMed1998

Peripheral plasma levels of beta-endorphin in alcoholics and highly trained athletes and the relationship to a measure of central opioid tone.

Human beta-endorphin-like immunoactivity was measured in highly trained athletes (n = 10), alcoholics in the early phase of abstinence (n=9) and normal controls (n=15) using the Nichols Allegro immunoradiometric assay. The assay was examined for cross reactivity against related peptides, beta-lipotropin and human N-acetyl beta-endorphin. Venous blood sampling was carried out in the morning at 0900 and 1100 hours in a fasting state. Using two-way analysis of variance there was a significant effect of subject group on beta-endorphin concentration (p=0.029). Post-hoc analysis using the Bonferroni t-test showed that the source of the difference was the alcoholic group having significantly lower beta-endorphin immunoreactivity (p < 0.05). There was no difference between the controls and the athletes. There was a positive correlation between plasma beta-endorphin level at 1100 hours and the subsequent ACTH incremental response to naloxone in the group as a whole (r=0.48, p=0.004). The assay showed 100% cross reactivity with beta-lipotropin and 73% cross reactivity with N-acetyl-beta-endorphin. We conclude that alcoholics have reduced levels of beta-endorphin-like immunoactivity. While beta-endorphin is known not to cross the blood-brain barrier, levels of plasma beta-endorphin-like immunoactivity may indirectly reflect central opioid activity.

Adrenocorticotropic Hormone↗
PubMed1998

Arginine vasopressin V1-receptor antagonism in an ovine model of acute myocardial infarction.

Arginine vasopressin (AVP) has an uncertain role in the pathogenesis of increased myocardial and other regional vascular resistance after cardiac injury. The extreme increase in plasma AVP levels observed in some individuals after myocardial infarction potentially exacerbates already compromised myocardial perfusion. We assessed whether blockade of AVP, by administration of the specific V1-receptor antagonist OPC-21268, can reduce the severity of myocardial injury after embolization in our ovine model of acute myocardial infarction. Embolizations resulted in a pattern of changes in ECG and cardiac enzymes consistent with moderate to severe acute myocardial infarction, resulting in left ventricular dysfunction [left ventricular ejection fraction (LVEF) reduced from 52-53% to 38%]. However, no statistically significant differences were observed between groups in hemodynamic or neurohumoral indices of myocardial damage. By contrast, the hypothalamus-pituitary-adrenal (HPA) response [including plasma AVP (p < 0.01), adrenocorticotropic hormone (ACTH; p < 0.01), and cortisol (p < 0.01)) to embolizations was significantly increased in the sheep infused with OPC-21268. In conclusion, whereas plasma HPA responses differed between the two groups, the similar responses in cardiac enzymes, LVEF, and hemodynamic and neurohumoral factors in both groups does not support a role of V1 receptor-mediated exacerbation of myocardial injury in this model of myocardial infarction. Assessment of different receptor antagonists or examination of other models of cardiac injury may further clarify the role of the markedly increased AVP levels that can occur in myocardial infarction.

Adrenocorticotropic Hormone↗
PubMed1998

The effect of glycerol and desmopressin on exercise performance and hydration in triathletes.

BACKGROUND: Hydration is an important determinant of athletic performance, and glycerol-containing solutions have been demonstrated to produce a state of hyperhydration. Secretions of arginine vasopressin (AVP) and/or other renal mechanisms may account for reduced urine output following glycerol ingestion. This study examined the effect of glycerol and the AVP analog desmopressin (DDAVP) on hydration and exercise performance in triathletes ingesting routine volumes of prerace fluids. METHODS: Eight male triathletes ages 19 to 43 participated. After determination of their VO(2peak), each athlete completed a strenuous exercise protocol three times involving 60 min of exercise at 70% VO(2peak) followed immediately by an incremental increase in workload every 2 min until exhaustion. RESULTS: Pretreatment with 1 gxkg(-1) glycerol or 20 microgram of DDAVP intranasally failed to produce hyperhydration or any enhancement of athletic performance. There was a significant difference in reduction in body mass between DDAVP and control (P < 0.05) but no change in sweat volume. No physiologically relevant differences in plasma sodium, renin, or hemoglobin were seen with either active agent. Plasma osmolality did have a different time course in response to exercise following glycerol (P < 0.03) owing to a smaller incremental increase. Urine osmolality was also raised at baseline following glycerol (P < 0.05). Responses to exercise of plasma AVP, cortisol, and indices of carbohydrate metabolism were similar, although AVP was elevated following DDAVP administration (P < 0.01) owing to assay cross-reactivity. CONCLUSION: Although maintaining adequate hydration remains important for the endurance athlete, the routine use of either glycerol of DDAVP before athletic training or competition in a thermoneutral environment does not seem to confer any advantage over conventional fluid replacement.

Adult↗
PubMed1998

Prolonged exercise increases peripheral plasma ACTH, CRH, and AVP in male athletes.

We wished to determine whether the increased ACTH during prolonged exercise was associated with changes in peripheral corticotropin-releasing hormone (CRH) and/or arginine vasopressin (AVP). Six male triathletes were studied during exercise: 1 h at 70% maximal oxygen consumption, followed by progressively increasing work rates until exhaustion. Data obtained during the exercise session were compared with a nonexercise control session. Venous blood was sampled over a 2-h period for cortisol, ACTH, CRH, AVP, renin, glucose, and plasma osmolality. There were significant increases by ANOVA on log-transformed data in plasma cortisol (P = 0.002), ACTH (P < 0.001), CRH (P < 0.001), and AVP (P < 0.03) during exercise compared with the control day. A variable increase in AVP was observed after the period of high-intensity exercise. Plasma osmolality rose with exercise (P < 0.001) and was related to plasma AVP during submaximal exercise (P < 0.03) but not with the inclusion of data that followed the high-intensity exercise. This indicated an additional stimulus to the secretion of AVP. The mechanism by which ACTH secretion occurs during exercise involves both CRH and AVP. We hypothesize that high-intensity exercise favors AVP release and that prolonged duration favors CRH release.

Adrenocorticotropic Hormone↗
PubMed1997

Neurohormonal response to head-up tilt and its role in vasovagal syncope.

In a controlled study, 26 patients with a history of recurrent syncope were found to have increased arginine vasopressin, corticotrophin, and atrial natriuretic factor levels after 5 minutes of 60 degrees head-up tilt, long before they became hypotensive. The exaggerated neurohormonal response in these patients may indicate a greater sensitivity to central hypovolemia which may predispose to vasovagal syncope, mediated by the vasodilatory effects of atrial natriuretic factor or the sensitization of mechanoreceptors by arginine vasopressin.

Adrenocorticotropic Hormone↗
PubMed1997

Generation of action potentials in a mathematical model of corticotrophs.

Corticotropin-releasing hormone (CRH) is an important regulator of adrenocorticotropin (ACTH) secretion from pituitary corticotroph cells. The intracellular signaling system that underlies this process involves modulation of voltage-sensitive Ca2+ channel activity, which leads to the generation of Ca2+ action potentials and influx of Ca2+. However, the mechanisms by which Ca2+ channel activity is modulated in corticotrophs are not currently known. We investigated this process in a Hodgkin-Huxley-type mathematical model of corticotroph plasma membrane electrical responses. We found that an increase in the L-type Ca2+ current was sufficient to generate action potentials from a previously resting state of the model. The increase in the L-type current could be elicited by either a shift in the voltage dependence of the current toward more negative potentials, or by an increase in the conductance of the current. Although either of these mechanisms is potentially responsible for the generation of action potentials, previous experimental evidence favors the former mechanism, with the magnitude of the shift required being consistent with the experimental findings. The model also shows that the T-type Ca2+ current plays a role in setting the excitability of the plasma membrane, but does not appear to contribute in a dynamic manner to action potential generation. Inhibition of a K+ conductance that is active at rest also affects the excitability of the plasma membrane.

Action Potentials↗