Increased Plasma Adrenocorticotropic Hormone Research Articles

The Effect of Neuropeptide Y on the Hypothalamic-pituitary-adrenal Axis in the Dog

There is increasing evidence that neuropeptide Y (NPY) affects the release of pituitary hormones, including adrenocorticotropic hormone (ACTH). The present study was designed to clarify the mechanism by which NPY activates the hypothalamic-pituitary-adrenal (HPA) axis in the dog. Mongrel dogs were equipped with a chronic cannula allowing intra-third (i.t.v.) or intra-lateral (i.l.v.) cerebroventricular administration. A 1.19 nmol, i.t.v. dose of NPY produced as great an ACTH and cortisol response as did equimolar ovine corticotropin releasing factor (CRF). This action of NPY was dose-dependent and shared by peptide YY (PYY) and pancreatic polypeptide (PP), other members of the PP family peptide. Intravenously (i.v.) administered NPY (1.19-11.9 nmol) was much less potent than i.v. CRF in stimulating ACTH and cortisol secretion. However, i.v. NPY significantly increased plasma ACTH and cortisol concentrations, raising the possibility that NPY may modulate the activity of corticotrophs. We next investigated the possible relationship between NPY and CRF on the HPA axis. Pretreatment with a novel CRF antagonist, alpha-helical CRF9-41 (130.9 nmol i.t.v. or 261.5 nmol i.v.), partly but significantly attenuated the ACTH and cortisol responses to i.t.v. NPY (1.19 nmol). Furthermore, adding a subthreshold dose of i.t.v. NPY (0.119 nmol) to i.t.v. CRF (1.19 nmol) or i.v. NPY (2.38 nmol) to i.v. CRF (0.595 nmol) resulted in the potentiation of CRF-induced ACTH secretion. These results indicate that NPY may activate the HPA axis in concert with CRF probably at hypothalamic and/or pituitary levels. The present findings that NPY evokes ACTH secretion and potentiates the effectiveness of CRF as a secretagogue, together with high concentrations of NPY in the hypothalamus and pituitary portal blood, suggest the NPY is involved in the multihormonal control of ACTH release.

Involvement of organum vasculosum of lamina terminalis and preoptic area in interleukin 1 beta-induced ACTH release

Intravenous administration of recombinant human interleukin 1 beta (IL-1 beta, 1 micrograms/100 g body wt) resulted in a marked elevation of plasma adrenocorticotropic hormone (ACTH) levels, with peak levels at 10 min, in conscious unrestrained rats. One week after the placement of a lesion by radiofrequency or microinjection of kainic acid in the organum vasculosum of lamina terminalis (OVLT) but not in subfornical organ, ACTH response to intravenous IL-1 beta was enhanced, whereas both radiofrequency-induced lesion and kainic acid in the preoptic area (POA) suppressed the response. Indomethacin or a prostaglandin E (PGE) antagonist microinjected into the OVLT or POA suppressed or abolished the response. On the other hand, PGE, but not PGD2, microinjected into the POA increased plasma ACTH levels. These results suggest an important role for the OVLT, which lacks blood-brain barrier, as a possible site of entry of blood-borne IL-1 beta into the brain and for the POA, which may contain the neurons required for the response. Involvement of PGE in the OVLT and POA in the ACTH response to intravenous IL-1 beta is also suggested.

Role of vagosympathetic fibers in the control of adrenocorticotropic hormone, vasopressin, and renin responses to hemorrhage in fetal sheep.

Hemorrhage stimulates endocrine and cardiovascular reflex responses that are appropriate for returning blood volume and pressure to prehemorrhage levels. Fetal sheep respond to hemorrhage with increases in plasma adrenocorticotropic hormone (ACTH), cortisol, and vasopressin concentrations and plasma renin activity, but little is known about the afferent limb of the reflex(es) controlling these responses. Fetal sheep between 128 and 133 days' gestation were chronically prepared with vascular catheters. Five fetal sheep were subjected to bilateral section of the cervical vagosympathetic trunks; six fetal sheep were not vagotomized. Four to six days after surgery, the fetuses were subjected to withdrawal of 10 ml of blood every 10 minutes for 2 hours (130 ml total). Vagotomized fetal sheep responded to the hemorrhage with a greater decrease in central venous pressure than the intact fetuses and a slower restitution of fluid to the vascular space (estimated to be 17% of the hemorrhage volume in 2 hours) than the intact fetuses (estimated to be 28% of the hemorrhage volume in 2 hours). Both groups of fetuses, however, responded to the hemorrhage with increases in fetal plasma ACTH, cortisol, and vasopressin concentrations and plasma renin activity that were not significantly different. A posteriori analysis of the data by correlation analysis revealed that the fetal ACTH, vasopressin, and renin responses to the hemorrhage were more highly correlated to the changes in fetal arterial pH than to changes in fetal mean arterial pressure or central venous pressure. The results suggest that the ACTH, vasopressin, and renin responses to hemorrhage in the fetus be mediated by chemoreceptors, not by cardiovascular mechanoreceptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Paraventricular stimulation with glutamate elicits bradycardia and pituitary responses

The excitatory neurotransmitter, L-glutamate (0.5 M, pH 7.4), or the organic acid, acetate (0.5 M, pH 7.4), was microinjected (50 nl over 2 min) directly into the paraventricular nuclei (PVN) of pentobarbital sodium-anesthetized rats while arterial blood pressure and heart rate and plasma adrenocorticotropic hormone (ACTH), vasopressin, and oxytocin were measured. Activation of PVN neurons with L-glutamate led to increases in plasma ACTH, vasopressin, and oxytocin and a profound bradycardia (approximately 80 beats/min) with little change in arterial blood pressure. Microinjection of acetate had no effect on the above variables. The decrease in heart rate was shown to be dependent on the concentration of glutamate injected and the volume of injectate. The bradycardia was mediated through the autonomic nervous system because ganglionic blockade (pentolinium tartrate) eliminated the response; atropine and propranolol severely attenuated the bradycardia. The bradycardia was greatest when L-glutamate was microinjected into the caudal PVN. Injections into the rostral PVN or into nuclei surrounding the PVN led to small or nonsignificant decreases in heart rate. Focal electric stimulation (2-50 microA) of the PVN also led to decreases in heart rate and arterial blood pressure. These data suggest that activation of PVN neurons leads to the release of ACTH, vasopressin, and oxytocin from the pituitary and a bradycardia that is mediated by the autonomic nervous system.

Correlation between the Stress-Induced Transient Increase in Corticotropin-Releasing Hormone Content of the Median Eminence of the Hypothalamus and Adrenocorticotropic Hormone Secretion

Intravenous angiotensin II and ether stress were found to produce a rapid, transient increase in the corticotropin-releasing hormone (CRH) content of the median eminence as measured by a radioimmunoassay employing an antibody against rat CRH(1-41). This confirms previous reports of transient increases in CRH measured by bioassay. The increase did not occur in the paraventricular region or in other parts of the brain. It occurred along with an increase in plasma adrenocorticotropic hormone (ACTH) when a second ether stress was administered 1 h after the first, and it also occurred when rats that had been adrenalectomized for 5 days were exposed to ether. The increases in CHR and the ACTH responses to ether were reduced or abolished by dexamethasone and pentobarbital. Four days after semicircular knife cuts in the posterior hypothalamus, resting CRH in the median eminence was increased but there was no further rise after ether stress. Plasma ACTH was normal at rest after the cuts, but the increase produced by ether was reduced. The ACTH responses to angiotensin II and immobilization were also reduced. Because the posterior knife cuts reduced hypothalamic catecholamine content, the effects of reducing hypothalamic norepinephrine and epinephrine by administration of the dopamine-beta-hydroxylase inhibitor diethyldithiocarbamate (DDC) were tested. Five hours after DDC, plasma ACTH was elevated but there was no further increase with ether stress. The median eminence CRH content was normal but failed to increase after exposure to ether.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of neuropeptide Y on the hypothalamic-pituitary-adrenal axis in the dog

There is increasing evidence that neuropeptide Y (NPY) affects the release of pituitary hormones, including adrenocorticotropic hormone (ACTH). The present study was designed to clarify the mechanism by which NPY activates the hypothalamic-pituitary-adrenal (HPA) axis in the dog. Mongrel dogs were equipped with a chronic cannula allowing intra-third (i.t.v.) or intra-lateral (i.l.v.) cerebroventricular administration. A 1.19 nmol, i.t.v. dose of NPY produced as great an ACTH and cortisol response as did equimolar ovine corticotropin releasing factor (CRF). This action of NPY was dose-dependent and shared by peptide YY (PYY) and pancreatic polypeptide (PP), other members of the PP family peptide. Intravenously (i.v.) administered NPY (1.19–11.9 nmol) was much less potent than i.v. CRF in stimulating ACTH and cortisol secretion. However, i.v. NPY significantly increased plasma ACTH and cortisol concentrations, raising the possibility that NPY may modulate the activity of corticotrophs. We have next investigated the possible relationship between NPY and CRF on the HPA axis. Pretreatment with a novel CRF antagonist, alpha-helical CRF 9−41 (130.9 nmol i.t.v. or 261.8 nmol i.v.), partly but significantly attenuated the ACTH and cortisol responses to i.t.v. NPY (1.19 nmol). Furthermore, adding a subthreshold dose of i.t.v. NPY (0.119 nmol) to i.t.v. CRF (1.19 nmol) or i.v. NPY (2.38 nmol) to i.v. CRF (0.595 nmol) resulted in the potentiation of CRF-induced ACTH secretion. These results indicate that NPY may activate the HPA axis in concert with CRF probably at hypothalamic and/or pituitary levels. The present findings that NPY evokes ACTH secretion and potentiates the effectiveness of CRF as a secretagogue, together with high concentrations of NPY in the hypothalamus and pituitary portal blood, suggest that NPY is involved in the multihormonal control of ACTH release.

Effects of CRF and ANG II on ACTH and vasopressin release in conscious dogs.

The aim of the present study was to examine the effects of corticotropin-releasing factor (CRF) in conscious dogs and to determine whether the stimulation of adrenocorticotropic hormone (ACTH) release by angiotensin II (ANG II) results from potentiation of the action of CRF. In addition, the possible role of CRF in the stimulation of vasopressin released by ANG II was investigated. The following experiments were performed: 1) intravenous saline infusion; 2) ANG II (10 ng.kg-1.min-1) alone; 3) vasopressin (1 ng.kg-1.min-1) alone; 4) CRF (0.001, 0.01, or 0.1 microgram/kg iv) bolus; 5) vasopressin (1 ng.kg-1.min-1) and CRF (0.1 microgram/kg) together; 6) CRF (0.001, 0.01, or 0.1 microgram/kg) and ANG II (10 ng.kg-1.min-1) together; 7) ANG II (10 ng.kg-1.min-1) followed 15 min later with CRF (0.001, 0.01, or 0.1 microgram/kg). Each dose of CRF was tested on a different day. Infusion of ANG II alone stimulated the release of ACTH, cortisol, and vasopressin. Administration of CRF produced dose-dependent increases in plasma ACTH and cortisol concentrations, and the highest dose of CRF increased plasma vasopressin concentration. CRF given together with ANG II did not potentiate the stimulation of ACTH release by CRF. Vasopressin at the dose tested did not stimulate ACTH release but potentiated the ACTH response to CRF. ANG II stimulated vasopressin release but did not potentiate the AVP response to CRF. These results show that, in conscious dogs, ANG II and CRF each increase plasma ACTH concentration and that the ACTH response to CRF is potentiated by vasopressin but not by ANG II.(ABSTRACT TRUNCATED AT 250 WORDS)

Neonatal capsaicin treatment of rats reduces ACTH secretion in response to peripheral neuronal stimuli but not to centrally acting stressors.

1. Plasma adrenocorticotrophic hormone (ACTH) concentrations were measured in rats following exposure to anaesthetic agents, after stimulation of peripheral sensory nerves, and during psychological stress. 2. In rats, kept in their home cages, the i.p. injection of sodium pentobarbitone did not cause an increase in plasma ACTH, whereas injection of urethane increased plasma ACTH several times. In rats transferred to a glass dessicator and inhaling oxygen, plasma ACTH was more than 3 fold higher than in rats in their home cage. Exposure to nitrous oxide, halothane or ether in a glass dessicator produced significantly higher plasma ACTH concentrations when compared to exposure in the home cage. 3. In rats anaesthetized with pentobarbitone, the electrical stimulation of large myelinated afferents in the sciatic nerve did not trigger a measurable increase in ACTH secretion, whereas stimulation of afferent A delta- and C-fibres significantly elevated plasma ACTH concentrations. Rats treated as neonates with capsaicin showed an attenuated ACTH response to A and C-fibre stimulation. 4. Similarly, capsaicin pretreatment reduced the increase in ACTH secretion during morphine withdrawal; a similar effect was produced by clonidine. 5. ACTH secretion following open field exposure, ether stress or hypoglycaemia was not changed by capsaicin pretreatment. 6. It was concluded that capsaicin-sensitive afferents are involved in the secretion of ACTH elicited by somatosensory forms of stress. Centrally evoked ACTH release is not affected by capsaicin pretreatment.

Role of brain serotonergic pathways and hypothalamus in regulation of renin secretion.

To investigate the role of brain serotonergic neurons in the regulation of renin secretion, we measured changes in plasma renin activity (PRA), and, in some instances, plasma renin concentration (PRC), plasma angiotensinogen, and plasma adrenocorticotropic hormone (ACTH) in rats with lesions of the dorsal raphe nucleus and lesions of the paraventricular nuclei, dorsomedial nuclei, and ventromedial nuclei of the hypothalamus. We also investigated the effects of p-chloroamphetamine (PCA), immobilization, head-up tilt, and a low-sodium diet in the rats with dorsal raphe, paraventricular, and dorsomedial lesions. Lesions of the dorsal raphe nucleus abolished the increase in PRA produced by PCA but had no effect on the increase produced by immobilization, head-up tilt, and a low-sodium diet. Paraventricular lesions, which abolish the increase in plasma ACTH produced by PCA, immobilization, and head-up tilt, decreased plasma angiotensinogen. The paraventricular lesions abolished the PRA and the PRC responses to PCA and the PRA but not PRC response to immobilization, head-up tilt, and a low-sodium diet. The ventromedial lesions abolished the PRA and PRC responses to PCA and did not reduce plasma angiotensinogen. The data suggest that paraventricular lesions depress angiotensinogen production by the liver and that the paraventricular and ventromedial nuclei are part of the pathway by which serotonergic discharges increase renin secretion. They also suggest that the serotonergic pathway does mediate the increases in renin secretion produced by immobilization, head-up tilt, and a low-sodium diet.

Stress induced ACTH release in capsaicin treated rats.

The plasma concentrations of adrenocorticotropic hormone (ACTH) in rats pretreated with capsaicin as neonates were compared with those of control rats pretreated with the capsaicin vehicle. Capsaicin pretreatment has been shown earlier to abolish the increase in plasma ACTH concentration induced by cold stress while not affecting that induced by restraint stress. In the present experiments rats pretreated with capsaicin showed the same increase in plasma ACTH concentration in response to an i.v. infusion of ovine-corticotropin releasing factor as control rats pretreated with the capsaicin vehicle. Intraperitoneal injection of formalin, surgical stress and intravenous infusion of (-)-isoprenaline increased plasma ACTH concentrations in control rats. In capsaicin pretreated rats the increase in plasma ACTH was significantly attenuated. It is concluded that capsaicin-sensitive sensory neurones mediate the activation of pituitary ACTH secretion in response to somatosensory stimuli. The function of the corticotroph cells of the anterior pituitary is not impaired by capsaicin treatment.

Intracerebroventricular infusion of a cyclic hexapeptide analogue of somatostatin inhibits hemorrhage-induced ACTH release.

This study examines the effect of intracerebroventricular infusion of the 'superactive' somatostatin (SRIF) analogue cycl--(N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe) on the plasma adrenocorticotrophic hormone (ACTH) response to hemorrhage in conscious sheep. Hemorrhage (15 ml/kg over 15 min) increased plasma ACTH from 55 +/- 20 to 815 +/- 148 pg/ml at 30 min (p less than 0.001). Infusion of the SRIF analogue intracerebroventricularly at 0.08 microgram/min for 10 min prior to and for 60 min after commencement of hemorrhage resulted in a partial inhibition of the plasma ACTH response. Infusion of the analogue at 0.8 microgram/min blocked the increase in plasma ACTH at 30 min. Plasma ACTH was 21 +/- 3 pg/ml as control and 66 +/- 47 pg/ml at 30 min. The SRIF analogue had no effect on plasma ACTH in the same animals in control experiments with no hemorrhage. These studies suggest that SRIF may act as a central inhibitor of ACTH release. The mechanism by which the SRIF analogue inhibits ACTH secretion is unknown but could involve inhibition of corticotropin-releasing factor release and/or an inhibition of ACTH release from the pituitary gland. The route of administration of the SRIF analogue and the finding that the SRIF analogue did not prevent systemic corticotropin-releasing factor stimulation of ACTH suggest an effect of the SRIF analogue in the hypothalamus.

Site at which angiotensin II acts to stimulate ACTH secretion in vivo.

To investigate the site at which angiotensin II (AII) acts to increase adrenocorticotrophic hormone (ACTH) secretion, the effects of intraventricular (IVT) or intravenous (IV) injection of the AII antagonist saralasin on the ACTH responses to IVT or IV injection of AII were examined in conscious male rats. AII does not cross the blood-brain barrier, but IVT as well as IV saralasin are known to prevent the binding of circulating AII to circumventricular organs. IV AII (0.2-200 ng) induced dose-related increases in ACTH secretion and a transient increase in the corticotrophin-releasing hormone (CRH) content of the median eminence. IVT injection of saralasin (10 micrograms) blocked the ACTH responses to IV AII. The same dose of saralasin given intravenously did not produce a comparable decrease in the ACTH response to IV AII. IVT injection of 1 and 10 ng AII increased plasma ACTH in a dose-related manner. The increase in plasma ACTH induced by IVT administration of angiotensin was not inhibited by IV infusion of saralasin (12 micrograms/kg/min). On the other hand IV infusion of this dose of saralasin abolished or reduced the ACTH response to IV injection of larger doses of AII. These data support the conclusion that circulating AII stimulates ACTH secretion by acting on the circumventricular organs to increase CRH secretion. They also suggest that AII receptors inside the blood-brain barrier as well as AII receptors in the circumventricular organs trigger increases in ACTH secretion.

Potentiation of vasopressin secretion by footshocks in rats.

Effects of footshocks (FS) on antidiuretic hormone (vasopressin, VP) in the plasma were studied in rats. Continuously applied FS of 60 s period with 5 ms pulses at 50 Hz frequency significantly increased VP as well as adrenocorticotrophic hormone (ACTH) in the plasma in a time- and shock intensity-dependent manner. Contrarily, the 50 Hz FS of 2 s period as repeated intermittently at every 15 s for over the period of 2, 10, and 30 min were much less effective for increasing plasma VP, whereas these intermittent FS increased plasma ACTH to an extremely high level. During the inter-shock intervals of 13 s between successive two shock periods rats exhibited a "freezing" behavior. Hypertonic saline or urethane injected I.P. immediately after termination of the intermittent FS significantly increased VP as well as ACTH in the plasma. These data clearly indicate that FS potentiate VP secretion and suggest the possibility that emotional stress may suppress the noxious stimuli-induced VP secretion.

Corticotropin-releasing factor-induced adrenocorticotropic hormone release in the sheep fetus: Blockade by cortisol

We administered intravenous injections of synthetic ovine corticotropin-releasing factor to chronically cannulated sheep fetuses and monitored fetal plasma adrenocorticotropic hormone and cortisol concentrations. The three doses of corticotropin-releasing factor used (10, 100, or 1000 ng · kg−1) increased fetal plasma adrenocorticotropic hormone; fetal plasma cortisol levels rose with the highest dose of corticotropin-releasing factor. Administration of corticotropin-releasing factor at these concentrations did not change fetal heart rate or blood pressure. Elevation of fetal plasma cortisol levels to 40 to 80 ng · ml−1 by infusions of the steroid blocked the adrenocorticotropic hormone responses to all three doses of corticotropin-releasing factor. These data indicate that corticotropin-releasing factor can increase plasma adrenocorticotropic hormone concentrations in the late-gestation fetus and that these increases can be blocked by elevations in fetal plasma cortisol levels within a physiologic range. This suggests that cortisol modulates adrenocorticotropic hormone release by the fetal pituitary gland late in gestation.

NIH conference. Clinical applications of corticotropin-releasing factor.

Ovine and human corticotropin-releasing factors (CRF) have similar potencies in causing adrenocorticotropic hormone (ACTH) and cortisol secretion in normal humans. Using long-acting ovine CRF (1 microgram/kg body weight as an intravenous bolus), we tested patients with Cushing's syndrome, adrenal insufficiency, and psychiatric conditions with mild hypercortisolism. Over 95% of hypercortisolemic patients with a pituitary adenoma responded with increases in plasma ACTH and cortisol concentrations; patients with the ectopic ACTH syndrome had no ACTH or cortisol responses; patients with ACTH-independent hypercortisolism of adrenal origin had low or undetectable plasma ACTH concentrations before and after CRF without any cortisol response. The differences in responses of patients with adrenal insufficiency of primary, pituitary, or suprapituitary type likewise suggest value of the CFR test in their differential diagnosis. The responses in the psychiatric patients should permit differentiation between Cushing's syndrome and hypercortisolism of psychiatric origin.

Plasma adrenocorticotropin and cortisol responses to submaximal and exhaustive exercise.

Adrenocorticotropic hormone (ACTH) levels were compared before and after submaximal and exhaustive isotonic exercise in six normally active college students (3 men and 3 women). Each subject participated in three experiments conducted at the same morning hour. Venous plasma was obtained before and immediately after 20-min runs at 65 and 80% of maximal O2 consumption (VO2 max) and after a run of gradually increasing work intensity which resulted in exhaustion (100% VO2 max) in 12.6 +/- 1.3 min. ACTH (mean +/- SE) was 48 +/- 15, 57 +/- 12, and 61 +/- 11 pg/ml before the 65, 80, and 100% VO2 max runs, and increased to 61 +/- 15 (NS), 128 +/- 18 (P less than 0.05), and 292 +/- 72 (P less than 0.05) pg/ml, respectively. Plasma glucose, growth hormone, cortisol, and lactic acid concentrations increased in a similar fashion. Cortisol and ACTH levels were significantly correlated at the higher levels of exertion: r = 0.18 (NS) for the 65% VO2 max run, r = 0.65 (P less than 0.05) for the 80% VO2 max run, and r = 0.64 (P less than 0.05) for the run to exhaustion. Both the change in ACTH with exercise and its postrun concentration were significantly related to the change in plasma lactic acid (r = 0.65, P less than 0.05) and the postrun plasma lactic acid (r = 0.64, P less than 0.05). We conclude that exercise-induced increases in plasma ACTH and their correlation with circulating cortisol depend on the intensity of isotonic exercise. Our observations also suggest that plasma lactic acid may influence ACTH release during exercise.

Effects of low level administration of dichlorvos on adrenocorticotrophic hormone secretion, adrenal cholesteryl ester and steroid metabolism

The effects of the organophosphate insecticide dichlorvos [ O, O-dimethyl- O-(2,2-dichlorvinyl phosphate)] on diurnal changes in the rat pituitary-adrenal axis have been studied. At 2 p.p.m. in the drinking water, it did not inhibit erythrocyte or plasma acetylcholinesterase activity. Dichlorvos ingestion markedly increased plasma adrenocorticotrophic hormone (ACTH) levels at the 9:00 a.m. sampling period, but did not further enhance the diurnally elevated ACTH levels at 5:00 p.m. Adrenal acyl-CoA:cholesterol acyltransferase (ACAT) and neutral cytosolic cholesterol ester hydrolase (CE hydrolase) were significantly inhibited at 9:00 a.m. while at 5:00 p.m. the enzymes were stimulated. Adrenal cholesterol ester levels were depressed at 9:00 a.m. and increased at 5:00 p.m. Adrenal free cholesterol levels did not change. Neither adrenal nor plasma corticosterone levels were significantly altered after dichlorvos. The results indicate that significant alterations in adrenal cholesterol ester levels may take place without corresponding changes in plasma and adrenal corticosterone levels.

Cortisol Production by Testicular Tumors in Adrenogenital Syndrome

A patient had bilateral testicular tumors complicating the adrenogenital syndrome. This is the first such instance of the complication fully documented to have occurred with the simple virilizing type of congenital virilizing adrenal hyperplasia (CAH) and the first demonstration of cortisol synthesis by the testicular tumors associated with this disorder. A review of the literature concerned with the origin of these testicular tumors suggests that they arise primarily from testicular interstitial cells under the stimulus of increased plasma adrenocorticotropic hormone (ACTH).