Adrenal Epinephrine Depletion Research Articles

Catecholamines in Experimentally Growth‐Retarded Rat Fetus

This study was designed to evaluate the sympathoadrenal system in rat IUGR fetuses prepared by the Wigglesworth method. Samples were obtained on day 20 of gestation. In the amniotic fluid, concentrations of norepinephrine (NE) and particularly epinephrine (E) were significantly higher in IUGR fetuses than in normally developed fetuses (NE: p less than 0.05, E: p less than 0.01). L-Dopa and three catecholamines in the adrenal glands were decreased in IUGR fetuses. The mol ratios (L-dopa: dopamine: NE: E) were 1: 4: 35: 63 in IUGR fetuses and 1: 5: 39: 87 in normal fetuses. The ratio for epinephrine to L-dopa was significantly lower in IUGR fetuses (p less than 0.05). Adrenal phenylethanolamine-N-methyltransferase activities showed no difference between the two groups. From these results, adrenal epinephrine synthesis in IUGR fetuses was thought to be normal. Because of the depletion of adrenal epinephrine in IUGR fetuses, the plasma epinephrine concentrations were significantly lower after acute hemorrhagic shock (p less than 0.01). However, the plasma concentrations of dopamine and norepinephrine were significantly higher (dopamine: p less than 0.01, NE: p less than 0.001) in IUGR fetuses. These findings suggest that the hypersecretion of adrenal epinephrine is a protective response to chronic stress and the decrease of adrenal epinephrine may be a causative factor for the reduced reserves in the defense mechanism of IUGR fetuses.

Modulation of insulin activity by hydrochloride salts.

The influence of hydrochloride salts of various amino acids and other drugs on the activity of exogenously administered insulin was studied in the rat. Insulin activity was assessed in terms of insulin's effects on lowering of blood glucose and nonesterified fatty acids (NEFA), release of adrenaline (epinephrine) from the adrenal medulla, and the elevation of urinary catecholamines. Insulin alone produced a 60-70% fall in blood glucose and NEFA, 70% depletion of adrenal epinephrine, a 10-fold increase in urinary epinephrine, and a 2-fold elevation of adrenal dopamine. Concurrent administration of hydrochloride salts completely abolished all clinical manifestations that usually accompany insulin injection. Serum glucose and NEFA remained unchanged, the fall in adrenal epinephrine was blocked, and the increase in urinary catecholamines was abolished. These data suggest that certain hydrochloride salts possess an anti-insulin property. They decrease tissue responsiveness to insulin, thus rendering its action ineffective. The implication of these findings on the treatment of diabetic subjects requiring insulin therapy is discussed.

Development of cardiac sympathetic and adrenal-medullary responses in borderline hypertensive rats

Borderline hypertensive (BHR) rats are the first generation offspring of a cross of spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) normotensive rats. In adulthood, BHRs have systolic blood pressures in the 140–160 mm Hg range. If subjected to chronic stress paradigms, however, BHRs develop sustained and permanent elevations in systolic blood pressure (180–200 mm Hg). In the present study, we examined the functional development of cardiac and adrenal medullary responses to reflex activation of the sympathetic nervous system in preweanling BHR and WKY rats. Pups of the two groups were injected with insulin or saline at 4, 8, 12, or 16 days of age and sacrificed 3 h later. Insulin produces an acute lowering of blood glucose which is attended by a centrally mediated increase in sympathetic activity. The induction of ornithine decarboxylase (ODC) activity in heart and the depletion of epinephrine from the adrenal medulla were biochemical indicators of functional sympathetic neurotransmission. WKY and BHR pups had similar levels of cardiac ODC activity under basal conditions and following administration of insulin. In contrast, BHRs had higher amounts of adrenal norepinephrine and epinephrine from 4 to 16 days of age and greater depletion of adrenal epinephrine following insulin administration at 8, 12 and 16 days of age. These findings indicate that BHRs have a greater capacity for catecholamine biosynthesis, storage and release in the adrenal medulla during the preweanling period compared to age-matched normotensive WKY controls. This alteration in the adrenal medulla during the preweanling period may contribute to the susceptibility of adult BHR rats to stress-induced hypertension.

Regulation of adrenal chromaffin cell development by the central monoaminergic system: Differential control of norepinephrine and epinephrine levels and secretory responses

In the mature rat, reflex sympathetic stimulation by insulin-induced hypoglycemia resulted in profound depletion of adrenal epinephrine, and to a lesser extent, norepinephrine. In the developing rat, insulin evoked little or no secretory response from the adrenals prior to 1 week of age. By 7 days, a moderate depletion of epinephrine was seen and the magnitude of the response increased with age. In contrast, during the first 3 weeks of postnatal life, insulin failed to deplete norepinephrine from the adrenal medulla and in fact, produced an increase. This chiefly resulted from de novo biosynthesis of the amine, as the rise was blocked by alpha-methyl-p-tyrosine. These results suggest that the ontogeny of the two chromaffin cell types (norepinephrine and epinephrine-containing) in the adrenals and the maturation of their secretory responses are under differential regulation. Because descending supraspinal catecholaminergic and serotonergic systems have been implicated to play key roles in regulating adrenomedullary function, the ontogeny of the sympatho-adrenomedullary axis was evaluated after neonatal central lesioning with 6-hydroxydopamine or 5,7-dihydroxytryptamine. 6-Hydroxydopamine resulted in a preferential elevation of epinephrine in the developing adrenals as well as an increase in the responsiveness of the adrenals to reflex stimulation by insulin; the mature secretory pattern was obtained as early as at 4 days postnatally for epinephrine and 9 days for norepinephrine. In contrast, 5,7-dihydroxytryptamine led to a preferential reduction of basal adrenal norepinephrine content. These results suggest that central monoaminergic neurons impose both inhibitory and facilitatory influences on the maturation of specific chromaffin cell types in the adrenal medulla and that supraspinal catecholaminergic inputs may play a role in determining the set-point for reflex adrenomedullary responses.

Ontogeny of functional sympathetic innervation to the heart and adrenal medulla in the preweanling rat

The development of functional sympathetic innervation to the heart and adrenal medulla was examined in Long-Evans and Sprague-Dawley rats during the preweanling period. Insulin-induced hypoglycemia was used to produce a centrally mediated activation of the sympathetic nervous system and the induction of ornithine decarboxylase activity in the heart and the depletion of adrenal epinephrine were used as indices of sympathetically mediated responses in these target organs. First, dose by time response curves were performed in 11–13 day old Sprague-Dawley pups to establish an insulin dose which would simultaneously produce stimulation of cardiac ornithine decarboxylase activity and depletion of adrenal medullary epinephrine at an appropriate time post-injection. This dose of insulin was then administered to pups of different postnatal ages to determine the onset of functional sympathetic innervation to these target organs. Significant increases in heart ornithine decarboxylase activity were seen by two postnatal days of age in both rat strains examined. In contrast, adrenal epinephrine depletions were not found until 8–12 postnatal days of age. These results indicate that functional sympathetic neurotransmission to the heart is present in the first few days after birth, and this precedes the onset of sympathetic control of adrenal epinephrine release, which matures near the end of the first postnatal week in laboratory rats.

Sympathetic responses of the heart and adrenal medulla in developing Dahl hypertensive rats

Functional development of the sympathetic nervous system was examined in inbred Dahl salt-sensitive (S/JR) and salt-resistant (R/JR) rats by assessing cardiac and adrenal medullary responses to insulin-induced hypoglycemia at 2, 4, 8, 12, and 16 days of age. Heart ornithine decarboxylase (ODC) activity and adrenal catecholamine content were measured in pups of the two strains 3 hours after administration of either saline or insulin. The centrally mediated increase in sympathetic outflow caused by insulin-induced hypoglycemia was attended by induction of heart ODC activity and depletion of adrenal epinephrine (EPI). No significant differences were found overall between R/JR and S/JR strains with regard to either heart ODC activity or adrenal epinephrine. This was true for basal values obtained from saline-injected pups as well as for measures from insulin-injected pups. Functional innervation of the heart was present in pups of both strains as early as 2 days of age, while in the adrenal medulla a significant response to stimulation was not detected until 8 days of age. While the susceptibility for hypertension in the salt-sensitive animals may well be linked to increased sympathetic tone, the present findings indicate that S/JR rats do not have an accelerated development or a hyperresponsiveness of sympathetic input to either the heart or the adrenal medulla during the pre-weanling period.

Trimethyltin as a selective adrenal chemosympatholytic agent in vivo: Effect precedes both clinical and histopathological evidence of toxicity

Trimethyltin (TMT) is a potent neuronotoxiciant but there is little data regarding its systemic effects. In this study, female BALB/c mice were administered either 0.9% saline or 2.75 mg TMT/kg intraperitoneally (i.p.). The animals were then housed in room air or in glass chambers flushed with either 10%, 40%, or 100% oxygen. Mice were sacrificed at 4,8,24, and 48 h after treatment and adrenals analyzed for various neurotransmitters by ion-pairing HPLC with electrochemical detection. In addition, adrenal S-adenosylmethionine (SAM) and blood ketone bodies were determined Sections of adrenals were evaluated by electron microscopy for histopathological changes. In vivo treatment with the toxicant resulted in a significant decrease in adrenal epinephrine and norepinephrine levels as early as 8 h following treatment. This effect preceded the appearance of both clinical signs and histopathological changes in the hippocampus by 12–24 h. With exposure to TMT in room air, mouse adrenal content of epinephrine fell from 1861.3 ± 97.3 ng/4 mg to 1493.3 ± 137.0 ng/4 mg while norepinephrine levels fell from 779.6 ± 32.3 ng/4 mg to 503.4 ± 44.3 ng/4 after 8 h. Supplementation with 40% oxygen did not attenuate this effect but in the case of mice treated with TMT and housed in 100% oxygen for 48 h, actually exacerbated the adrenal epinephrine depletion. Housing in approximately half normal atmospheric oxygen (10%) neither prevented nor enhanced the effects of TMT. The epinephrine/norepinephrine ratios were: control, 2.44; TMT (room air), 1.56; TMT (10% O 2), 1.72; TMT (40% O 2), 1.44; TMT

Adrenal medullary responses to insulin-induced hypoglycaemia in the young rat. Influence of thyroid hormones

The adrenal medulla of normal, hypothyroid and hyperthyroid young rats was stimulated by insulin-induced hypoglycaemia. In normal rats, insulin-induced adrenal epinephrine secretion increases during the first 10 days of post-natal life. Hypothyroidism retards the development of adrenal response; hyperthyroidism facilitates the development of this response. At 14 days, when insulin-induced adrenal epinephrine depletion is the same for all groups, the recovery of adrenal catecholamines stores after depletion is linear and takes less than 48 h. Recovery rate is slightly slower for hyperthyroid rats than for either hypothyroid or control rats at 14 days. Following epinephrine depletion, adrenal tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DBH) activities are increased for a few days in the control rats, corresponding to a transsynaptic induction. Hypothyroidism impairs TH induction and completely suppresses DBH induction; hyperthyroidism impairs TH induction, but has no effect on DBH induction. These data show that the various processes related to CA synthesis, in the adrenal medulla of the developing rat, are controlled in different ways by the thyroid hormones.

Adrenal epinephrine depletion after insulin-induced hypoglycaemia in young hypothyroid rats

We studied the influence of the thyroid hormones on the development of the ability of the adrenal glands to release epinephrine after stimulation by insulin-induced hypoglycaemia in the young rat. In animals rendered hypothyroid from birth, this development is delayed as compared to control rats. Administration of thyroxin to these animals restores the ability of the adrenals to deplete epinephrine. These results may indicate an influence of the thyroid hormones on the development of the functional innervation of the adrenal medulla in the young rat.

Adrenal catecholamines content in fetal and newborn rats.

The adrenal epinephrine content of newborn rats delivered by caesarian section on day 21.5 of gestation and maintained at thermal neutrality (37 degrees C) did not decrease over the 6 h following birth in spite of a transient phase of hypoglycemia. Cold exposure (30 or 24 degrees C) of the newborn rats immediately after birth did not decrease their adrenal epinephrine content. A decrease in adrenal epinephrine content is observed in 21.5-day-old rat fetuses after insulin-induced hypoglycemia for 4 h, after 2-deoxy-D-glucose injection or after anoxia. In 20.5-day-old rat fetuses, insulin-induced hypoglycemia for 4 h or 2-deoxy-D-glucose did not decrease the adrenal epinephrine content of the fetus. No variation was observed in norepinephrine content of the adrenal gland in all these situations. It is concluded that spontaneously occurring hypoglycemia or cold exposure are not sufficient stimuli to induce adrenal epinephrine depletion. It is suggested that hypoxia is perhaps the physiological stimulus for epinephrine secretion in newborn rats.

Effect of Hypophysectomy on Immobilization-Induced Elevation of Tyrosine Hydroxylase and Phenylethanolamine-N-methyl Transferase in the Rat Adrenal

The depletion of adrenal epinephrine observed after immobilization stress in normal rats is even greater in hypophysectomized rats. The activities of adrenal tyrosine hydroxylase (TH) and phenylethanolamine-N-methyl transferase (PNMT), enzymes in the epinephrine biosynthetic pathway, are decreased following hypophysectomy. After repeated immobilization TH levels in hypophysectomized rats increase significantly but do not reach control levels. In hypophysectomized rats PNMT levels remain markedly decreased with repeated immobilization. When ACTH is administered to hypophysectomized rats before each period of immobilization there is less depletion of adrenal epinephrine and levels of TH and PNMT approach those found in sham-hypophysectomized immobilized rats. When dexamethasone is given prior to immobilization there is again less depletion of adrenal epinephrine and an increase in PNMT levels but no change in TH levels. Thyroxine does not increase epinephrine or enzyme levels in hypophysectomized immobilize...

Effect of DDT on the urinary excretion of epinephrine and norepinephrine by rats

DDT in an oral dose of 100 mg/kg increases the excretion of norepinephrine in the urine, whereas a dose of 150 mg/kg increases excretion of norepinephrine and epinephrine. Depletion of adrenal epinephrine indicates that the adrenal glands are the source of the epinephrine excreted. Increased urine output follows an oral dose of 116 mg/kg of p,p′-DDT or 150 mg/kg of technical grade DDT.