Biomedical subjects

L L Bellush

Publications and source records attributed to L L Bellush.

At least 19 recordsLinked to original sources

PubMed2000

Protection against diabetes-induced nephropathy in growth hormone receptor/binding protein gene-disrupted mice.

To further investigate the role of GH in diabetic nephropathy, experimental diabetes was induced with streptozotocin (STZ) in mice in which the GH receptor/binding protein gene was disrupted. Body weight, blood glucose, and renal histology and morphometry were studied 10 weeks after diabetes induction in wild-type (+/+) mice and in mice heterozygous (+/-) and homozygous (-/-) for the disruption. Equivalent levels of hyperglycemia developed in all diabetic groups. Normal weight gain was absent in +/+ and +/- diabetic groups, and -/- diabetics lost weight during the study. Diabetic +/+ and +/- groups both showed evidence of glomerulosclerosis, increases in glomerular volume, and increases in the ratio of mesangial area to total glomerular area, whereas diabetic -/- mice showed none of these pathological changes. These results extend our previous findings of protection against diabetes-associated kidney damage in transgenic mice expressing a GH antagonist. Taken together, the results argue for an important role of GH in the development of diabetes induced end-organ damage.

Animals↗

PubMed2000

Assessment of growth parameters and life span of GHR/BP gene-disrupted mice.

GH has many biological roles, including promotion of growth. Most, if not all, of its roles are achieved through interaction with its receptor. We chose to study the effects of loss of GH signaling on growth and aging in a mouse model for Laron Syndrome (LS) in which the GHR/BP gene has been disrupted. We observed that mice homozygous for the disruption (-/-) were significantly smaller than normal wild-type (+/+) mice as well as mice heterozygous for the disruption, even at 1.5 yr of age. IGF-I levels were also significantly lower in the -/- mice and remained low as the mice aged. IGFBP-3 levels were severely reduced in the -/- mice, whereas IGFBP-1, -2, and -4 levels remained unchanged. Finally, the -/- mice lived significantly longer than +/+ and +/- mice. The latter result contradicts the anti-aging GH data and suggests the need for further analysis of GH and aging.

Aging↗

PubMed1999

Transgenic models of growth hormone action.

A growth-promoting principle of the pituitary gland was discovered in 1921, and bovine growth hormone (GH) was isolated in 1944. Since then, the structure of GH as it relates to its biological activities has been an exciting research topic. Equally fascinating is the relationship between GH structure and its metabolic activities. In attempts to define some of these activities, several investigators have used GH transgenic mice as models. In this review we summarize what is known about the molecular mechanisms of GH action. We then describe some of the GH transgenic models and point out potential targets for nutrition research.

Animals↗

PubMed1999

Activation of bulbospinal serotonergic neurons during cold exposure.

In a four-part study, we expand on our previous report that bulbospinal serotonin (5HT) neuronal activation occurs with 24 h of cold exposure. To characterize temporal aspects, rats were exposed to 3 degrees C or were maintained at 22 degrees C for 2, 8, 48, or 96 h (experiment 1) or for 15, 30, or 60 min (experiment 2). To ensure that cold-induced changes in 5HT activity were not due to disturbances in diurnal pattern, rats in experiment 3 were exposed to cold (8 h) during the dark cycle. To explore the hypothesis that cold-induced 5HT activation is part of a broad metabolic response that includes activation of the sympathetic nervous system, metabolically impaired (hypothyroid) rats were exposed to 8 degrees C in experiment 4. Significant increments in 5-hydroxyindoleacetic acid (SHIAA) concentration were evident by 60 min of cold exposure and existed at all later time points measured. These findings were most robust in spinal cord and rostral brainstem. Activation in spinal cord was also found when rats were exposed to 8 h of cold during the dark cycle, the active period for rats. In experiment 4, hypothyroid rats exhibited significantly greater norepinephrine excretion compared with control rats exposed to the same cold stimulus; this finding was accompanied by significantly greater increments in 5HIAA concentration in rostral brainstem and spinal cord of hypothyroid rats. In addition, significant elevations in tryptophan concentration were noted throughout the brainstem and spinal cord of cold-exposed, hypothyroid rats relative to room temperature, hypothyroid rats. This finding suggested that elevations in 5HIAA concentration in these rats were due to increases in precursor availability. The implications of these findings relative to autonomic and metabolic control are discussed.

Animals↗

PubMed1998

Bulbospinal serotonergic activity during changes in thyroid status.

A three-part study explored the basis for an interaction between changes in thyroid status and bulbospinal serotonin (5HT) metabolism. In experiment 1, three well-characterized models of primary hypothyroidism were all accompanied by significant increases in 5HT metabolism. In experiment 2, circulating thyroid hormone levels were experimentally varied from very low methimazole (Meth) treatment to very high (T3 implants: 2.5, 5.0, or 7.5 mg triiodothyronine). As in experiment 1, Meth led to elevated 5HT. Hyperthyroidism was accompanied by significant reductions in 5HT, while urinary norepinephrine excretion paralleled 5HT. In experiment 3, rats were subjected to Meth either 2 weeks before or after induction of diabetes with streptozotocin (Stz). Meth prevented Stz-associated reductions in 5HT and attenuated development of hyperphagia. Meth could not reverse established Stz-associated reduction in 5HT or hyperphagia, although both were slightly attenuated. Thus, although the first two experiments argue for a simple inverse relationship between circulating thyroid hormone levels and 5HT in the brain, experiment 3 demonstrated that Stz-associated decrements in 5HT could not be reversed by subsequent lowering of circulating thyroid hormone. Nor did accompanying measurements indicate that glycemic status or circulating levels of leptin were important predictors of 5HT. Thus the interaction between thyroid hormones and 5HT is both more subtle and more complex than previously thought.

Animals↗

PubMed1996

Caloric restriction and spatial learning in old mice.

Spatial learning in old mice (19 or 24 months old), some of which had been calorically restricted beginning at 14 weeks of age, was compared to that of young mice, in two separate experiments using a Morris water maze. In the first experiment, only old mice reaching criterion performance on a cued learning task were tested in a subsequent spatial task. Thus, all old mice tested for spatial learning had achieved escape latencies equivalent to those of young controls. Despite equivalent swimming speeds, only about half the old mice in each diet group achieved criterion performance in the spatial task. In the second experiment, old and young mice all received the same number of training trials in a cued task and then in a spatial task. Immediately following spatial training, they were given a 60-s probe trial, with no platform in the pool. Both groups of old mice spent significantly less time in the quadrant where the platform had been and made significantly fewer direct crosses over the previous platform location than did the young control group. As in Experiment 1, calorie restriction failed to provide protection against aging-related deficits. However, in both experiments, some individual old mice evidenced performance in spatial learning indistinguishable from that of young controls. Separate comparisons of "age-impaired" and "age-unimpaired" old mice with young controls may facilitate the identification of neurobiological mechanisms underlying age-related cognitive decline.

Aging↗

PubMed1994

Metabolic and neurochemical profiles in insulin-treated diabetic rats.

Plasma glucose concentration was measured at 3-h intervals in streptozotocin-induced diabetic rats placed on various insulin replacement regimens using three different kinds of insulin. High insulin dosages produced at least periodic hypoglycemia, even though there were no overt signs of insulin overdose. Low- and single-dose regimens produced periods of hyperglycemia. Both high and low doses of protamine zinc insulin normalized diabetes-induced reductions in 5-hydroxyindole-3-acetic acid [5-HIAA; the principal metabolite of 5-hydroxytryptamine (5-HT)] and 5-HT turnover (5-HIAA/5-HT), despite the failure of the low-dose regimen to normalize plasma glucose. Diabetic rats evidenced continued hyperphagia and hyperdipsia during insulin treatment, and insulin treatment also induced hyperphagia and excessive weight gain in nondiabetic rats. Insulin treatment only partially normalized diabetes-induced adrenal hypertrophy. Adrenal hypertrophy is an indication of a continued stresslike physiological state in diabetes even during insulin therapy. This state may be involved in the enhanced risk in diabetic humans for development of anxiety disorders and clinical depression.

Analysis of Variance↗

PubMed1992

Reemergence of spontaneous hypertension in hypoxia-protected rats returned to normoxia as adults.

Five-week-old male spontaneously hypertensive rats (SHR) were either exposed to hypoxia or maintained in normoxia. Groups of rats were returned to normoxia after 8 or 12 weeks exposure to hypoxia while others remained in hypoxia or normoxia throughout the study. Subdivisions of the groups were sacrificed 2 or 6 weeks after return to normoxia at the same time as were rats continuously exposed to either normoxia or hypoxia. Hypoxia attenuated the development of systemic hypertension (P less than 0.05); however, this protection dissipated partially when rats were returned to normoxia. Norepinephrine concentration was significantly elevated and serotonin turnover (5-hydroxyindoleacetic acid/serotonin 5HIAA/5HT) was significantly decreased in caudal brainstem of hypoxic SHR and both were gradually normalized upon return to normoxia. Similarly, left ventricular hypertrophy was attenuated and adrenal catecholamine contents were increased with hypoxic exposure. Both gradually normalized upon return to normoxia. Mechanisms associated with the development of spontaneous hypertension reemerge when adult, previously hypoxic SHR are returned to a normoxic environment. These findings implicate long-term changes in central noradrenergic and serotonergic function as components of the cardiovascular adaptation to hypoxia which includes hypoxic moderation of spontaneous hypertension.

Altitude↗

PubMed1992

Streptozotocin-induced decreases in serotonin turnover are prevented by thyroidectomy.

Although characterized as hypothyroid, streptozotocin-diabetic rats have reduced serotonin turnover (5-hydroxyindoleacetic acid/serotonin, 5-HIAA/5-HT) in brain stem, while hypothyroid rats have increased 5-HIAA/5-HT. In the present study the two treatments were combined to determine if they affected 5-HIAA/5-HT through the same mechanism. In addition, an alternative method was used to assess 5-HT activity in thyroidectomized (TX) rats, i.e. measurement of 5-HT disappearance after inhibition of tryptophan hydroxylase with p-chlorophenylalanine (PCPA). Adult male rats were first TX (experiment 1) or given methimazole (METH; experiment 3). Two weeks later, diabetes (DB) was induced with streptozotocin in hypothyroid rats and euthyroid controls. Two weeks later, functional measurements were taken. Rats were then killed, and spinal cord and brain stem serotonin turnover (5-HIAA/5-HT), as well as plasma T3, T4 and corticosterone (CORT) concentrations were measured. TX attenuated diabetic hyperphagia and weight loss. DB alone led to moderate reductions in T3 and T4, but the hormones were barely detectable in plasma of TX and METH rats. CORT was elevated in DB but was not affected by TX. Open field activity was not affected by DB or TX. TX and METH significantly increased 5-HIAA/5-HT in both spinal cord and brain stem. TX also led to enhanced disappearance of 5-HT after PCPA. DB significantly reduced 5-HIAA/5-HT, suggesting independent effects of the treatments. However, DB-TX rats still had significantly higher 5-HIAA/5-HT than control-sham surgery rats, while DB-METH rats had 5-HIAA/5-HT indistinguishable from controls. In both cases, prior induction of primary hypothyroidism interfered with the expected diabetes-induced reduction in 5-HT turnover.

Animals↗

PubMed1992

Hypoxic attenuation of brain stem serotonin does not influence sodium-induced hypertension.

Sodium (Na+)-dependent hypertension was studied in hypoxia in an effort to determine the basis for hypoxia-mediated attenuation of hypertension. Hypoxia attenuated spontaneous hypertension while Na+ increased blood pressure in SHR. A lack of interaction between the effects of hypoxia and Na+ indicated additivity of effects. As a result, hypoxia-exposed, Na(+)-supplemented SHR had similar blood pressure as did normoxic, nonsupplemented SHR although both groups had lower blood pressure than normoxic, Na(+)-supplemented SHR. Hypoxia decreased serotonin turnover (5-HIAA/5-HT) in the brain stem of SHR while supplemental Na+ had no influence on this measurement. Hypoxic exposure in DOCA-treated rats failed to prevent the development of hypertension although hypoxia decreased 5-HIAA/5-HT in the brain stem of hypoxic rats, irrespective of DOCA treatment. The finding in SHR that Na+ counteracts the protection of hypoxia could be argued to support a similar mechanism of action for hypoxia and sodium. However, the results with DOCA treatment clearly refute such an interpretation. Our findings indicate that the pressor influence of Na+ does not occur through the modulation of brain stem 5-HIAA/5-HT.

Animals↗

PubMed1991

The functional significance of biochemical alterations in streptozotocin-induced diabetes.

These experiments examined the effects of restraint stress on dopamine (DA) and 5-hydroxytryptamine (5-HT) and their principal metabolites dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA), respectively, in 4 brain regions, as well as on plasma corticosterone concentration (CORT) and behavior in streptozotocin-induced diabetic rats and nondiabetic controls. Diabetic rats had widespread reductions in DA and 5-HT turnover (DOPAC/DA and 5-HIAA/5-HT ratios). Restraint led to equivalent increases in DA turnover in diabetics and nondiabetics, but attenuated increases in 5-HT turnover in diabetic rats. CORT concentration of diabetics and nondiabetics measured in complete quiet did not differ. Relative to these measures, only diabetics had elevated CORT when either restrained or kept in the same room with restrained rats with food and water removed. Open-field exploration was suppressed by restraint in diabetics only. All diabetic rats showed decreased locomotion in a novel environment which was normalized during a second exposure to the apparatus. Together, these results suggest that diabetes-induced disruptions in open-field activity are related to anxiety rather than to motor or energy deficits, and may be related to impaired 5-HT and CORT systems.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1991

Hypothyroidism increases serotonin turnover and sympathetic activity in the adult rat.

Adult, male Sprague-Dawley rats underwent surgical thyroidectomy (Tx) or sham surgery. In all three experiments from which data are reported, a 3-week recovery period was allowed. In experiments I and II, baseline measurements of colonic temperature (Tc) and urinary norepinephrine excretion (NE) were obtained, and both variables were monitored daily for the duration of the studies. After baseline measurements, half of each surgical group was given either triiodothyronine (T3) or vehicle injections subcutaneously; in experiment I replacements continued for 1.5 days, while in experiment II T3 replacement continued for 3.5 days. Rats were decapitated at the end of each experiment and serotonin (5-HT) turnover was measured in brainstem. Serotonin turnover in rostral and caudal brainstem was increased with Tx (p less than 0.05). Increased turnover in caudal brainstem was normalized by T3 only in experiment II. Similarly, decreased Tc and elevated NE with Tx were normalized in experiment II but not in experiment I. In experiment III, NE measurements normalized on a creatinine excretion basis indicated that increased NE is evident with Tx, irrespective of normalization procedure. Significant correlations between 5-HT in caudal brainstem and metabolic correlates of sympathetic function, concurrent normalization of NE and 5-HT in caudal brainstem, plus work from other laboratories describing sympathoexcitatory serotonergic neurons located in the caudal brainstem suggest that the central and peripheral changes in the hypothyroid rat are causally related.

Animals↗

PubMed1991

Altered behavior and neurochemistry during short-term insulin withdrawal in streptozocin-induced diabetic rats.

Amphetamine-induced stereotypy and turnover of dopamine (DA) and serotonin (5-HT) in the CNS were assessed in streptozocin-induced diabetic rats 48 h after withdrawal from insulin treatment and compared with nondiabetic controls, diabetic rats receiving continued insulin treatment, and chronically hyperglycemic diabetic rats. Stereotypy was attenuated in chronically hyperglycemic diabetic rats but normalized in insulin-treated diabetic rats. Stereotypy in insulin-withdrawn rats was intermediate, being attenuated significantly relative to controls but not significantly different from either insulin-treated diabetic rats or chronically hyperglycemic diabetic rats. DA turnover was significantly reduced in striatum and hypothalamus in all diabetic groups. 5-HT turnover was reduced in chronically hyperglycemic diabetic rats in all four brain regions but normalized in insulin-treated diabetic rats. Insulin-withdrawn diabetic rats had significantly reduced 5-HT turnover in frontal cortex. Taken together, the findings indicate that insulin replacement does not normalize diabetes-induced reduction in DA turnover and that short-term insulin withdrawal, e.g., occurring clinically with noncompliance, affects both 5-HT turnover in some brain regions and behavior.

Amphetamine↗

PubMed1990

Altered responses to environmental stress in streptozotocin-diabetic rats.

Metabolic and biochemical adaptations were compared in streptozotocin-diabetic and nondiabetic control rats exposed for 24 hours to a cold environment (4 degrees C) or hypobaric hypoxia (simulated altitude = 12,000 ft). In the cold, diabetic rats had greater reductions in adrenal norepinephrine (NE) and greater elevations in urinary NE and epinephrine excretion. However, diabetics did not increase food intake, whereas cold-exposed nondiabetic rats did. 5-HT turnover was reduced in hypothalamus and elevated in brain stem in both diabetics and nondiabetics. Responses to hypoxia were different. Both diabetics and nondiabetics reduced food and water intake and had elevated plasma glucose concentrations. Diabetics had elevated urinary NE excretion. Hypothalamic NE concentration and dopamine turnover were significantly reduced by hypoxia. Brain stem 5-HT turnover was also reduced in nondiabetics but not in diabetics. Thus, diabetics had a different response profile to the environmental stressors than nondiabetics. In addition, the two stressors elicited different responses. Some stressors may be more debilitating in diabetics. The greater reactivity of the sympathetic nervous system in diabetics suggests a mechanism by which stress leads to increased risk of metabolic complications in diabetes mellitus.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1989

Central catecholaminergic responses in hypoxic moderation of spontaneous hypertension.

Exposure to hypobaric hypoxia (H; simulated altitude = 3658 m) was initiated in 5-week-old, male spontaneously hypertensive (SHR) and Wistar-Kyoto (WKy) normotensive rats while normoxic controls (N) for both groups were maintained under laboratory conditions. Significant attenuation of systolic arterial blood pressure was evident in SHR-H relative to SHR-N (125 +/- 6 vs. 145 +/- 5, mmHg; p less than 0.05) while blood pressure in the normotensive, Wistar-Kyoto rat was not affected by 20 days of exposure to hypoxia (WKy-H, 116 +/- 2 vs. WKy-N, 117 +/- 5, mmHg). Increased contents of norepinephrine and dopamine in brain stem, striatum, hypothalamus, and frontal cortex in SHR versus WKy indicated a possible involvement of central catecholaminergic mechanisms with spontaneous hypertension. Hypoxia significantly decreased neuronal contents of both neurotransmitters, typically on both days studied (days 4 and 21 of altitude treatment). In striatum and hypothalamus, dihydroxyphenylacetic acid to dopamine ratios indicated that dopamine turnover was decreased with hypoxia. Hypoxia elicits catecholaminergic responses consistent with profiles found following ICV administration of 6-hydroxydopamine, a sympatholytic agent that also prevents the development of spontaneous hypertension. Hypoxic mitigation of spontaneous hypertension may occur via mechanisms initiated at the level of the CNS.

Animals↗

PubMed1989

Diabetes mellitus: stress, neurochemistry and behavior.

Neurochemical alterations in several rodent models of insulin-dependent diabetes are compared and their relevance to behavioral and physiological pathology in the clinical disorder is discussed. In the majority of rodent models, reductions in metabolism of norepinephrine (NE), dopamine (DA) and serotonin (5HT) in the central nervous system (CNS) have been reported. While there are two reports of increased 5HT turnover in CSF or post-mortem brains of diabetic humans experiencing severe ketoacidosis, these patients were receiving insulin therapy. Insulin appears to have effects on monoamines opposite to that of chronic hyperglycemia. Both in rodent models and in clinical populations, there is widespread evidence of enhanced hormonal and behavioral responsiveness to stress. There are findings in rodent models indicating that hormonal responses to stress are related to CNS monoamine activity. The mechanisms responsible for both hormonal and CNS alterations in diabetes, as well as their involvement in behavioral pathology, can best be investigated further using animal models.

Animals↗

PubMed1989

Stress and behavior in streptozotocin diabetic rats: biochemical correlates of passive avoidance learning.

Retention of one-trial passive avoidance training was compared in diabetic and nondiabetic rats. Also compared were corticosterone concentrations associated with both training and retention testing, catecholamine excretion related to training, and regional brain catecholamine concentrations accompanying retention testing. Diabetic rats showed significantly better retention for the task than did nondiabetic rats. Associated with retention differences, diabetic rats had higher epinephrine excretion and nondiabetic rats had lower excretion after footshock training relative to baseline measures. Norepinephrine excretion was elevated in diabetics both in baseline measurement and during the 24 hr following footshock training. No differences were found in baseline or stimulated corticosterone concentration between diabetic and nondiabetic rats. Diabetic rats had higher concentrations of norepinephrine (NE) and dopamine (DA) and lower 3,4-dihydroxyphenylacetic acid/dopamine (DOPAC/DA) ratios in hypothalamus and higher NE in brain stem and amygdala than did nondiabetics, although both diabetic and nondiabetic rats had reduced DA and NE following retention testing. The results indicate that there are biochemical alterations in diabetes that may have important behavioral impact.

Animals↗

PubMed1989

Sympathetic and metabolic correlates of hypoxic moderation of spontaneous hypertension in the rat.

Exposure to hypobaric hypoxia (H; simulated altitude = 3658 m) was initiated in 5-week-old, male spontaneously hypertensive (SHR) and Wistar-Kyoto (WKy) normotensive rats while normoxic controls (N) for both groups were maintained under laboratory conditions. Significant attenuation of systolic arterial blood pressure was evident in SHR-H relative to SHR-N (125 +/- 6 vs 145 +/- 5 mm Hg; P less than 0.05) but not in WKy-H relative to WKy-N (WKy-H, 116 +/- 2 vs WKy-N, 117 +/- 5 mm Hg). Hypoxia significantly decreased metabolic efficiency in both normotensive and hypertensive rats, although being both more severe and accompanied by significantly impaired growth rate in SHR-H. Urinary excretion of norepinephrine in the SHR was elevated relative to WKy, irrespective of altitude treatment, while hypoxia elicited similar increases in urinary excretion of norepinephrine in both SHR and WKy. Myocardial and adrenal contents of norepinephrine were significantly reduced following 3 days of simulated altitude exposure in both strains of rats. Tissue contents of norepinephrine in hypoxic rats returned to normoxic levels by 21 days of simulated altitude. Both urine and tissue indices provided consistent indirect evidence that changes in sympathetic neuronal activity in response to hypoxia were similar in normotensive and hypertensive rats. These findings suggest that prior reports of reduced alpha-adrenergic responsiveness in vasculature from hypoxia-exposed SHR reflect a postsynaptic event that is regulated independently of norepinephrine release from sympathetic nerve terminals.

Adrenal Glands↗