Inflammatory Cell Findings in the Female Rabbit Heart and Stress-associated Exacerbation with Handling and Procedures Used in Nonclinical Studies.

Despite the use of rabbits in biomedical research, including regulatory toxicology and cardiovascular studies, little data exist on heart findings in this species. This study was designed to document myocardial findings in female rabbits and the impact of study-related procedures typical for vaccine toxicology studies. One hundred and forty 6- to 8-month-old female New Zealand White rabbits were divided equally into 2 groups, high and low study procedure groups (group 1 and group 2, respectively). All animals received intramuscular (IM) injections of sterile saline every 2 weeks for 5 times and were necropsied 2 days after the final IM injection. Clinical chemistry, hematology, and urinalysis were evaluated. Blood for stress biomarkers (norepinephrine, epinephrine, cortisol, and corticosterone), C-reactive protein, cardiac troponin I, and creatine kinase were collected at time 0 (just before dose administration) and then at 4, 24, and 48 hr after dose administration in group 1 only. Hearts were assessed histologically. Focal to multifocal minimal inflammatory cell infiltrates were common (∼80%), particularly in the left ventricle and interventricular septum, and were similar to the types of infiltrates identified in other laboratory animal species. Additionally, study-related procedures elevated serum stress biomarkers and exacerbated the frequency and severity of myocardial inflammatory cell infiltrates.

Glucocorticosteroids as markers of death from hypothermia.

In the course of hypothermia, biochemical changes occur that are associated with stimulation of protective thermogenic mechanisms as well as mobilization of internal energy resources mediated by the hormone system. The objective of the investigation was the assessment of validity of determinations of cortisol, cortisone and corticosterone as hypothermia markers in cases of fatal hypothermia combined with concomitant insobriety of the victims. The experimental group consisted of blood samples collected in the course of medico-legal autopsies of 23 hypothermia victims. The controls included blood samples originating from 34 victims of violent sudden deaths (deaths by hanging and traffic road accidents at the scene) and from ten individuals deceased after prolonged agony in consequence of post-traumatic subdural hematomas. In both groups, three subgroups were distinguished that included cases with ethanol levels within the following ranges: 0.0-0.99, 1.0-2.99 and ≥3.0‰. The comparison of determination results showed that irrespectively of blood ethanol concentration, cortisol, cortisone and corticosterone levels seen in hypothermia victims were significantly higher as compared to the controls (P<0.001).

Hypertension and virilization caused by a unique desoxycorticosterone- and androgen-secreting adrenal adenoma.

We describe a rare androgen and desoxycorticosterone (DOC)-secreting adrenal tumor in a non-Cushingoid 14 year-old Haitian girl with secondary amenorrhea, hypertension and virilization. Her steroid pattern simulated an 11 beta-hydroxylation defect with notable elevation of adrenal androgens, 11-desoxycortisol (S), DOC, 17 alpha-hydroxyprogesterone and pregnenelone. Exogenous ACTH stimulated steroidogenesis. A CAT scan unfortunately failed to delineate an adrenal mass. Dexamethasone (DEX) was administered, therefore, which partially suppressed androgen levels, reduced DOC and S by 80% and 82% respectively, and normalized blood pressure. Nevertheless, the response to glucocorticoid was incomplete and an MRI was obtained, which revealed a right adrenal tumor. Post surgery, the patient promptly resumed menses and became normotensive. This case illustrates that ACTH and DEX cannot reliably differentiate tumor from hyperplasia, whereas the simultaneous increase of delta 4 and delta 5 steroids, present here, may favor a tumor. This case also allows speculation that the hypersecretion of DOC may result from inhibition of 11 beta-hydroxylase activity by excess androgens. The importance of appropriate imaging for diagnosis is underscored.

Effects of altered dietary sodium intake on hormonal profiles in salt-sensitive hypertensive rats.

Blood pressure and selected putatively influential hormones were measured in Brattleboro rats which were without diabetes insipidus and which were subjected to various manipulations in dietary sodium intake. Rats fed a control diet from weaning to 16 weeks of age showed a slow increase in blood pressure whereas rats fed a sodium-enriched diet for the same period exhibited sustained hypertension (115 +/- 3 versus 169 +/- 5 (S.E.M.) mmHg). In animals fed a sodium-enriched diet plasma concentrations of antidiuretic hormone (ADH) were significantly increased from 55 +/- 8 to 108 +/- 5 fmol/l. Rats fed the control diet from weaning (group A) and subsequently maintained on that diet or changed to a sodium-enriched diet or sodium-deficient diet showed no differences in their blood pressure. Plasma hormone concentrations were similar in these groups, with the exception of aldosterone suppression in rats switched from control to a sodium-enriched diet (0.26 +/- 0.04 versus 0.08 +/- 0.03 nmol/l; P less than 0.001). Animals fed the sodium-enriched diet from weaning to 16 weeks of age (group b) and either maintained on that diet or changed to a control diet showed little change in their established hypertension. Transfer to the control diet was associated with increased plasma renin concentrations (PRC) (13.8 +/- 2.1 to 122.6 +/- 6.2 nmol/l) and plasma aldosterone concentrations (0.04 +/- 0.01 to 0.08 +/- 0.01 nmol/l; P less than 0.001) but corticosteroids and ADH concentrations were unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

[Changes in the functional state of the adrenal glands in experimental bronchospasm in dogs]. / Izmeneniia funktsional'nogo sostoianiia nadpochechnikov pri éksperimental'nom bronkhospazme u sobak.

Changes in the adrenal functional state were revealed during the development of bronchoconstriction induced by allergen inhalation in 7 dogs sensitized with ovalbumin. The decrease in V1 (expiratory flow-volume) on an average by 58% was noted after inhalation of 1000 microG of ovalbumin. The significant decrease in II-hydroxycorticosteroids (II-OCS), adrenaline, noradrenaline, dopamine, and a tendency to the increase in histamine content were observed in the venous blood plasma. The decrease in the adrenaline content in plasma apparently contribute to the development of early bronchoconstrictor response, and the decrease in II-OCS maintain the development and the progress of late bronchoconstrictor response.

Adrenal steroidogenic function in a black and Hispanic population with precocious pubarche.

Adrenal steroidogenic function was evaluated in 34 children with precocious pubarche (PP; onset of pubic hair, less than 8 yr in girls and less than 9 yr in boys). The adrenal steroid response to an iv bolus of ACTH-(1-24) in the patients (aged 9 months to 9 7/12 yr) was compared to that in 16 normal controls (prepubertal, n = 9; Tanner stage II pubic hair, n = 7). The patient population consisted of 20 Hispanics (17 from the Dominican Republic), 13 black Americans, and 1 black Haitian. All patients had normal stimulated levels of 17-hydroxyprogesterone (17-OHP), 11-deoxycortisol (compound S), and desoxycorticosterone, thereby ruling out 21-hydroxylase deficiency and 11 beta-hydroxylase deficiency, respectively. To evaluate for the presence of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) deficiency, the patients were classified on the basis of their 60-min delta 5-17-hydroxypregnenolone/17-OHP (delta 5-17P/17-OHP) ratio [PP1 (n = 13), less than or equal to 2 SD of Tanner I controls; PP2 (n = 17), greater than 2 SD above Tanner I controls and less than or equal to 2 SD Tanner II controls; and PP3 (n = 4), greater than 2 SD above Tanner II controls; 2.1 +/- 1.0, 6.1 +/- 1.7, and 16.1 +/- 3.3 for PP1, PP2, and PP3, respectively. delta 5-17P/17-OHP for PP1 vs. PP2, PP2 vs. PP3, and PP1 vs. PP3 were significantly different (P less than 0.05) by analysis of variance and multiple comparison testing using the Student-Newman-Keuls procedure. The four patients in PP3 were considered to have a possible nonclassical 3 beta-HSD deficiency. This diagnosis was supported by the fact that these patients had the greatest increment in delta 5-17P and dehydroepiandrosterone (DHEA) levels as well as the highest stimulated delta 5-17P/cortisol (delta 5-17P/F) ratio among the patient groups. In contrast to the ACTH-stimulated androgens there were no differences in the baseline delta 5-17P/170HP or androgens among the patient groups. Additionally, the 60-min delta 5-17P/17-OHP within the patient groups was highly correlated with the 60 min-values for delta 5-17P, DHEA, DHEA/delta 4-androstendione, and delta 5-17P/F. In the children with PP the mean bone age/chronological age (BA/CA) was 1.27 +/- .27, the mean BA/height age (BA/HA) was 1.09 +/- 0.25, and the mean HA/CA was 1.18 +/- 0.17. No differences were noted between the patient population groups in mean BA/CA, mean BA/HA, or mean HA/CA.(ABSTRACT TRUNCATED AT 400 WORDS)

Splanchnic nerve stimulation modulates steroid secretion in hypophysectomized dogs.

To test whether or not splanchnic neural input to the adrenal gland affects secretion of steroids from the adrenal cortex, the thoracic splanchnic nerve was electrically stimulated in pentobarbital-anesthetized dogs after hypophysectomy and replacement with physiological concentrations of ACTH. An adrenal vein cannula was placed to permit measurement of cortisol, corticosterone, 11-deoxycortisol, epinephrine and norepinephrine secretion rates and adrenal blood flow. Plasma ACTH was measured and the presentation rate of ACTH was calculated as the product of plasma ACTH concentration and adrenal plasma flow. Dogs were infused initially with ACTH for 60 min at 2 ng/min followed by infusion for 60 min at 10 ng/min. Within each infusion period, the distal end of the nerve was stimulated (20 V; 0.5-ms pulse duration) at 4 and at 20 Hz for 10 min each. Nerve stimulation resulted in a frequency-dependent increase in mean arterial pressure, in epinephrine and norepinephrine secretion and in adrenal blood flow. Arterial ACTH remained constant during nerve stimulation; however, increased adrenal blood flow resulted in increased presentation rate of ACTH to the adrenal. Cortisol secretion increased in response to nerve stimulation at 4 and 20 Hz during infusion of 2 and 10 ng/min ACTH and occurred prior to changes in presentation rate of ACTH. Corticosterone secretion also increased after stimulation at both frequencies, but the response was observed only during infusion of 10 ng/min ACTH. In contrast, 11-deoxycortisol decreased after nerve stimulation at 4 Hz but showed no response after stimulation at 20 Hz during infusion of 2 and 10 ng/min ACTH.(ABSTRACT TRUNCATED AT 250 WORDS)

[Effects of o,p'-DDD on pituitary-gonadal function in patients with Cushing's disease].

O,p'-DDD has a cytotoxic action and inhibits the cholesterol side chain cleavage enzyme, 11 beta-hydroxylase, 3 beta-hydroxysteroid dehydrogenase coupled with delta 5 to 4 isomerase and 21-hydroxylase of the adrenal cells. However, the effects of o,p'-DDD on gonadal steroidogenesis are still unknown. In the present study, the effects of o,p'-DDD on Plasma cortisol, pregnenolone, 17 alpha-hydroxypregnenolone (17-OH-pregnenolone), progesterone, 17 alpha-hydroxyprogesterone (17-OH-progesterone), 11-deoxycorticosterone (DOC), corticosterone, dehydroepiandrosterone (DHEA), delta 4-androstenedione (androstenedione), estradiol, and LH and FSH were investigated in 3 patients with Cushing's disease before and after the administration of o,p'-DDD. The results are presented here. In Case 1 (18 yr old female) who had had secondary amenorrhea for 2 years, the plasma levels of cortisol, pregnenolone, 17-OH-pregnenolone, DHEA, androstenedione, testosterone, estradiol and corticosterone were elevated. The basal levels of plasma LH and FSH and the responses of both gonadotropins were lower than those of women with eumenorrhea. The plasma levels of progesterone, DHEA and testosterone decreased to normal 2 months after the beginning of the administration of o,p'-DDD. She restored menstrual cycles ranging from 40 to 50 days 3 months after the administration of o,p'-DDD, but with anovulatory bleeding. She showed a biphasic body temperature pattern with plasma progesterone and estradiol levels indicating corpus luteum formation 11 months after the start of the treatment, when plasma cortisol as well as progesterone and androgen were reduced to normal. The basal levels of FSH and LH and responses of these gonadotropins were slightly improved at that time. The plasma levels of cortisol, DHEA and androstenedione were high in Case 2 (38 yr old male) and Case 3 (45 yr old male), whereas plasma testosterone level was normal in Case 2 and low in Case 3. The plasma levels of these 3 steroids were normalized 28 days after the beginning of the o,p'-DDD administration. These results suggest that o,p'-DDD does not interfere with gonadal steroidogenesis in Cushing's disease.

Positive inotropic effects of an ACTH analogue (ACTH 1-17) on myocardial performance.

The aim of the present investigation was to study the effects of a single 100-micrograms i.v. administration of the synthetic heptadecapeptide [beta-Ala1-Lys17]ACTH1-17-4-amino-N-butylamide (ACTH 1-17) on the left ventricular performance. The systolic time intervals (STI) were recorded in 20 healthy adult young subjects (10 treated with ACTH 1-17 and 10 receiving placebo) before as well as 20, 40, 60 and 80 min after the i.v. ACTH 1-17 or placebo infusion. The STI were recorded immediately after blood withdrawal for measuring cortisol, aldosterone, adrenaline and noradrenaline plasma levels. A highly significant statistical difference was demonstrated for preejection period (PEP) and preejection period/left ventricular ejection time (PEP/LVET) ratio between subjects treated with ACTH 1-17 and subjects receiving placebo. As expected, a significant increase of cortisol and aldosterone plasma levels was observed in subjects treated with ACTH 1-17. The difference of adrenaline and noradrenaline plasma levels was statistically highly significant between subjects treated with ACTH 1-17 and those receiving placebo. The lack of increase in PEP and PEP/LVET ratio recorded in subjects treated with ACTH 1-17 is consistent with an increased left ventricular contractile performance. An increased plasma catecholamine release is postulated as the mechanism of this improvement.

Effect of metoclopramide on the secretion of aldosterone and other adrenocortical steroids.

The aim of this study was to determine the effect of metoclopramide, a dopamine antagonist, on the secretion of aldosterone and other adrenocortical steroids in normal subjects. An i.v. bolus injection of 10 mg of metoclopramide significantly increased the plasma PRL, plasma aldosterone and 18-hydroxycorticosterone, but the plasma renin activity, plasma deoxycorticosterone, corticosterone and cortisol remained unchanged. The changes in plasma aldosterone induced by metoclopramide were significantly correlated with the basal levels of plasma aldosterone and renin activity. These results suggest that the response of plasma aldosterone to metoclopramide in normal subjects is influenced by the basal activity of renin-angiotensin-aldosterone system and the late step of aldosterone synthesis is stimulated by metoclopramide.

Fetal-maternal gradients of steroid hormones in the nine-banded armadillo (Dasypus novemcinctus).

Gonadal and adrenal steroid hormone levels in plasma were measured in pregnant, non-pregnant and fetal armadillos. Progesterone demonstrated the largest placental gradient with levels 6 to 10-fold higher in the fetus. Testosterone levels were higher in male and lower in female fetuses, when compared to the respective maternal serum values. Dehydroepiandrosterone, and cortisol were consistently high in maternal as compared to matched fetal serum samples whereas the reverse was true for androstenedione. Tissue incubations with labelled pregnenolone indicated the major source of progesterone production to be the fetal adrenal whereas the fetal testes demonstrated a major conversion product consistent with dehydroepiandrosterone.

Genetically mediated resistance to naturally occurring aortic sclerosis in spontaneously hypertensive as against Sprague-Dawley and Wistar-Kyoto breeder rats.

Male and female, normotensive, Sprague-Dawley (S-D), Wistar-Kyoto (WKy), and spontaneously hypertensive rats (SHR) were bred repeatedly until the females had given birth to and nursed 6 litters of pups. At the close of the 2nd, 4th and 6th breeding, breeder males and females, along with celibate males and females of equal age, were killed. S-D and WKy breeder rats manifested progressively increasing adiposity and high blood pressure with each successive breeding; breeder SHR showed mild exacerbation of their pre-existing high blood pressure. Adrenocortical hyperplasia and thymus-gland involution suggested increasing pituitary-adrenal activity in breeder rats. Circulating aldosterone levels decreased with repeated breeding in parallel with increased deoxycorticosterone and corticosterone secretion. The repeatedly bred normotensive rats manifested worsening aortic sclerosis as against little or no aortic sclerosis in the repeatedly bred SHR. Breeder SHR developed fibrinohyalin intimal lesions limited exclusively to the arterioles of the testis and ovary. Virgin rats did not develop any vascular disease. It is suggested that a diverse spectrum of adrenal steroids in breeder HSR combined with genetic direction control the morphogenesis of arterial disease in breeder SHR.

[Stress and aging (author's transl)]. / Stress und Altern.

Under the influence of stress the function of hypothalamic-pituitary system seems to show aging changes, whereas the adrenocortical function is not changed in spite of degenerative morphological changes in aging. By the performance and interpretation of experiments it is necessary to pay attention to the different reaction of young and old animals.

[Biochemical and hematological changes in sows during estrus]. / Biochemické a hematologické zmeny u prasnic v údobí ríje.

After the second and fourth parturition of piglets, ten clinically healthy sows, weaned on the second day of life, were subjected to examination two to three days before heat, during heat (defined by typical changes on the outer genitals and immobilization in the presence of a boar) and two days after insemination. During the morning hours, four hours after the last feeding, blood was taken from V. cava cranialis. Seventeen parameters were determined in whole blood and in the blood serum. In the period of oestrus, compared with the period two to three days before this period and two days after insemination, a marked increase was observed in the concentration of the serum levels of 11-hydroxycorticosteroids, iron, and in the activity of alanine aminotransferase. The activity of aspartate aminotransferase was increased in heat only in comparison with the period of the two days after insemination. The concentration of haemaglobin in whole blood was significantly increased in comparison with the period before oestrus and after insemination. Further, in the heat period -- as compared with the time before it -- a considerable drop was observed in the content of inorganic phosphorus and vitamin A. The possible mechanism of the occurrence of other changes is discussed.

[Radioimmunologic method of determining 11 steroids in small samples of monkey blood plasma]. / Radioimmunologicheskii metod opredeleniia 11 steroidov v malom ob''eme plazmy krovy obez'ian.

A radioimmunological method is described for simultaneous estimation of hestagenes, estrogenes, androgenes and their precursors in small samples of blood plasma obtained from peripheric blood of hamadryads (Papio hamadryas) and macaques (Macaca rhesus). Use of highly specific antisera and of chromatographic isolation of each steroid on columns with celite enabled to estimate the concentration of 11 steroids in 1.1 ml of blood plasma with high accuracy. Standard curve and analysis of its linearity were carried out in the coordinate system logit-log.