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Biomedical subjects

A S Clark

Publications and source records attributed to A S Clark.

At least 55 records · Page 3Linked to original sources
PubMed1987

Effective intervals for the administration of estradiol pulses and the induction of sexual behavior in female rats.

The interval between two pulses of estradiol was varied and subsequent progesterone-facilitated female sexual behavior was observed. The total dose of estradiol (2 micrograms free estradiol) has been shown previously to elicit little receptivity when administered in a single pulse. In the present study, two pulses of 1.0 microgram free estradiol separated by anywhere from 3-36 hours induced high levels of progesterone-facilitated receptivity when observed 18 hours after the second estrogen pulse. Various intervals between the second estrogen pulse and the time of testing were also evaluated. Female rats tested at 18, 24 and 36 hours after the second estrogen pulse (plus progesterone) were highly receptive. These results raise new possibilities about the time course of cellular events underlying the estrogen induction of feminine sexual behavior.

Animals↗
PubMed1987

Dichloroacetate inhibits glycolysis and augments insulin-stimulated glycogen synthesis in rat muscle.

The decrease in plasma lactate during dichloroacetate (DCA) treatment is attributed to stimulation of lactate oxidation. To determine whether DCA also inhibits lactate production, we measured glucose metabolism in muscles of fed and fasted rats incubated with DCA and insulin. DCA increased glucose-6-phosphate, an allosteric modifier of glycogen synthase, approximately 50% and increased muscle glycogen synthesis and glycogen content greater than 25%. Lactate release fell; inhibition of glycolysis accounted for greater than 80% of the decrease. This was associated with a decrease in intracellular AMP, but no change in citrate or ATP. When lactate oxidation was increased by raising extracellular lactate, glycolysis decreased (r = - 0.91), suggesting that lactate oxidation regulates glycolysis. When muscle lactate production was greatly stimulated by thermal injury, DCA increased glycogen synthesis, normalized glycogen content, and inhibited glycolysis, thereby reducing lactate release. The major effect of DCA on lactate metabolism in muscle is to inhibit glycolysis.

Acetates↗
PubMed1987

Regional sex differences in progestin receptor induction in the rat hypothalamus: effects of various doses of estradiol benzoate.

In the rat, sex differences in behavioral responsiveness to progesterone have been correlated with a sex difference in estrogen-induced progestin receptor induction in the ventromedial nucleus (VMN). It has recently been suggested that this sex difference in progestin receptor induction may only be present after treatment with large doses of estrogen. We have evaluated the sex difference in hypothalamic cytosol progestin receptor induction in gonadectomized/adrenalectomized rats treated with moderate doses of estradiol benzoate (EB; 20 micrograms/kg body weight). No sex differences were detected in cytosol progestin binding in mediobasal hypothalamus or preoptic area of animals treated with this dose 48 hr before they were killed. However, a higher level of progestin binding in the VMN of females than of males was found when these brain regions were examined using a microdissection technique. Saturation binding analysis of progestin binding in the VMN indicated that this sex difference in binding reflects a difference in the number of progestin binding sites, and not a difference in binding affinity. A dose-response study of progestin receptor induction in the medial preoptic nucleus (mPON), arcuate-median eminence region (ARC-ME), and VMN of male and female rats indicated a sex difference in cytosol progestin binding in the VMN at all EB doses tested (2, 8, 40, or 200 micrograms/kg body weight). No sex differences in cytosol progestin binding in the mPON or ARC-ME were observed at any of the tested doses. These results support the idea that the differences in behavioral sensitivity to progesterone may result in part from sex differences in the estrogen induction of progestin receptors in the VMN.

Animals↗
PubMed1985

Selectivity of the insulin-like actions of vanadate on glucose and protein metabolism in skeletal muscle.

To determine if vanadate has insulin-like actions in skeletal muscle, we measured its effects on glucose and protein metabolism in epitrochlearis muscles of rats. Compared with insulin, vanadate increased glucose uptake, glycogen synthesis and glycolysis to a lesser degree, but caused a greater stimulation of lactate and glucose oxidation. Unlike insulin, vanadate did not change either protein synthesis or degradation. These different metabolic responses could be related to the different pattern of insulin-receptor phosphorylation caused by insulin and vanadate.

Adenine Nucleotides↗
PubMed1985

Inhibition of sexual receptivity by anesthesia during estrogen priming.

Anesthetics such as pentobarbital have been used to infer a role of neural activity in several neuroendocrine responses. The present experiments tested the hypothesis that neural activity during estrogen priming is necessary for the induction of sexual receptivity. Sexual behavior was induced in ovariectomized female rats by two pulses of unesterified estradiol 6 h apart, followed by progesterone at 19 h and testing at 24 h. Anesthetizing animals for approximately 1 h during each exposure to estradiol inhibited the induction of receptivity. Anesthesia immediately before each exposure to estradiol did not interfere with the induction of sexual receptivity. The induction of neural progestin receptors by estradiol was not prevented by anesthesia. Anesthesia had no effect on the uterine weight response to estradiol. These results suggest that neural activity during estrogen priming is required for the induction of sexual receptivity, and point to differences in the mechanism of action of estrogens in the brain and the uterus.

Anesthesia↗
PubMed1985

A possible physiological basis for the dud-stud phenomenon.

Intact male rats were tested on two successive weekly tests with females to determine their level of sexual activity. Nuclear estrogen receptor content was measured in specific brain regions of individual sexually responsive and sexually nonresponsive males. Sexually nonresponsive male rats had significantly reduced nuclear estrogen receptor levels in the preoptic area compared to sexually responsive males. Sexually active males did not differ from inactive males in nuclear estrogen receptors in the medialbasal hypothalamus.

Animals↗
PubMed1985

Behavioral insensitivity to progesterone during lactation in female rats.

Lactating female rats failed to display sexual receptivity after receiving 50 micrograms of estradiol benzoate followed by 1 mg of progesterone. Lactating rats appear to be insensitive to progesterone, based on several experiments. In ovariectomized control rats receiving moderate estrogen priming (1 microgram EB for 3 days), progesterone greatly facilitated sexual receptivity; similarly estrogen-primed lactating females showed no responsiveness to progesterone injections, even at a high dose of progesterone (10 mg). Consistent with this reduced behavioral responsiveness to progesterone, lactating females had significantly reduced nuclear progestin receptor levels after an injection of 1 mg progesterone compared to ovariectomized controls. On the other hand, both ovariectomized controls and lactating rats responded with high levels of receptivity to 3 days of priming with 10 micrograms of estradiol benzoate (without progesterone). Lactating females treated for 3 days with a moderate dose (1 microgram) of estradiol benzoate showed slightly reduced receptivity compared to ovariectomized controls; this result could reflect a reduced sensitivity to estrogen but is more likely related to the somewhat lower serum levels of estradiol and consequently lower nuclear estrogen leading to a reduced sensitivity to progesterone cannot be eliminated (since animals respond to progesterone only after estrogen priming); however, the reported results favor the idea that lactating females are primarily refractory to progesterone and do not have a generalized insensitivity to estrogen.

Animals↗
PubMed1985

Specific defects in insulin-mediated muscle metabolism in acute uremia.

The mechanisms underlying the abnormal insulin-mediated muscle glucose metabolism occurring in acute uremia (ARF) have not been identified. To characterize the defects, insulin dose-response curves for glucose uptake, glycogen synthesis, glucose oxidation, glycolysis, and lactate release were measured in incubated rat epitrochlearis muscles. ARF did not affect insulin sensitivity, but decreased the responsiveness to insulin of glucose uptake, glycogen synthesis, and glucose oxidation. Glycogen synthesis was subnormal at all levels of insulin and at the maximal insulin concentration; it was 54% lower in muscles of ARF compared to control rats. This inhibition of glycogen synthesis in ARF could be caused by a 23% decrease in the total activity of muscle glycogen synthase and the percentage of enzyme in the activated form. Glycogen phosphorylase activity was unchanged by ARF. ARF also increased the ratio of muscle lactate release to glucose uptake at concentrations of insulin from 10 to 10(4) microU/ml. In the absence and presence of insulin, muscle protein degradation was increased by ARF. In individual muscles incubated with insulin, the rate of proteolysis was correlated with the ratio of lactate release to glucose uptake (r = + 0.82; P less than 0.01). From the insulin dose-response relationships and changes in enzyme activities, we conclude that ARF increases protein degradation in muscle and causes abnormal insulin-mediated glucose metabolism. The abnormalities in glucose metabolism are caused by changes in post-receptor events.

Animals↗
PubMed1984

Specificity of the effects of leucine and its metabolites on protein degradation in skeletal muscle.

The effects of leucine, its metabolites, and the 2-oxo acids of valine and isoleucine on protein synthesis and degradation in incubated limb muscles of immature and adult rats were tested. Leucine stimulated protein synthesis but did not reduce proteolysis when leucine transamination was inhibited. 4-Methyl-2-oxopentanoate at concentrations as low as 0.25 mM inhibited protein degradation but did not change protein synthesis. The 2-oxo acids of valine and isoleucine did not change protein synthesis or degradation even at concentrations as high as 5 mM. 3-Methylvalerate, the irreversibly decarboxylated product of 4-methyl-2-oxopentanoate, decreased protein degradation at concentrations greater than or equal to 1 mM. This was not due to inhibition of 4-methyl-2-oxopentanoate catabolism, because 0.5 mM-3-methylvalerate did not suppress proteolysis, even though it inhibited leucine decarboxylation by 30%; higher concentrations of 3-methylvalerate decreased proteolysis progressively without inhibiting leucine decarboxylation further. During incubation with [1-14C]- and [U-14C]-leucine, it was found that products of leucine catabolism formed subsequent to the decarboxylation of 4-methyl-2-oxopentanoate accumulated intracellularly. This pattern was not seen during incubation with radiolabelled valine. Thus, the effect of leucine on muscle proteolysis requires transamination to 4-methyl-2-oxopentanoate. The inhibition of muscle protein degradation by leucine is most sensitive to, but not specific for, its 2-oxo acid, 4-methyl-2-oxopentanoate.

Amino Acids, Branched-Chain↗
PubMed1984

Systemic response to thermal injury in rats. Accelerated protein degradation and altered glucose utilization in muscle.

Negative nitrogen balance and increased oxygen consumption after thermal injury in humans and experimental animals is related to the extent of the burn. To determine whether defective muscle metabolism is restricted to the region of injury, we studied protein and glucose metabolism in forelimb muscles of rats 48 h after a scalding injury of their hindquarters. This injury increased muscle protein degradation (PD) from 140 +/- 5 to 225 +/- 5 nmol tyrosine/g per h, but did not alter protein synthesis. Muscle lactate release was increased greater than 70%, even though plasma catecholamines and muscle cyclic AMP were not increased. Insulin dose-response studies revealed that the burn decreased the responsiveness of muscle glycogen synthesis to insulin but did not alter its sensitivity to insulin. Rates of net glycolysis and glucose oxidation were increased and substrate cycling of fructose-6-phosphate was decreased at all levels of insulin. The burn-induced increase in protein and glucose catabolism was not mediated by adrenal hormones, since they persisted despite adrenalectomy. Muscle PGE2 production was not increased by the burn and inhibition of prostaglandin synthesis by indomethacin did not inhibit proteolysis. The increase in PD required lysosomal proteolysis, since inhibition of cathepsin B with EP475 reduced PD. Insulin reduced PD 20% and the effects of EP475 and insulin were additive, reducing PD 41%. An inhibitor of muscle PD, alpha-ketoisocaproate, reduced burn-induced proteolysis 28% and lactate release 56%. The rate of PD in muscle of burned and unburned rats was correlated with the percentage of glucose uptake that was directed into lactate production (r = +0.82, P less than 0.01). Thus, a major thermal injury causes hypercatabolism of protein and glucose in muscle that is distant from the injury, and these responses may be linked to a single metabolic defect.

Adrenalectomy↗
PubMed1983

Comparison of protein synthesis and degradation in incubated and perfused muscle.

Rates of muscle protein synthesis and degradation measured in the perfused hindquarter were compared with those in incubated epitrochlearis muscles. With fed or starved mature rats, results without insulin treatment were identical. With insulin treatment, protein synthesis in perfused hindquarters was greater, though protein degradation was the same. Thus rates of muscle protein degradation estimated by these two methods in vitro correspond closely.

Animals↗
PubMed1983

Behavioral and cellular responses to pulses of low doses of estradiol-17 beta.

The effectiveness of single vs. separate pulses of low doses of free estradiol on the induction of sexual receptivity in ovariectomized female rats was examined. Two separate subcutaneous pulses of low doses of free estradiol at 0 and 6 hours induced high levels of progesterone facilitated receptivity at 24 hours. However, a single pulse of the same total dose of estradiol induced little or no receptivity at 24 hours (or at 18 hours). In fact, approximately 10 times as much estradiol was required in a single pulse to induce comparable receptivity. The smaller behavioral response to a single pulse was not likely due to a ceiling effect or an unutilized excess of the hormone after one injection. This suggestion is based on measurements of the redistribution of estrogen receptors from the cytoplasm to cell nuclei as an index of an initial cellular stimulus. Doses of estradiol used in the behavioral studies included several doses that were subsaturating with regard to hypothalamic estrogen receptors. The greatly enhanced behavioral response to two separated pulses of estradiol is consistent with the hypothesis that an initial action of estradiol may be to sensitize target tissues to further stimulation by the hormone.

Animals↗
PubMed1983

Muscle protein turnover and glucose uptake in acutely uremic rats. Effects of insulin and the duration of renal insufficiency.

Acute renal failure (ARF) in rats is associated with increased amino acid release from peripheral tissues and insulin resistance. To study whether abnormal protein and carbohydrate metabolism are linked in ARF, the effects of insulin on net muscle protein degradation (T) and on glucose uptake were measured in the perfused hindquarters of paired ARF and sham-operated (SO) rats. The basal rate of T increased 40% after 24 and 98% after 48 h of ARF. Insulin was less effective in decreasing T in ARF (-79% SO vs. -22% ARF 24 h and -64% SO vs. -23% ARF 48 h; P less than 0.01). Protein synthesis (PS) and protein degradation (PD) were measured independently in incubated epitrochlearis muscles; the increase in T after 24 h of ARF was due specifically to increased PD, while PS was unchanged. At this stage, insulin was less effective in decreasing PD in ARF (-10% ARF vs. -23% SO; P less than 0.02), although PS responded normally. After 48 h of ARF, the further increment in T was caused by the additional appearance of depressed basal and insulin-stimulated PS. This was confirmed in the perfused hindquarter (26 +/- 3 ARF vs. 38 +/- 3 SO, basal; 54 +/- 5 ARF vs 73 +/- 7 SO, insulin-stimulated, nmol phenylalanine/g per h; P less than 0.05). Although basal glucose uptake by hindquarters of ARF and SO rats was comparable, insulin-stimulated glucose uptake was 33% less at 24 and 44% less after 48 h of ARF. After 48 h of ARF, lactate and alanine release were increased and net glycogen synthesis in muscle was depressed. These abnormalities were even more apparent in the presence of insulin. Inefficient glucose utilization, estimated as the ratio of lactate release to glucose uptake, was correlated with T (r = +0.78; P less than 0.001). In conclusion, after 24 h of ARF, both increased PD and altered glucose utilization could be detected. After 48 h of ARF, T increased further because PS was depressed. At this time, glucose utilization was clearly abnormal and the results suggest that abnormal net protein degradation in ARF may be a consequence of defective glucose utilization.

Acute Disease↗
PubMed1983

Muscle protein turnover in uremia.

Abnormalities of muscle protein stores in uremia result from changes in the components of protein turnover. In vivo measurements of protein synthesis and degradation in uremia are subject to several errors. There may be incomplete equilibration of the infused labeled amino acid with the precursor pool for protein synthesis because of abnormal amino acid transport into muscle and increased catabolism of the infused amino acid. The infusion technique for measuring protein degradation cannot differentiate between rates occurring in different tissues. Moreover, measurement of 3-methylhistidine as an estimate of muscle protein degradation is invalid in uremia because its renal clearance is impaired. In vitro studies using radiolabeled amino acids should give more reliable estimates of the components of muscle protein turnover. Estimation of the rate of protein synthesis with a labeled amino acid still requires measurements of its specific activity in the precursor pool for protein synthesis, but this can be accomplished more easily in vitro. The factors known to affect protein synthesis and degradation in normal muscle, which are most likely to affect protein turnover in uremic muscle, are insulin-resistance and maladaptation to fasting. Few studies of the components of protein turnover in uremia have examined the effect of these or other factors.

Amino Acids↗