Anti-anabolic Effects Research Articles

Nephrology: An Annotated Bibliography of Recent Literature

Nephrology: An Annotated Bibliography of Recent Literature

GLUCOCORTICOID EFFECT ON REPAIR PROCESSES IN VASCULAR CONNECTIVE TISSUE

Male rabbits were injured by a single mechanical dilatation of the aorta and then injected with prednisone 2 mg/kg saline for 14 days or starved. Morphological studies and biochemical measurements of the collagen metabolism, the content of alpha-amino nitrogen, RNA, DNA, water and fat, and the aorta to serum ratio of 125I-albumin were performed on the intima-media layer of the descending thoracic aorta. Prednisone inhibited the intimal thickening. In the media the infiltration by mononuclear cells, the proliferation and regeneration of the smooth muscle cells and the calcification were reduced. Prednisone caused a decrease in 0.45 M NaCl soluble collagen as well as in the dialysable and non-dialysable 14C-hydroxyproline fractions. The total amount of collagen, elastin and alpha-amino nitrogen was unchanged, whereas the 14C-proline incorporation in the non-dialysable protein fraction was inhibited to a greater extent than the 14C-hydroxyproline synthesis. The findings indicate that prednisone inhibits the biosynthesis of collagen, which is inhibited to a greater extent than the general protein synthesis. Prednisone increased the dialysable to non-dialysable 14C-hydroxyproline ratio consistent with a relative increase in the catabolism of newly synthesized collagen. The aortic content of RNA and DNA was reduced consistent with the inhibition of protein synthesis and cell proliferation. Finally prednisone decreased the aortic content of water when related to the wet weight and increased the aortic content of fat. The aorta to serum ratio of 125I-albumin was not influenced by prednisone. It is concluded that administration of glucocorticoid for 14 days exerts an inhibitory action on the histological reaction to injury as well as on the biosynthesis of collagen of the repair processes in vascular connective tissue. A comparison with the effects of prednisone on undamaged rabbit aorta (Manthorpe et al. 1974) demonstrates that the metabolism of collagen of vascular connective tissue during repair is more sensitive to the antianabolic effects of prednisone than collagen in the non-injured aorta. Starvation caused an increase of the aortic percentage of water but otherwise had no influence on the repair processes in the vascular connective tissue.

Anti-anabolic effects of adenosine 3':5'-cyclic monophosphate. Inhibition of protein synthesis.

1. Evidence is presented that cyclic AMP inhibits the incorporation of l-[4,5-(3)H]leucine into protein in a cell-free system from rat liver. This inhibition occurs after aminoacyl-tRNA formation. 2. Microsomal fractions, isolated after the incubation of postmitochondrial supernatant with cyclic AMP and ATP, show a diminished ability to synthesize protein. Both cyclic AMP and ATP are required for this effect. 3. A possible physiological role for the anti-anabolic action of cyclic AMP is discussed in terms of the control of gluconeogenesis.

The Anti-Anabolic Effect of Glucagon on Albumin Synthesis by the Isolated Perfused Rat Liver

The Anti-Anabolic Effect of Glucagon on Albumin Synthesis by the Isolated Perfused Rat Liver

Evaluation of doxycycline administration in patients with renal failure and in normal subjects.

Summary The biological half-life of doxycycline in serum was determined in 6 normal subjects and in 8 patients on maintenance haemodialysis. There was no significant difference in the half-life in the 2 groups. In 6 patients on maintenance haemodialysis the half-life of doxycycline was determined both during and between haemodialysis. There was a tendency for the half-life to be shorter during haemodialysis, but the differences were not statistically significant. It is concluded that no adjustment of dosage is required when doxycycline is employed in patients with severe renal failure, whether they are undergoing haemodialysis or not. Renal function was studied in 2 normal subjects who were given doxycycline in normal doses for 1 month. During this period there was no change in blood urea concentration, endogenous creatinine clearance or renal concentrating ability. Doxycycline was administered in normal doses to 8 patients with varying degrees of chronic renal failure for periods varying from 10 to 15 days. There was no evidence that doxycycline had any anti-anabolic effect and there was no evidence of nephrotoxicity. No toxic effects were noted in any of the patients studied. Doxycycline is therefore of particular value when a broad spectrum antibiotic is required in patients with renal failure.

An anti-anabolic role of adenosine 3',5'-cyclic monophosphate in the control of liver metabolism. a hypothetical mechanism for gluconeogenesis

1. 1. It is shown that in rat liver slices cyclic AMP caused a co-ordinated inhibition of protein, fatty acid, and cholesterol synthesis (anti-anabolic) from several radioactive precursors. 2. 2. The inhibition of cholesterol and fatty acid synthesis was due to a genuine decrease in the activity of the biosynthetic pathway. 3. 3. Under conditions when the anti-anabolic effect was obtained, the incorporation of [ 14CJbicarbonate into glucose was increased, confirming that cyclic AMP favours glyconeogencsis. 4. 4. The mechanism by which cyclic AMP produced these effects was studied further by the use of cell-free preparations from rat liver. Cyclic AMP was shown to inhibit protein synthesis in a postmitochondrial supernatant. This inhibition only occurred in the presence of an excess of the postmicrosomal supernatant fraction. These results are discussed on the basis that cyclic AMP might interact with a component in the posticrosomal fraction capable of modifying the activity of the protein synthetic machinery. 5. 5. Examples are provided to suggest that this anti-anabolic effect of cyclic AMP may operate in vivo.

Suppression of growth hormone-dependent human serum sulfation factor by estrogen.

In view of the demonstrated metabolic antagonism of estrogen and growth hormone, the effect of estrogen administration upon serum sulfation factor was studied in four acromegalic patients, and in three growth hormone-treated hypopituitary patients. Sulfation factor was measured by a modification of Daughaday's rat rib cartilage method permitting statistical evaluation of validity, precision and fiducial limits for each individual assay. Estrogen in vitro had no effect upon the sulfation factor bioassay system. Shortterm estrogen therapy (7–18 days) promptly reduced elevated sulfation factor levels, hypercalciuria and hydroxyprolinuria in the acromegalic patients, without significantly affecting basal plasma growth hormone levels. Estrogenic antianabolic effect was frequently observed, as shown by elevations of BUN and of urinary nitrogen. In each of the growth hormone-deficient patients, subnormal sulfation factor levels rose to normal or high levels during HGH administration for four or six days, returning to initial levels within two days after cessation of HGH therapy. Estrogen given concurrently with an identical second course of HGH treatment completely prevented the rise of serum sulfation factor, of urinary calcium, and probably of hydroxyproline excretion, but did not affect the anabolic response to growth hormone. The parallel variations of urinary calcium and hydroxyproline with those of serum sulfation factor, suggest that the latter may participate in the mediation of the bone-resorptive action of growth hormone. However, responses to growth hormone in the estrogen-treated hypopituitary patients seemed to indicate that the stimulation of serum sulfation factor was not a necessary condition for the overall anabolic action of growth hormone.

Alterations in the phosphorylation of (3H)uridine and RNA synthesis in rat thymus cells after glucose depletion and treatment with prednisolone.

Alterations in the phosphorylation of [3H]uridine and in RNA synthesis resulting from restrictions in the availability of glucose as the only source of energy were studied in rat thymus cells in vitro and compared to the influence of prednisolone injected in vivo on both parameters. The following results were obtained: 1 In the absence of glucose, an impairment in the phosphorylation of [3H]uridine is observed after 15–30 min of incubation. A corresponding decrease in the formation of RNA is not clearly established before 60 min of incubation. 2 Fluctuations in the concentration of glucose in the incubation medium between 1.0 mg and 0.1 mg of glucose/ml produce only modest changes in the capacity of rat thymus cells to synthesize RNA. 3 Phosphorylation of [3H]uridine and RNA synthesis appear to be inhibited in a synchronous rather than a sequential fashion after the administration of prednisolone. 4 The phosphorylation of [3H]uridine is also inhibited in rat thymus cells under the influence of prednisolone when RNA synthesis is completely blocked by actinomycin D or by incubation of thymus cells at 0°. 5 On the other hand, thymus nuclei from prednisolone-treated rats which were depleted of their capacity to phosphorylate [3H]uridine by repeated treatment with a buffer solution containing Triton X-100, still displayed an impairment in their capacity to utilize [3H]ATP for RNA synthesis as compared to corresponding nuclear preparations from normal animals. 6 The steroid-mediated decrease in the phosphorylation of [3H]uridine does not reflect a direct steroid-effect on the kinases but appears to be caused by changes in the structural environment to which these enzymes are normally bound. Our results appear to indicate that prednisolone exerts its catabolic or antianabolic effect on rat thymus cells by at least two distinct mechanisms, one of which involves a decrease in precursor phosphorylation while the other leads to an impairment of RNA synthesis.

Effect of cortisone on the growth of the ventral prostate, the dorsolateral prostate, the coagulating glands and the seminal vesicles in castrated adrenalectomized and castrated non-adrenalectomized rats.

ABSTRACT The growth of the ventral and the dorsolateral prostate, the coagulating glands and the seminal vesicles was studied in cortisone-treated and non-treated castrated non-adrenalectomized and castrated adrenalectomized rats. The cortisone was administered in daily doses of 3 mg or 9 mg for a period of 15 days. Combined castration and adrenalectomy resulted in a greater degree of atrophy of the ventral prostate than castration alone, thus indicating some maintenance effect of the adrenals on the ventral prostate. No differences in the other accessory reproductive organs were demonstrated when comparing non-treated castrated non-adrenalectomized with castrated adrenalectomized rats. Both doses of cortisone stimulated the growth of the dorsolateral prostate, the coagulating glands and the seminal vesicles, but the larger dose resulted in a greater degree of stimulation. Only the larger dose of cortisone gave histological changes in the ventral prostate indicative of a slight stimulating effect. Catabolic or anti-anabolic effects of cortisone as registered by a decrease in body weight and weight of the levator ani muscle did not inhibit the growth stimulating effect of cortisone on the accessory reproductive organs. Cortisone stimulated the growth of both the epithelium and the smooth muscle tissue of the glands. The effect on the different accessory reproductive organs after cortisone administration was contrary to previous studies, which demonstrated the stimulating effects of androgens in the rat, in that the ventral prostate was relatively unstimulated. Possible mechanisms for the stimulation of the growth of the accessory reproductive organs are discussed in the light of our present knowledge of cortisone metabolism and of the secretion in the cortisone-treated rats of hormones which have been found to modify the growth of the accessory reproductive organs.

The mode of action of hydrocortisone on the protein metabolism in rat carrageenin granuloma

Involution of pre-existing carrageenin granuloma in rats was brought about by local injection of hydrocortisone acetate(HC). In in vitro incubation of minced granuloma removed from rats injected locally with HC 6 hr prior to sacrifice, the release of perchloric acid soluble tyrosine (Tyr) into the medium was significantly elevated, while non-steroidal anti-inflammatory drugs had no effect on the release of Tyr. The increase of degradation, in minced granuloma exposed in vivo to HC for 6 hr, of 3H-Tyr-IabeIed tissue protein was suggested with a similar method as the incubation of non-labeled granuloma. Both in vivo and in vitro incorporation of 3H-Tyr into tissue protein of the granuloma was reduced by HC administered in vivo 6 hr before. Thus, both the enhancement of catabolism and the reduction of anabolism were manifested as the effect of HC on the granuloma. The predominance of anti-anabolic effect was deduced from the result of incubation experiments in which puromycin or cycloheximide was used in vitro with or without HC-treatment.

Metabolic studies on renal homograft patients

Five renal homotransplant patients on the Metabolic Ward of the University of Colorado Medical Center were studied preoperatively and postoperatively. Nitrogen balance data accumulated on these patients indicated that azathioprine had no notable effect upon the balance. These patients were severely depleted prior to therapy. Prednisone administration resulted in an increased nitrogen excretion; however, the patients returned to a stable nitrogen balance near equilibrium despite the continued administration of rather massive daily doses of prednisone. The findings indicate that a gain in protein stores rather than continual depletion is possible even with long term massive prednisone and azathioprine therapy. Evidence is also presented that prednisone exerted a rather significant catabolic effect upon endogenous protein stores in homograft patients in addition to any anti-anabolic effect it may have exerted. Finally, it was noted that with the massive nitrogen intakes, the patients exhibited an apparent decrease in efficiency of absorption by the gastrointestinal tract. As a result, the fecal nitrogen output was found to be well in excess of normal values. Five renal homotransplant patients on the Metabolic Ward of the University of Colorado Medical Center were studied preoperatively and postoperatively. Nitrogen balance data accumulated on these patients indicated that azathioprine had no notable effect upon the balance. These patients were severely depleted prior to therapy. Prednisone administration resulted in an increased nitrogen excretion; however, the patients returned to a stable nitrogen balance near equilibrium despite the continued administration of rather massive daily doses of prednisone. The findings indicate that a gain in protein stores rather than continual depletion is possible even with long term massive prednisone and azathioprine therapy. Evidence is also presented that prednisone exerted a rather significant catabolic effect upon endogenous protein stores in homograft patients in addition to any anti-anabolic effect it may have exerted. Finally, it was noted that with the massive nitrogen intakes, the patients exhibited an apparent decrease in efficiency of absorption by the gastrointestinal tract. As a result, the fecal nitrogen output was found to be well in excess of normal values.

Paramethasone, a new corticosteroid, in selected dermatoses; preliminary report.

During the past several years there has been a concentrated attack upon the problem of divorcing the anti-inflammatory effect of systemic corticosteroids from the sequelae. 1-3 With the advent of prednisone, the sequelae associated with water and sodium retention and potassium loss have been pretty well eliminated. There remained, however, the major sequelae due probably to the antianabolic effects: steroid-induced peptic ulcer, osteoporosis, muscle wasting, steroid-induced or steroid-exaggerated diabetes mellitus, plus a host of relatively infrequent sequelae of varying importance involving the skin and its adnexae, the eye, the psyche, blood vessels, and the immunologic apparratus. 4-9 The newer corticosteroids have had little or no effect on the incidence of these sequelae. As yet it has been impossible to separate completely the anti-inflammatory effects of corticosteroid therapy from most of these sequelae. 4,6-8,12 It is doubtful that this will be accomplished, since it appears probable that any attempt to

Uptake on radiosulfate in growing bones of cockerels treated with cortisone and certain anabolic-androgenic steroids.

The effect of cortisone and certain androgenic anabolic steroids on the radiosulfate uptake by the three long bones of the young cockerel's leg, was investigated. Cortisone diminished and 17-cthyl-19-nortestosterone increased the capacity of growing bones to bind labelled sulfate. This was interpreted as a manifestation of the anti-anabolic and anabolic effect of these hormones respectively, on the synthesis of certain mucopolysaccharides of growing connective tissue, which specifically incorporate radiosulfate. The anabolic steroid 17-ethyl-19-nortestosterone counteracted the anti-anabolic effect of cortisone on growing bone, when both hormones were administered simultaneously. Neither methyl testosterone nor testosterone propionate showed any significant effect on S35 uptake by the studied bones, nor did they counteract the anti-anabolic effect of cortisone.

Roentgenologic changes of the skeletal system in Cushing's syndrome.

Although many articles have been written about the clinical features, pathology, and pathologic physiology of Cushing's syndrome, only two reports have dealt primarily with the roentgenographic aspects (1, 2). These and other studies have indicated that the most characteristic skeletal roentgenographic findings are osteoporosis and attendant fractures, without features peculiar to Cushing's syndrome. The present report was stimulated by an impression obtained by one of the authors (Pugh) that the spinal osteoporosis in this syndrome frequently is accompanied by an unusual condensation of the margins of some of the collapsed vertebral bodies of a degree seldom seen in other forms of osteoporosis. From a physiologic standpoint, the osteoporosis of Cushing's syndrome and most of its other clinical and laboratory features (abnormal distribution of fat, muscular wasting and weakness, hypertension, amenorrhea, impotence, cutaneous atrophy and striation, easy bruising, hirsutism, acne, lymphopenia, eosinopenia, metabolic alkalosis, and impaired carbohydrate tolerance) are attributable to the metabolic effects of hydrocortisone-like steroid hormones that are produced in excessive amounts by hyperplastic or neoplastic adrenal cortices. In the case of bone, such steroids, through a catabolic or an antianabolic effect (3–6), or both, induce a loss of protein matrix, so that formation of bone is diminished and osteoporosis results. Materials and Methods The case records and roentgenograms of 141 patients with the clinical diagnosis of Cushing'S syndrome established at the Mayo Clinic during the years 1947–1955 were reviewed. Since compressed vertebral bodies were the subject of special interest, only the 69 cases in which lateral views of the spinal column were available were subjected to complete analysis. Post-treatment roentgenograms (with a minimal interval of six months after adrenalectomy or removal of an adrenal cortical tumor) had been taken in 19 instances, and there were complete oral roentgenograms for 6 patients. As a control, to aid in the determination of the differential roentgenologic features, the records and roentgenograms of 50 patients with severe generalized osteoporosis due to other causes were reviewed. Only severe cases were included, since it was considered that any roentgenographic features present in mild or moderate osteoporosis would be accentuated in more severe states. The control patients were taken at random from persons examined at the clinic during 1956, the only criteria for selection being a clinical and roentgenographic diagnosis of severe osteoporosis and absence of any malignant condition. Clinical and Pathologic Findings Cushing's Syndrome: The 69 patients included 19 males and 50 females. The average age at the time of diagnosis was 36.4 years, the youngest patient being thirteen years of age and the oldest sixty years.