H David Mosier

The Effect of Glucocorticoids on Plasma Insulin-Like Growth Factor I Concentration in the Rat Fetus

ABSTRACT: Radioimmuno- and radioreceptor-assayable insulin-like growth factor I (IGF-I) concentration was determined in plasma pools of rat fetuses on gestation day 21 following treatment of the pregnant rats with pharmacologic doses of betamethasone, dexamethasone, or cortisone on gestation days 12 and 13. Dose-related reduction of plasma concentration of IGF-I occurred after betamethasone or dexamethasone treatment. There was no change in IGF-I concentration after cortisone treatment. The changes in fetal IGF-I concentration after steroid treatment were parallel between the two assays. Comparison of the results with previous data showing the effects of identical treatment of pregnant rats on fetal body and organ growth suggests that the IGF-I changes correlate better with reduction of liver/body ratio than with reduction of body weight. The findings indicate that growth retardation after steroid treatment in the fetus is in part the result of factors other than IGF-I. This may include a direct effect of the glucocorticoids on skeletal tissue. Reduced IGF-I concentration may contribute to the growth deficit.

Increase in pulsatile secretion of growth hormone during failure of catch-up growth following glucocorticoid-induced growth inhibition.

Abstract The pattern of growth hormone (GH) secretion was determined in rats injected with cortisone acetate, 5 mg/rat/day subcutaneously, or with an equivalent volume of saline for 4 days from age 40 days. Cortisone injections resulted in inhibition of growth of body weight and tail length. During recovery the rats resumed a normal rate of growth but failed to show catch-up growth acceleration. From 17 to 27 days of recovery, plasma was sampled at 15-min intervals through the lights-on period, 06:00 to 18:00, via a catheter chronically implanted in the superior vena cava. During sampling each rat was housed singly in an insulated chamber, unrestrained, and with food and water ad lib.Cortisone-treated animals had a normal periodicity of GH plasma concentration, but they showed a reduction in values in the range of 50 to 99 ng/ml (P0.01) and an increase of values in the range of 200 to 499 ng/ml (P0.025) and above 1000 ng/ml (P 0.05). The area under the GH concentration curve of the cortisone-treated rats was significantly greater than that of the controls, 100.9 ± 18.7 (mean ± SE) units vs 55.3 ± 7.4 (P0.025). Thus, increased growth hormone secretion during the light phase persisted in spite of failure of catch-up growth acceleration. The findings indicate that the mechanism involved in GH release is linked to the catch-up growth control.

Growth Hormone Secretion in the Stunted Head-Irradiated Rat

ABSTRACT: Pulsatile secretion profiles of pituitary growth hormone (GH) and size and number of cells of brain, heart ventricles, liver, kidney, and gastrocnemius muscle were determined in male Long-Evans rats which received 600 rad x-irradiation to the head only at 2 days of age. Controls consisted of sham-irradiated littermates. The irradiated rats showed significant stunting of body weight and tail length beginning prior to weaning and lasting throughout the period (64 days) of observation. In irradiated rats at 20–21 days of age, just prior to weaning, organ weight was significantly reduced in all organs studied. Brain showed a decrease in organ/body ratio (p < 0.0005) and in total DNA content {p < 0.0005), but these values were not significantly changed in the other organs. DNA/organ ratio was increased significantly in heart (P < 0.025) and gastrocnemius muscle (p < 0.025); brain, liver, and kidney had nonsignificant increases. Protein/DNA ratios were decreased significantly in brain (p < 0.005), heart (p < 0.01), and gastrocnemius muscle (p < 0.05); liver and kidney had nonsignificant decreases. Blood samples were removed for GH determination from cannulated undisturbed irradiated and control rats at 15-min intervals for 18-h periods (9 h light and 9 h dark) at 47–64 days of age. Irradiated rats had normal periodicity of bursts of GH secretion. The area under the curve of GH concentration versus time of the irradiated rat was decreased in light (p < 0.025) and in dark (p < 0.05). Assessments of cell size and cell number suggest that neonatal hypopituitarism and/or undernutrition are unlikely causes of the delayed growth of the head-irradiated rat, and the GH results show that brain controls of rhythmic secretion of GH are intact in this model. The finding of reduced GH secretion, is compatible with the hypothesis that the head irradiation has altered a centrally located control of catch-up growth.

Lack of synchrony between feeding activity and pulsatile growth hormone secretion in rats

Plasma growth hormone (GH) was determined in blood sampled at 15 minute intervals in undisturbed chronically cannulated adult male rats while continuously monitoring feeding activity. Ten animals were studied; five were optic nerve sectioned from 24 days of age and five were intact. The sampling time was from 15:00 hours to 21:00 hours, which included 5 hours of light and the first hour of dark. Both GH secretion and feeding activity exhibited a pulsatile pattern. There was no consistent coordination of bursts of feeding activity and GH secretion. We conclude that feeding activity and GH secretion may be controlled by central timing mechanisms; however, it appears that these mechanisms are separate and are not synchronized.

A simplified method for chronic portal vein cannulation in the rat

A simple technique is described for chronic cannulation and repeated blood sampling from the portal vein of the conscious undisturbed rat. The method employs a straight cannula and allows precise location of the tip. Blood flow in the portal vein is not obstructed. The present technique was used in combination with chronic cannulation of the superior vena cava. Simultaneous blood sampling from the two cannulas was successfully carried out at fifteen minute intervals over six hour periods. The system and the sampling were well tolerated by the rats.

EPINEPHRINE (E) SECRETION IN THE RAT FETUS IN RESPONSE TO NICOTINE ADMINISTERED TRANSPLACENTALLY - RESISTANCE TO CHANGE OF FETAL PLASMA LIPIDS

We have shown previously that nicotine readily crosses the rat placenta. The present experiments were undertaken to determine whether nicotine causes catecholamine release by the feat rat adrenal, and whether acute or chronic dosage of the fetus with nicotine causes lipid increases in fetal plasma. Pregnant Long-Evans rats were fed stock diets containing 0.05 or 0.1 mg/g added nicotine during 10-20 or 0-20 d of pregnancy. Control rats were fed stock diet during 0-20 d. Mean nicotine intake ranged up to 6.03 mg/kg/d. No significant changes occurred in fetal plasma on day 20 with respect to triglyceride (TG), P-lipid or cholesterol levels. Pregnant rats were given single doses of 1 mg/kg nicotine ip on day 20. Maternal plasma free fatty acids (FFA) and TG rose, but fetal values did not change. Fetal adrenal E content decreased after nicotine injection and then rose to slightly higher than control values. There was no decrease after saline injection. The results indicate that the fetal adrenal of the rat secretes E in response to nicotine entering the fetus trans-placentally. The resistance of fetal FFA to change after nicotine is probably due to resistance to E induced elevation of FFA. The placenta may be responsible for maintaining the steady state of fetal plasma lipids.

166 DO TROPHOBLASTIC RECEPTORS FOR INSULIN, IGF-I, AND IGF-II PLAY A ROLE IN FETAL OVERGROWTH IN DIABETIC PREGNANCY?

Fetal overgrowth in diabetic pregnancy (DP) is popularly attributed to hyperinsulinism. However, the roles of other growth-promoting peptides in the mother and the fetus and of their receptors in the placenta remain unclear. We measured at term, concentration and affinity of placental trophoblastic membrane receptors (TR) for insulin (I), IGF-I and IGF-II in 8 DPs (White Class B, 1-dependent) and 8 non-DPs and correlated these with maternal and cord serum IGF-I and IGF-II levels, infant and placenta weights, and maternal body mass index (BMI). DP and non-DP differed significantly in infant weight (g), 4248±114 (M±SEM) vs 3555±119 (P<.0001); placental weight (g), 765±51 vs 575±24 (P<.005); cord IGF-I (ng/ml), 137±15 vs 86±12 (P<.025); and maternal BMI, 33±4 vs 21±1 (P<.02). No significant differences existed in cord IGF-II, maternal IGF-I and -II, and concentration and affinity of TR for I, IGF-I and IGF-II. ANOVA revealed an interaction between placenta weight and infant weight (P<.01), cord IGF-I (P<.02) and maternal IGF-I (P<.025); there was no significant interaction between BMI and infant weight. We conclude that in DP: placental overgrowth is concomitant with fetal somatic overgrowth; fetal and maternal IGF-I may contribute to fetal overgrowth; concentration and affinity of TR for I, IGF-I, and IGF-II play no roles in fetal overgrowth.

Production of generalized learning deficit and permanent growth stunting by bilateral brain stem lesions.

ABSTRACT: Bilateral lesions of the globus pallidus, ventrolateral thalamus, substantia nigra, or the median raphe produce a generalized learning deficit in rats. Bilateral lesions of the dorsomedial hypothalamic nuclei stunt growth in rats without significantly disturbing endocrine functions and without producing a generalized learning deficit. Globus pallidus, ventrolateral thalamus, substantia nigra, median raphe, and dorsomedial hypothalamic nuclei lesions were produced in weanling Sprague-Dawley rats to compare their effect on physical growth. At approximately 72 d of age, all lesions had resulted in reduced body wt, tail length, and tibial length. The differences lacked significance only in body wt after median raphe lesions and tail length after ventrolateral thalamus lesions. In rats with the generalized learning deficit, body size was most stunted after substantia nigra lesions. Tibial epiphyseal width was modestly increased in rats with the generalized learning deficit. Food intake/average body wt ratio in substantia nigra and dorsomedial hypothalamic nucleli rats did not differ significantly from control values. Decreases in brain, heart, liver, kidney, and testes tended to occur after all the lesions, but brain and testis organ wt/body wt ratios were either increased or unchanged. We conclude that brain lesions producing a generalized learning deficit in rats result in impaired physical growth. The results indicated that the stunted animals maintain adequate food intake and have normal growth hormone function. The anatomical substrate for generalized learning impairment may overlap with that of a set point for body size.

473 GROWTH HORMONE AND STUNTED GROWTH FOLLOWING HEAD IRRADIATION

The role of growth hormone (GH) in stunting following head-irradiation in rodents and humans is unclear. We have reported no response to GH treatment in the stunted head-irradiated rat. Secretion profile of GH and cell size and number in brain, heart, liver, kidney and gastrocnemius muscle (gastroc) were determined in rats X-irradiated with 600 rads to the head only or sham-irradiated at 2 d of age. Blood was sampled for GH RIA from cannulated undisturbed rats at 15 min intervals for 18 h periods (9 h light and 9 h dark) at 47 to 64 d of age. Irradiated rats were significantly stunted in body weight and tail length. At 20-21 d of age they had significantly reduced weight of all organs; decreased brain organ/body ratio (p<0.0005) and total DNA (p<0.0005); increased DNA/organ in all organs, significant in heart (p<0.025) and gastroc (p<0.025); decreased protein/DNA in all organs, significant in brain (p<0.005), heart (p<0.01) and gastroc (p<0.05). Irradiated rats had normal rhythm of GH pulses; reduced numbers of GH values from 200 to 499 ng/ml (p<0.05) and 500 to 999 ng/ml (p<0.005), and reduced area under GH concentration vs time (p<0.025). We conclude that GH secretory rhythm is intact in the head-irradiated rat. Cell size and number results exclude neonatal hypopituitarism and/or undernutrition as causes of the growth stunting. Reduced GH secretion may thus only reflect setting of a putative centrally located growth regulator for a smaller body size.

34 EXPERIMENTAL EVIDENCE FOR CENTRAL NERVOUS SYSTEM CONTROL OF CATCH-UP GROWTH

In rats permanent stunting follows neonatal head-irradiation (Head-X); during the post-weaning period full catch-up growth (CU) occurs after fasting (F); failure of CU occurs after cortisone treatment (C); and superimposition of F or C on Head-X results in similar responses in the stunting after Head-X. In this study growth hormone (GH) secretory profiles were determined in rats treated with Head-X, F or C. Superior vena cava blood was sampled at 15 min intervals during the light phase in chronically cannulated undisturbed animals. Sampling duration was 9 h in Head-X, 6 h in F, and 12 h in C. The results, expressed as area units/15 min under the curve of plasma GH concentration vs. time, are as follows:Normal pulsatile GH rhythm existed in all three models. The data indicate that GH controls are linked to the CU control. That GH secretion is decreased in Head-X is compatible with the concept that brain injury has reset growth controls for a smaller body size. We conclude that GH release is linked to the putative CU control through a mechanism which senses the discrepancy between actual body size and normal body size for age.