Effect of steroids and diethylstilbestrol on cocaine toxicity, plasma concentrations and urinary excretion.

Comparative experiments were performed on female rats given pregnenolone-16 alpha-carbonitrile (PCN), spironolactone, triamcinolone, estradiol or diethylstilbestrol to study correlations between the toxic effect of cocaine, its blood clearance and its urinary excretion. PCN and estradiol significantly reduced the toxicity of the drug as well as its plasma levels and urinary excretion. Diethylstilbestrol and spironolactone, unlike triamcinolone, also diminished cocaine toxicity and plasma concentrations.

Hepatic intracellular distribution of pregnenolone-16alpha-carbonitrile and its influence on adenyl cyclase activity in rat liver cells.

Pregnenolone-16alpha-carbonitrile (PCN) enhanced adenyl cyclase activity in the liver cells of female Sprague-Dawley rats. Injection of 14C-PCN and fractionation of hepatocytes into nuclei, mitochondria, total ribosomes, endoplasmic reticulum (ER) membranes, cytosol and plasma membranes revealed that after 4 h there was a preferential localization of the cyanosteroid in ER membranes. Total ribosomes and cytosolar proteins seemed to contain less PCN after 4 h, the optimal time for maximal penetration and intracellular establishment. On the other hand, PCN was localized preferentially in plasma membranes after 2 h and this diminished with time. Only trace amounts of the cyanosteroid were found in the nuclei and mitochondria, from the time of its intracellular introduction to the time of its apparent removal from the hepatocyte.

Actions of prednisolone acetate, pregnenolone-16alpha-carbonitrile, and triamcinolone upon drug resistance and metabolism: a comparative study.

In female rats, pretreatment with prednisolone acetate diminished the duration of zoxazolamine-induced paralysis as well as its plasma concentrations and increased significantly the in vitro metabolism of zoxazolamine and ethylmorphine. These actions of prednisolone were compared with those of equimolar amounts of pregnenolone-16alpha-carbonitrile (PCN) (a known microsomal enzyme inducer) and of triamcinolone (an agent that reduces the sensitivity of the body to drugs although not via microsomal enzyme induction). Prednisolone proved to be a strong drug-metabolizing enzyme inducer but it was less potent than PCN.

Temperature-dependence of stress-induced hepatic autophagy.

In rats, restraint for 48 h elicits hepatic glycogen depletin, autophagy and other ultrastructural changes (e.g. mitochondrial enlargement and rough endoplasmic reticulum disorganization) associated with marked hypothermia. By restoring the body temperature of these animals, all the hepatocytic alterations are abolished.

Effects of chronic stress on pituitary hormone release induced by combined hemi-extirpation of the thyroid, adrenal and ovary in rats.

Morphologic and hormonal changes, induced by combined ablation of a thyroid lobe, one adrenal and one ovary, were studied over a 15-day period in rats, some of whom were subjected to 8 h of daily immobilization. The compensatory hypertrophy (CH) of the contralateral glands in non-stressed animals was associated with a significant increase in the plasma levels of LH (from the 1st to the 10th day), prolactin (PRL, from the 3rd to the 6th day), FSH (on the 3rd day) and corticosterone (from the 6th to the 15th day), whereas GH titers were not altered. Immobilization for 1, 3, 6, 10 or 15 days inhibited the b.w. gain, induced involution of the thymus, enhanced compensatory enlargement of the adrenal, and blocked the CH of the ovary and, to a lesser degree, of the thyroid. This chronic stressor produced a marked rise in plasma corticosterone, antagonized the surge of PRL, FSH and LH, and decreased the plasma levels of GH. On the basis of these morphological and hormonal variations, it appears that severe chronic stress in hemi-thyroidectomized-adrenalectomized-ovariectomized animals further increases the ACTH response but antagonizes the increased secretion of the other pituitary hormones.

Influence of steroids and stress on toxicity and disposition of tetraethylammonium bromide.

In female rats, pretreatment with dexamethasone acetate or triamcinolone reduced the toxicity and plasma concentrations of tetraethylammonium bromide while increasing its level in urine. Pretreatment with corticosterone acetate or pregnenolone-16alpha-carbonitrile shared none of these effects. Although starvation or restraint neither diminished the tetraethylammonium bromide concentrations in plasma nor accelerated its urinary excretion, its toxicity was diminished by the stress induced with spinal cord lesions, heat, cold, hydrocortisone, or reserpine as well as starvation or restraint. The protection offered against the toxicant by stress and by the potent glucocorticoids seemed to be mediated, at least partly, via different mechanisms. Stress-induced resistance to tetraethylammonium bromide could not be attributed to elevated plasma corticosterone levels, whereas glucocorticoid-induced resistance could be partially ascribed to increased urinary excretion of the toxicant.

Forty years of stress research: principal remaining problems and misconceptions.

An overview of the main problems and misconceptions in the clinical application and theoretic evaluation of the stress concept reveals that the same 10 problems appear to cause the greatest difficulties in its application, irrespective of the specialty in which it is used: (1) the correct definition of stress, stressors and the general adaptation syndrome; (2) the concept of nonspecificity in biology and medicine; (3) the conditioning of stress responses by diverse endogenous (mainly genetically determined) and exogenous (environmental) factors; (4) the relation between the genral and the local adaptation syndromes; (5) the difference between direct and indirect pathogens; (6) the definition of the morbid lesions in whose pathogenesis stress plays a particularly prominent role--the so-called diseases of adaptation; (7) the role of genetics versus that of factors under voluntary self-control in mastering biologic stress; (8) the mode of action of syntoxic and catatoxic hormones, drugs and behavioural attitudes; (9) the so-called first mediator of the stress response, which carries the message that a state of stress exists from the directly affected area to the neurohormonal regulatory centres; and (10) the prophylaxis and treatment of stress-induced damage by pharmacologic and behavioural techniques.