Corticosteroids.
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Administration, Inhalation↗
Biomedical subjects
R V Jackson
Publications and source records attributed to R V Jackson.
Naloxone-induced ACTH release: mechanism of action in humans.
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Adrenocorticotropic Hormone↗
A synergistic adrenocorticotropin response to naloxone and vasopressin in normal humans: evidence that naloxone stimulates endogenous corticotropin-releasing hormone.
Naloxone stimulates pituitary-adrenal function by blocking an endogenous inhibitory opioidergic tone which modulates pituitary adrenocorticotropin (ACTH) release. In animals, this action of naloxone is mediated by increased corticotropin-releasing hormone (CRH) secretion, but such a mechanism is disputed in humans. CRH and arginine vasopressin (AVP) are known to have a synergistic effect on ACTH secretion in both humans and animals. In vitro, this synergism is independent of L-type voltage-dependent Ca2+ channel function. The aims of this study were therefore: (i) to determine if the combined administration of naloxone and AVP is synergistic regarding ACTH release; (ii) to assess the effect of nifedipine, which blocks L-type Ca2+ channels, on the ACTH response to combined naloxone/AVP stimulation. Seven healthy volunteers were studied using a placebo-controlled, single-blind protocol. Naloxone (125 micrograms/kg) and/or AVP (10 units) were given in all four possible combinations, and oral nifedipine (20 mg) was also given with naloxone and AVP as an additional test. The mean AUC and the mean peak change in ACTH levels following combined naloxone/AVP administration were both significantly greater than the arithmetic sum of the ACTH responses to naloxone and AVP given on separate occasions (AUC: 1,576.4 +/- 417.9 vs. 567.1 +/- 106.1 pmol.min.l-1, p < 0.002; peak change: 37.9 +/- 14.0 vs. 11.8 +/- 2.0 pmol/l, p < 0.007). Nifedipine reduced the ACTH response to combined naloxone/AVP stimulation by 43% (AUC: 1,576.4 +/- 417.9 vs. 897.0 +/- 186.2; p < 0.05), but it remained greater than the sum of the individual responses (897.0 +/- 186.2 vs. 576.1 +/- 106.1, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Adrenocorticotropin hyperresponse to the corticotropin-releasing hormone-mediated stimulus of naloxone in patients with myotonic dystrophy.
We previously showed that CRH-mediated stimuli, including exogenous CRH, cause ACTH hypersecretion in many myotonic dystrophy (DM) patients. We confirmed this by giving naloxone, a stimulator of endogenous CRH release, to a large number of DM patients and controls. DM patients, first degree relatives, and normal controls received i.v. naloxone at 1400 h, and blood was taken for ACTH (RIA) and cortisol (high pressure liquid chromatography) measurements from 15 min before to 120 min after naloxone treatment. DM patients had basal ACTH levels approximately twice those of controls, and their ACTH responses were 4 times those of controls. In contrast, DM basal cortisol levels were not significantly different from those of relatives and were slightly higher than those of normal subjects. Cortisol responses were similar in the three groups, probably due to attenuation at high levels of adrenocortical stimulation, although some patients with inappropriately low cortisol responses for their level of ACTH stimulation warrant further investigation. Nineteen of the 36 patients whose ACTH responses were greater than 3 SD above the normal mean were classed as hyperresponders. Seven patients, who were tested more than once, had reproducible responses relative to those of the normal subjects. We conclude that ACTH hypersecretion after CRH-mediated stimuli, including naloxone, is an inherent, but variable, feature of DM, caused by expression of the genetic mutation at the anterior pituitary. The mechanism is probably a defect in the intracellular pathway initiated by CRH-receptor interaction as a result of abnormal levels of a cAMP-dependent kinase, DMPK, the product of the gene undergoing mutation in DM.
Adolescent↗
The effect of desipramine on basal and naloxone-stimulated cortisol secretion in humans: interaction of two drugs acting on noradrenergic control of adrenocorticotropin secretion.
Desipramine (DMI), a tricyclic antidepressant and norepinephrine (NE) reuptake blocker, is reported to induce ACTH and cortisol release acutely in humans, probably by facilitating central NE neurotransmission. Tricyclic antidepressant therapy, including DMI, normalizes the ACTH and cortisol hypersecretion that often accompanies depression. The mechanism of hypothalamic-pituitary-adrenal (HPA) axis inhibition by DMI in humans is unknown. In rats, DMI reduces the activity of the locus ceruleus, a major source of NE innervation of the hypothalamic paraventricular nucleus, the site of CRH neurons. Naloxone induces ACTH and cortisol release in humans through a noradrenergic-mediated mechanism and a probable consequent stimulation of hypothalamic CRH release. To study the interaction of these drugs on NE neurotransmission and, hence, HPA axis activity in humans, we administered DMI alone and with naloxone in a randomized, double blind, placebo-controlled protocol in eight healthy male volunteers. DMI (75 mg, orally) was given 180 min before naloxone (125 micrograms/kg BW, i.v.). Plasma ACTH and cortisol were measured at frequent intervals from 60 min before to 120 min after naloxone treatment. Plasma cortisol levels were 77% higher 180 min after DMI compared to those after placebo treatment (287 +/- 17 vs. 162 +/- 14 nmol/L; P = 0.000005). DMI reduced the naloxone-induced rise in cortisol (P = 0.02), but there was no change in the integrated cortisol response. The increase in basal plasma ACTH levels after DMI treatment did not reach statistical significance. DMI significantly increased systolic blood pressure and heart rate consistent with an effect on the noradrenergic control of the cardiovascular system. In summary, DMI increased basal cortisol levels consistent with facilitation of NE neurotransmission and, hence, hypothalamic CRH release. However, DMI had no enhancing effect on naloxone-induced cortisol release. This contrasts with the synergy observed when non-antidepressant agents that increase NE neurotransmission are given with naloxone to humans. DMI increases glucocorticoid feedback sensitivity in the rat HPA axis after several weeks through up-regulation of central corticosteroid receptors. However, this slowly developing effect is unlikely to occur during these acute studies. The effect of DMI on naloxone-induced cortisol release is consistent with an inhibitory effect on central noradrenergic control of ACTH release, perhaps at the locus ceruleus. This is the first human study to suggest an inhibitory effect of DMI on central noradrenergic control of ACTH release.
Adrenocorticotropic Hormone↗
Cell-mediated immunity in combat veterans with post-traumatic stress disorder.
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Humans↗
Effect of flumazenil on basal and naloxone-stimulated ACTH and cortisol release in humans.
1. Endogenous benzodiazepine receptor ligands are thought to influence the human hypothalamic-pituitary-adrenal (HPA) axis and naloxone, a known stimulator of adrenocorticotropic hormone (ACTH) release, is thought to act via release of hypothalamic corticotropin-releasing hormone. 2. The aim of the present study was to assess the influence of endogenous benzodiazepine-receptor ligands by administering flumazenil (Ro15-1788), a benzodiazepine antagonist, and measuring ACTH and cortisol release, both basal and during naloxone-stimulation. 3. Nine normal volunteers in a placebo-controlled double-blind design were studied. Flumazenil (0.5 mg, i.v. bolus) was given 2 min before naloxone (125 micrograms/kg bodyweight, i.v. bolus) immunoreactive-adrenocorticotropic hormone (IR-ACTH) and cortisol levels were measured at frequent intervals from 60 min before to 120 min after naloxone injection. 4. Flumazenil had no effect on ACTH and cortisol release when given alone; flumazenil area under the ACTH/time curve (pmol/L.min) = -36.5 +/- 63.5 compared with placebo = -53.5 +/- 31.8, flumazenil area under the cortisol/time curve (nmol/L.min x 10(-3)) = - 2.4 +/- 2.4 compared with placebo -0.56 +/- 1.4. Flumazenil did not change the ACTH and cortisol release achieved with naloxone; naloxone area under the ACTH/time curve (pmol/L.min) = 327.8 +/- 61.7 compared with flumazenil/naloxone = 366.3 +/- 88.1, naloxone area under the cortisol/time curve (nmol/L. min x 10(-3) = 12.2 +/- 3.4 compared with naloxone/flumazenil = 10.5 +/- 2.1. 5. The authors conclude that flumazenil dose not modify basal or stimulated ACTH and cortisol release in healthy humans. This would suggest that endogenous benzodiazepine-like ligands and the benzodiazepine/gamma-aminobutyric acid receptor complex do not tonically influence the hypothalamic-pituitary-adrenal axis.
Adrenocorticotropic Hormone↗
Sleep hypoxia in myotonic dystrophy and its correlation with awake respiratory function.
BACKGROUND: Tiredness and daytime respiratory failure occur frequently in myotonic dystrophy. Sleep hypoxaemia was studied in 12 patients with myotonic dystrophy and correlations were sought with their daytime lung and respiratory muscle function. METHODS: All patients underwent overnight sleep studies, clinical assessment, measurement of flow-volume loops and carbon monoxide transfer factor, arterial blood gas analysis, and physiological assessment of both thoracic muscle function and upper airways obstruction. RESULTS: The mean nadir of oxygen saturation during sleep was 75% (95% confidence interval 69% to 81%). A mean of 3.4% of total sleep duration was spent at an oxygen saturation level below 85%. Five of the 12 patients had an apnoea index of > 5, the group mean apnoea/hypopnoea index being 15.8 events/sleep hour. The mean awake arterial oxygen tension (PaO2) was 10.7 kPa. There was a trend to hypercapnoea with a mean awake arterial carbon dioxide tension of 6.1 kPa; carbon dioxide retention worsened during sleep. Respiratory muscle dysfunction was mainly evident as a low maximum expiratory mouth pressure. Upper airway obstruction assessed by physiological criteria was found in four of the 12 patients. The proportion of total sleep duration with oxygen saturation levels below 85% was directly related to body mass index (weight/height2) and inversely related to the awake PaO2. Body mass index was inversely related to the overnight nadir of oxygen saturation. CONCLUSIONS: Patients with myotonic dystrophy are often hypoxic during sleep and the subgroup that are obese, or have symptoms of sleep apnoea, or both, are particularly at risk. Sleep studies should be considered in this subgroup of patients with myotonic dystrophy.
Adult↗
Paradoxical inhibition by aspirin of naloxone-induced adrenocorticotropin secretion in myotonic dystrophy.
The ACTH response to endogenous or exogenous CRH is increased in patients with myotonic dystrophy (DM), possibly because of abnormal function of cAMP-dependent protein kinases in this condition. Arachidonic acid (AA) metabolites are believed to interact with the cAMP-dependent second messenger system activated by CRH; therefore, drugs that interfere with AA metabolism may alter ACTH secretion in DM. In this study, seven DM patients were given naloxone, which stimulates endogenous CRH release, and aspirin, which inhibits the synthesis of prostaglandins from AA via the cyclooxygenase metabolic pathway. Pretreatment with aspirin reduced the mean integrated ACTH response to naloxone by 33% (P < 0.05). However, the corresponding 18% reduction in cortisol levels was not statistically significant (P > 0.10). These findings are in contrast to those of a previous study using an identical protocol, in which aspirin increased the ACTH response to naloxone in six normal volunteers. This difference between DM and control subjects is consistent with the hypothesis that the interaction between AA metabolites and the cAMP-dependent protein kinase-A second messenger system is abnormal in the corticotrophs of persons with DM.
Adrenocorticotropic Hormone↗
Alprazolam attenuates vasopressin-stimulated adrenocorticotropin and cortisol release: evidence for synergy between vasopressin and corticotropin-releasing hormone in humans.
Alprazolam (APZ), a triazolobenzodiazepine with unique clinical utility, has potent inhibitory effects on the human hypothalamic-pituitary-adrenal axis. Because APZ inhibits CRH secretion from isolated rat hypothalami and inhibits the probable CRH-mediated effect of naloxone on ACTH release, it is likely APZ acts as an inhibitor of hypothalamic CRH release in humans. The two principal physiological ACTH secretagogues are CRH and arginine vasopressin (AVP). We studied the ACTH and cortisol responses to an ACTH-releasing dose of AVP with and without preadministration of APZ in humans. Our hypothesis was that acute CRH deprivation by APZ would attenuate the ACTH response to vasopressin, as CRH and AVP act synergistically to control ACTH release. This synergy may depend on activation of subpopulations of corticotropes, some of which require both CRH and AVP together to elicit an ACTH response and/or intracellular "cross-talk" between second messenger pathways stimulated by the secretagogues. APZ (2 mg, orally) was given to eight healthy volunteers 90 min before AVP (0.0143 IU/kg BW, iv) in a randomized, double blind, placebo-controlled design during afternoon studies. ACTH and cortisol levels were measured at frequent intervals from 60 min before to 120 min after AVP injection. APZ reduced the mean integrated ACTH and cortisol responses to AVP by 67% and 70% respectively [ACTH, 161.6 +/- 59.7 vs. 53.0 +/- 20.9 pmol/min.L (P = 0.022); cortisol, 9314 +/- 3310 vs. 2763 +/- 1472 nmol/min.L (P = 0.020, AVP vs. APZ/AVP, respectively)]. APZ reduced the mean peak ACTH and cortisol responses to AVP by 57% (P = 0.023) and 40% (P = 0.0012), respectively. AVP levels were not significantly different in those who received APZ or placebo. This study provides further evidence of the potent inhibitory effects of APZ on ACTH and cortisol release in humans and is the first to find that APZ inhibits AVP-stimulated ACTH and cortisol release. This study also suggests that CRH/AVP synergy is an important physiological mechanism for ACTH release in humans, as indicated by the blunted ACTH response to AVP after APZ-mediated acute CRH deprivation. Inhibition of the pituitary-adrenal axis by APZ may explain its unique efficacy in psychiatric disorders thought to be associated with dysregulation of hypothalamic CRH release.
Adrenocorticotropic Hormone↗
Naloxone stimulation of ACTH secretion during petrosal sinus sampling in Cushing's syndrome.
1. Petrosal sinus sampling has been used to establish the source of adrenocorticotropin (ACTH) in ACTH-dependent Cushing's syndrome. Naloxone, an opioid antagonist, stimulates ACTH secretion, probably via release of endogenous hypothalamic corticotropin releasing hormone (CRH). 2. Three patients with hypercortisolism were studied. Two showed suppressed (> 50%) urinary-free cortisol excretion with high-dose dexamethasone treatment (2 mg every 6 h for 2 days), one did not suppress. The patients were subjected to bilateral simultaneous inferior petrosal sinus sampling (BSIPSS) with simultaneous peripheral venous (forearm) samples. Basal (unstimulated) samples were taken and naloxone (125 micrograms/kg bodyweight) was given intravenously with subsequent simultaneous sampling. Plasma ACTH was measured by radio-immunoassay (RIA). 3. All cases exhibited a marked rise in immunoreactive (IR)-ACTH levels (pmol/L) after naloxone injection, basal to peak: case 1, left 11.5-22.1, right 9.8 with no rise, peripheral 9.1-9.5; case 2, left 456-863, right 125-501, peripheral 59-82; case 3, left 12.7-13.0, right 277-431, peripheral 12.1-11.7. All results indicate pituitary Cushing's syndrome, with a central to peripheral ratio > 2.3:1. Pituitary Cushing's syndrome was confirmed on the results of trans-sphenoidal pituitary surgery in cases 1 and 3. 4. It is suggested that naloxone injection during petrosal sinus sampling in Cushing's syndrome may assist in the diagnosis of ACTH source, by enhancing ACTH release from a pituitary micro-adenoma.
Adrenocorticotropic Hormone↗
Alprazolam blocks the naloxone-stimulated hypothalamo-pituitary-adrenal axis in man.
Alprazolam (APZ) is a benzodiazepine with unique antidepressant activity for a drug of its class. There is some evidence of inhibition of the unstimulated hypothalamo-pituitary-adrenal axis by APZ which may be important in its therapeutic action, and could be detrimental in APZ-treated subjects who encounter stressful stimuli. To assess the effect of APZ on stimulated ACTH and cortisol secretion, we studied 14 normal subjects in a randomized, double-blind, placebo-controlled design. APZ or placebo capsule was administered orally in doses of 0.5 mg and 2 mg, 90 min before either naloxone, 125 micrograms/kg body weight i.v. bolus dose, a known stimulator of ACTH and cortisol release, or placebo. After naloxone stimulation, the area under the plasma ACTH/time curves was significantly reduced by APZ, in both the 2 mg (P < 0.0005) and 0.5 mg (P < 0.005) doses, compared to their respective placebo studies; similar reductions in area under the plasma cortisol/time curves occurred after 2 mg (P < 0.00002) and 0.5 mg (P < 0.0005) APZ doses. We conclude that APZ is a potent inhibitor of naloxone-stimulated ACTH and cortisol release in humans. Since APZ has been shown to inhibit CRH release in vitro, and naloxone-induced ACTH secretion is likely to be caused through CRH release, this suggests that APZ inhibition of naloxone action is via the parvocellular CRH neurons of the paraventricular nucleus and/or central neurotransmitter pathways impinging directly or indirectly on these CRH neurons. Thus APZ may exert at least some of its clinical effects through inhibition of central CRH release. APZ treatment could lead to a relative hyporesponse of the pituitary-adrenal axis during stress. APZ may be an important tool for manipulation of hypothalamic CRH release in studies of pituitary-adrenal function.
Adrenal Glands↗
Altered hypothalamic-pituitary-adrenal axis responsiveness in myotonic dystrophy: in vivo evidence for abnormal dihydropyridine-insensitive calcium transport.
In persons with myotonic dystrophy (DM), the ACTH response to CRH is greater than normal, while it is delayed in response to arginine vasopressin. Since influx of extracellular Ca2+ ions is a common step in signal transduction by both of these secretagogues, an abnormality of cellular Ca2+ transport may underlie the disturbances of hypothalamic-pituitary-adrenal axis function in this condition. Seven myotonic patients were given naloxone, which stimulates endogenous CRH release, and nifedipine, which blocks L-type voltage-dependent Ca2+ channels. Each subject underwent three tests, using different drug combinations, in a single blind, placebo-controlled protocol. Pretreatment with nifedipine delayed the time of the peak plasma hormone responses after naloxone [ACTH, 32.1 +/- 2.1 vs. 51.4 +/- 4.5 min (P < 0.05); cortisol, 42.9 +/- 2.1 vs. 70.7 +/- 4.3 min (P < 0.02); for naloxone and nifedipine/naloxone, respectively]. Additionally, nifedipine significantly reduced the proportion of the mean integrated ACTH response that had occurred by 30 min after naloxone administration (32.0 +/- 4.0% for naloxone vs. 17.6 +/- 2.4% for nifedipine/naloxone; P < 0.02) and the proportion of the mean integrated cortisol response by 45 min after naloxone administration (34.7 +/- 3.5% for naloxone vs. 25.0 +/- 2.6% for nifedipine/naloxone; P < 0.02). However, the total integrated responses did not change [ACTH, 1182.6 +/- 548.9 vs. 905.5 +/- 157.0 pmol/min.L (P = NS); cortisol 17,353 +/- 2,984 vs. 18,469 +/- 3,561 nmol/min.L (P = NS); for naloxone and nifedipine/naloxone, respectively]. We conclude that nifedipine delays, but does not reduce, the ACTH and cortisol responses to naloxone in DM. Since nifedipine has a different effect on normal controls (reduced response with unchanged timing), these findings imply an abnormality of dihydropyridine-insensitive Ca2+ transport (such as T-type Ca2+ channels) in the corticotrophs of DM patients.
Adolescent↗
Aspirin increases the human hypothalamic-pituitary-adrenal axis response to naloxone stimulation.
Prostaglandins are believed to influence hypothalamic-pituitary-adrenal (HPA) axis function, but their specific effects on ACTH and cortisol secretion in humans are unclear. Acetylsalicylic acid (aspirin) blocks the synthesis of prostaglandins from arachidonic acid. We studied the effects of oral aspirin on the plasma ACTH and cortisol responses to iv naloxone, which increases endogenous CRH release, in six normal volunteers and on the adrenocortical response to synthetic ACTH boluses in seven other healthy subjects, using placebo-controlled, single blinded protocols. Aspirin pretreatment significantly increased the ACTH response to naloxone [mean peak increase from basal, 8.3 +/- 1.2 vs. 5.9 +/- 0.8 pmol/L (P < 0.05); mean integrated response, 431.9 +/- 51.5 vs. 295.1 +/- 26.6 pmol/L.min (P < 0.005); for aspirin/naloxone and placebo aspirin/naloxone, respectively]. However, the corresponding cortisol results did not show statistically significant differences (P < 0.20). The mean integrated ACTH and cortisol responses were 46% and 26% greater with aspirin, respectively. Aspirin did not influence the cortisol responses to synthetic ACTH administration given according to a dose-response protocol. We conclude that aspirin augments the HPA axis response to naloxone stimulation in normal humans without having a direct effect at the adrenal level. The action of aspirin on the human HPA axis is probably mediated via inhibition of cyclooxygenase, resulting in changes in arachidonic acid metabolites, which influence ACTH release from corticotrophs.
Adrenocorticotropic Hormone↗
CRH-mediated pituitary-adrenal responses are inhibited by nifedipine in humans.
Sustained CRH-stimulated ACTH release in vitro depends on Ca2+ influx and is inhibited 30-40%, but not delayed, by dihydropyridine Ca2+ channel blockers. In five normal humans, we found that nifedipine pretreatment reduced integrated ACTH responses to the CRH-mediated stimulus of fenfluramine by 28% and cortisol responses by 34%, results comparable with those from in vitro reports. Nifedipine did not alter the timing of peak hormonal responses. We conclude that (1) in humans, nifedipine inhibits ACTH release by fenfluramine by blocking Ca2+ influx via L-type channels in corticotrophs; (2) the magnitude of fenfluramine-stimulated CRH release is probably unaltered by nifedipine and (3) because the timing is unaltered, nifedipine does not affect the rate of CRH delivery to the corticotroph.
Adrenocorticotropic Hormone↗
L-type calcium channels and CRH-mediated ACTH and cortisol release in humans.
1. The effect of pretreatment with nifedipine on naloxone-stimulated corticotrophin-releasing hormone (CRH)-induced adrenocorticotrophin (ACTH) release in humans was investigated. The mean peak plasma ACTH and cortisol levels and the mean peak change in cortisol levels from basal were significantly lower in the nifedipine/naloxone test than in the naloxone alone test. The integrated areas under the ACTH-time and cortisol-time curves were reduced by 33 and 49%, respectively, in the nifedipine/naloxone test compared with the naloxone alone test. These results correlate well with published in vitro studies. 2. Acute administration of oral nifedipine partially inhibited naloxone-stimulated ACTH and cortisol release, probably by blockade of plasma membrane voltage-dependent L-type calcium channels normally activated following binding of CRH to pituitary corticotroph receptors. 3. Naloxone-induced CRH release may replace insulin hypoglycaemia testing of pituitary ACTH reserve in humans.
Adrenocorticotropic Hormone↗
Naloxone-induced ACTH release in man is inhibited by clonidine.
1. Adrenergic mechanisms play an important role in regulation of ACTH release. We used the alpha 2-adrenergic agonist, clonidine, as a central nervous system inhibitor of ACTH release to see if it would alter naloxone-induced ACTH secretion in normal human volunteers. 2. There was a significant blunting of the mean peak level of ACTH and the mean peak change of ACTH from basal as well as the area under the ACTH-time curve when clonidine was given prior to naloxone. 3. We conclude that clonidine, by blocking central noradrenergic pathways, which stimulate corticotropin-releasing hormone secretion, inhibits naloxone-induced ACTH secretion. This suggests that naloxone causes ACTH release through these same central noradrenergic pathways.
Administration, Oral↗
Nifedipine blocks ACTH and cortisol release in man.
1. The present study investigated the effect of prior administration of nifedipine on AVP-induced ACTH release in seven normal volunteers. Three protocols were used: 20 mg oral nifedipine; 0.14 pressor units intramuscular (i.m.) per kg bodyweight aqueous AVP; oral nifedipine plus i.m. AVP 90 min later. Plasma ACTH and cortisol were measured at intervals for 2.5 h during each test. 2. The mean peak plasma ACTH and cortisol levels and the mean peak changes from basal in these levels were significantly lower in the nifedipine/AVP test than in the AVP alone test. The integrated area under the cortisol time curve was significantly lower for the nifedipine/AVP test than that for the AVP test alone. Nifedipine alone caused no changes in ACTH or cortisol. 3. Acute administration of oral nifedipine caused an inhibition of AVP-stimulated ACTH and cortisol release in normal humans. This effect may be due to blockade of plasma membrane calcium channels normally activated during AVP stimulation of pituitary corticotrophs.
Adrenocorticotropic Hormone↗