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Biomedical subjects

K Pacák

Publications and source records attributed to K Pacák.

At least 19 recordsLinked to original sources
PubMed2005

Increased lipolysis of subcutaneous abdominal adipose tissue and altered noradrenergic activity in patients with Cushing's syndrome: an in-vivo microdialysis study.

Cushing's syndrome is associated with typical central redistribution of adipose tissue. The aim of the study was to assess lipolysis and catecholamines and their metabolites in subcutaneous abdominal adipose tissue using an in-vivo microdialysis technique. Nine patients with Cushing's syndrome and nine age-, gender- and body mass index (BMI)-matched control subjects were included in the study. Local glycerol concentrations were significantly increased in subcutaneous adipose tissue of patients with Cushing's syndrome (p<0.001). Plasma noradrenaline, dihydroxyphenylglycol and dihydroxyphenylalanine were decreased in patients with Cushing's syndrome (p<0.02, p<0.05, and p<0.02, respectively). Adrenaline, noradrenaline, dihydroxyphenylglycol and dihydroxyphenylalanine concentrations in subcutaneous abdominal adipose were non-significantly higher in patients with Cushing's syndrome. In conclusion, we showed that lipolysis in subcutaneous adipose tissue of patients with Cushing's syndrome is significantly increased as compared to healthy subjects. This finding together with non-significantly increased local catecholamine concentrations in these patients suggests a possible link between increased lipolysis and catecholaminergic activity in subcutaneous adipose tissue.

Abdomen↗
PubMed2004

Increased subcutaneous abdominal tissue norepinephrine levels in patients with anorexia nervosa: an in vivo microdialysis study.

The present study was designed to measure interstitial levels of norepinephrine-regulating lipolysis (NE) in subcutaneous abdominal adipose tissue of anorexia nervosa (AN) patients and control subjects under basal conditions and after the local administration of an inhibitor of NE re-uptake, maprotiline. In vivo microdialysis technique was used to assess subcutaneous adipose NE levels in five women with AN (body mass index 14.62+/-0.47 kg/m(2)) and six age-matched controls (22.1+/-0.52 kg/m(2)). NE was assayed using high performance liquid chromatography with electrochemical detection after batch alumina extraction. Measured basal adipose tissue NE levels reflecting its interstitial levels were significantly increased in AN patients compared to the controls (106.0+/-20.9 vs. 40.0+/-5.0 pg/ml). The local maprotiline administration resulted in a significant increase in adipose tissue NE levels (AN patients: 440.0+/-28.6 vs. 202.0+/-33.0 pg/ml in the controls) in both groups. Markedly increased subcutaneous abdominal adipose tissue NE levels in AN patients compared to control subjects reflect increased sympathetic nervous system activity but not altered membrane noradrenergic transporter system in anorexia nervosa patients.

Abdomen↗
PubMed2003

Application of in vivo microdialysis to measure leptin concentrations in adipose tissue.

Microdialysis is a relatively new in vivo sampling technique, which allows repeated collecting of interstitial fluid and infusion of effector molecules into the tissue without influencing whole body function. The possibility of using microdialysis catheter with a large-pore size dialysis membrane (100 kDa) to measure concentrations of the adipocyte-derived peptide hormone leptin in interstitial fluid of adipose tissue was explored. Krebs-Henseleit buffer with 40 g/l dextran-70 was used to prevent perfusion fluid loss across the dialysis membrane. The relative recovery of leptin in vitro was determined using CMA/65 microdialysis catheter (100 kDa cut-off, membrane length 30 mm; CMA, Stockholm, Sweden) and four perfusion rates were tested (0.5, 1.0, 2.0, 5.0 microl/min). Furthermore, the microdialysis catheter CMA/65 was inserted into subcutaneous abdominal adipose tissue of 11 healthy human subjects and leptin concentrations in the interstitial fluid of adipose tissue in vivo were measured. The present findings are the first documentation on the use of microdialysis to study local leptin concentrations in the interstitial fluid of adipose tissue.

Adipocytes↗
PubMed2003

[Use of the in vivo microdialysis technique in basic and clinical research].

Microdialysis is in vivo technique that permits monitoring of local concentrations of metabolites and drugs at specific sites in the body that makes it an attractive tool for the basic and clinical research. Microdialysis entered the experimental studies of the brain, and later also of the peripheral tissues such as adipose and muscle tissues, kidney, lung, eye, skin, and blood. There are several critical factors in the experimental implementations of microdialysis: the probe, the perfusion solution, tissue integrity, and the sensitivity of microdialysate analysis method. When the experimental conditions are optimised to give valid results, microdialysis can provide numerous data from the relatively small number of individual subjects. It can bring about detailed clinical information reflecting free metabolite and drug concentrations in studied tissues and/or in plasma. With the progress of analytical methods, applications and importance of the microdialysis technique in clinical and pharmacokinetic research and diagnostics will increase.

Humans↗
PubMed2001

The role of dopamine in methylene blue-mediated inhibition of estradiol benzoate-induced anterior pituitary hyperplasia in rats.

Recently, we demonstrated that methylene blue partially inhibited estradiol-benzoate-induced anterior pituitary hyperplasia in rats. Since central dopaminergic systems participate in the regulation of estrogen-induced anterior pituitary growth and tumor transformation, this study examined whether a 3-week treatment with methylene blue could affect anterior pituitary levels of dopamine (DA), dihydroxyphenylalanine (DOPA), and dihydroxyphenylacetic acid and dopamine (D-2) receptors in male rats. Compared to controls, methylene blue significantly decreased anterior pituitary weight, increased basal anterior pituitary DA levels, and inhibited estradiol benzoate-induced decreases in anterior pituitary DA concentrations. Furthermore, we found that methylene blue alone decreased anterior pituitary D-2 receptor number. Methylene blue given in combination with estradiol benzoate partially inhibited estradiol benzoate-induced anterior pituitary growth and estradiol benzoate-induced increases in D-2 receptor number. Estradiol benzoate-treated rats had significantly lower anterior pituitary DOPA accumulation after intraperitoneal administration of 3,4-hydroxybenzyl-hydrazine dihydrochloride (NSD-1015), an irreversible inhibitor of L-aromatic amino acid decarboxylase whereas methylene blue did not affect anterior pituitary DOPA accumulation when compared to controls. Methylene blue decreased anterior pituitary prolactin levels and inhibited increases in anterior pituitary prolactin after estradiol benzoate administration. The present results suggest that anterior pituitary DA may play an important role in estrogen-induced anterior pituitary hyperplasia and tumor formation and that antioxidant drugs such as methylene blue may attenuate estrogen-induced pituitary growth. This may occur via increases in anterior pituitary DA levels associated with down-regulation of anterior pituitary D-2 receptors.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2001

Stressor specificity of central neuroendocrine responses: implications for stress-related disorders.

Despite the fact that many research articles have been written about stress and stress-related diseases, no scientifically accepted definition of stress exists. Selye introduced and popularized stress as a medical and scientific idea. He did not deny the existence of stressor-specific response patterns; however, he emphasized that such responses did not constitute stress, only the shared nonspecific component. In this review we focus mainly on the similarities and differences between the neuroendocrine responses (especially the sympathoadrenal and the sympathoneuronal systems and the hypothalamo-pituitary-adrenocortical axis) among various stressors and a strategy for testing Selye's doctrine of nonspecificity. In our experiments, we used five different stressors: immobilization, hemorrhage, cold exposure, pain, or hypoglycemia. With the exception of immobilization stress, these stressors also differed in their intensities. Our results showed marked heterogeneity of neuroendocrine responses to various stressors and that each stressor has a neurochemical "signature." By examining changes of Fos immunoreactivity in various brain regions upon exposure to different stressors, we also attempted to map central stressor-specific neuroendocrine pathways. We believe the existence of stressor-specific pathways and circuits is a clear step forward in the study of the pathogenesis of stress-related disorders and their proper treatment. Finally, we define stress as a state of threatened homeostasis (physical or perceived treat to homeostasis). During stress, an adaptive compensatory specific response of the organism is activated to sustain homeostasis. The adaptive response reflects the activation of specific central circuits and is genetically and constitutionally programmed and constantly modulated by environmental factors.

Adrenocorticotropic Hormone↗
PubMed2000

CRH deficiency impairs but does not block pituitary-adrenal responses to diverse stressors.

We have previously observed significant, albeit decreased, corticosterone responses to restraint stress in corticotropin releasing hormone (CRH)-deficient (knockout, CRH KO) mice. Because different stressors have been shown to engage different populations of hypophysiotropic neurons, we have used hypoglycemia and hypovolemia to test whether CRH-independent pituitary-adrenal activation is evoked by stimuli other than restraint. Insulin injection in fasted CRH KO mice elicited increases in corticosterone that were markedly lower than those in wild type but marginally significant relative to corresponding KO controls. Consistent with impaired adrenocortical function, hypoglycemia-induced epinephrine secretion was reduced in female CRH KO mice. Hypovolemia produced by retro-orbital bleeding also significantly elevated corticosterone in CRH KO mice. In contrast to significant stress-induced increases in corticotropin (ACTH) in wild-type mice, those in CRH KO mice were slight, transient and difficult to detect without frequent sampling. Restraint-induced interleukin-6 (IL-6) levels were similar between wild-type and CRH KO mice, arguing against compensatory changes in IL-6 responses to restraint due to CRH deficiency. CRH infusion enhanced adrenocortical responses to restraint independently of effects on basal corticosterone levels, suggesting that pituitary-adrenal activity is augmented by factors besides CRH during stress. We conclude that although stress-induced pituitary-adrenal activity does not require acute increases in CRH, CRH is required to support the normal amplitude of adrenocortical axis responsiveness to other endocrine or neural factors during stress.

Adrenocorticotropic Hormone↗
PubMed2000

Impaired basal and restraint-induced epinephrine secretion in corticotropin-releasing hormone-deficient mice.

CRH is thought to play a role in responses of the adrenocortical and adrenomedullary systems during stress. To investigate the role of CRH in stress-induced secretions of corticosterone and epinephrine, we subjected wild-type (WT) and CRH-deficient (knockout, KO) mice to restraint, and analyzed plasma corticosterone, plasma catecholamines, and adrenal phenylethanolamine N-methyltransferase (PNMT) gene expression and activity before and during 3 h of restraint. Plasma corticosterone increased over 40-fold in WT mice, but minimally in CRH KO mice. Adrenal corticosterone content tended to increase in CRH KO mice, although to levels 5-fold lower than that in WT mice. CRH KO mice had significantly lower plasma epinephrine and higher norepinephrine than WT mice at baseline, and delayed epinephrine secretion during restraint. Adrenal PNMT messenger RNA content in CRH KO mice tended to be lower than that in WT mice, though the degree of induction was similar in both genotypes. PNMT enzyme activity was significantly lower in CRH KO mice. Pharmacological adrenalectomy abolished restraint-induced corticosterone secretion and PNMT gene expression in WT mice, consistent with an absolute requirement of glucocorticoids for PNMT gene expression. We conclude that glucocorticoid insufficiency in CRH KO mice leads to decreased basal and restraint-induced plasma epinephrine and adrenal PNMT gene expression and enzyme activity.

Adrenalectomy↗
PubMed2000

Stressor-specific activation of the hypothalamic-pituitary-adrenocortical axis.

New information has accrued from in vivo microdialysis studies about stress-related changes in norepinephrine concentrations in extracellular fluid of the paraventricular nucleus (PVN) and the activation of the hypothalamic-pituitary-adrenocortical (HPA) axis. Our data on the effects of lower brainstem hemisections show that paraventricular noradrenergic terminals are derived mainly from medullary A1 and A2 catecholaminergic cells. The activation of these cells contributes importantly to stress-induced noradrenergic activation in the paraventricular nucleus of conscious animals. The results from brainstem hemisection experiments also indicate that baseline levels and immobilization-induced increments in corticotropin-releasing hormone (CRH) mRNA expression in the PVN depend on ipsilaterally ascending medullary tract. Thus, the prevalent concept that stress-induced noradrenergic activation of the HPA axis depends mainly on activation of locus ceruleus noradrenergic neurons requires re-evaluation. Our new stress concepts favor stressor-specific activation of the HPA axis. The present data also suggest the existence of stressor-specific central pathways that differentially participate in the regulation of sympathoneuronal and adrenomedullary outflows as well as of the activity of the HPA axis. Furthermore, the results are inconsistent with a founding tenet of Selye's stress theory, the doctrine of nonspecificity, which defines stress as the nonspecific response of the body to any demand. We expect that future studies in this area will focus on further examination of the notion of stressor-specific patterns of central neurotransmitter release and elucidate the genetic bases of these patterns.

Adrenocorticotropic Hormone↗
PubMed2000

The regulation of adenohypophyseal prolactin secretion: effect of triiodothyronine and methylene blue on estrogenized rat adenohypophysis.

Estrogens and thyroid hormones contribute importantly to cell proliferation and tumor transformation in the pituitary gland. We found that methylene blue antagonized estrogen-promoted adenohypophyseal enlargement and the enhancement of prolactin secretion. The purpose of the present article is to provide a review about neurotransmitters and their receptors involved in estrogen-induced anterior pituitary growth and in the antagonistic effects of triiodothyronine (T3) and methylene blue (MB). Central dopaminergic and noradrenergic systems are the most important factors regulating pituitary growth and function. Recently nitric oxide (NO) was added to the list of the neurotransmitters and neuropeptides involved in the control of the anterior pituitary secretion. Our data suggest that estrogen-induced anterior pituitary growth is associated with decreased synthesis and metabolism of central catecholamines, reduction of adenohypophyseal beta-adrenergic receptors and increase of dopamine DA-2 receptors. We found that the treatment with T3 or MB prevented both estrogen-induced catecholaminergic inhibition and dopamine DA-2 receptor increment in the anterior pituitary. In contrast to T3, MB given alone also slightly decreased the anterior pituitary weight. Serum levels and anterior pituitary content of prolactin were increased after treatment with estradiol benzoate (EB), whereas T3 or MB partially attenuated prolactin hypersecretion after estrogen administration. This is in accord with the attenuation of EB-induced inhibition of dopaminergic system by T3 and MB. MB given in combination with EB also partially attenuated EB-promoted rise of adenohypohyseal NO synthase activity which plays an important role in the regulation of prolactin secretion. Further studies on central catecholaminergic systems, pituitary receptors, the nitrergic system and mechanisms of intracellular signal transduction are necessary for better understanding of pituitary tumor transformation and possibly for the discovery of new approaches towards treating patients with these diseases.

Adrenergic beta-Agonists↗
PubMed2000

[Pharmacologic control of hypophyseal tumors: interactions of estrogens, thyroid hormones, growth and anti-growth factors].

Estrogens are involved in anterior pituitary (AP) growth and tumor transformation of AP. Central dopaminergic and noradrenergic systems are probably most important systems in regulation of AP growth. Estrogen-induced AP growth is associated with decreased metabolism of central catecholamines and increased dopaminergic DA-2 receptors. Application of thyroid hormones or methylene blue prevents both estrogen-induced catecholaminergic inhibition and dopamine DA-2 receptors increment in the AP. The alone given methylene blue increases the dopaminergic activity and the binding sites for dopamine. The study of interaction of natural regulators or synthetic compounds with estrogen-induced pituitary growth will be of value to understand better mechanisms of pituitary tumor formation and possibly find new approaches towards treating patients with these tumors.

Animals↗
PubMed1998

Estrogenic effect of estradiol-sulfamate on the male rat anterior pituitary.

Estrogen sulfamates (ES) are used for a new treatment strategy to avoid liver-hormone and hormone-liver interactions. ES represent new synthetic steroids having an increased systemic and reduced hepatic estrogenicity when given orally [1,2]. In the present study effects of ES and estradiol-benzoate (EB) on adenohypophyseal (AP) and serum concentrations of prolactin (PRL), luteinizing hormone (LH), and pituitary contents of cAMP and cGMP in the male rat are demonstrated. The weight gain of experimental animals treated by ES, EB or both hormones simultaneously was significantly lower compared to controls. EB but not ES significantly increased the weight of the AP. The amounts of PRL in the AP and serum were significantly increased after EB administration. ES significantly increased only AP content of PRL. EB administered simultaneously with ES exhibited an additive effect on the AP plasma concentrations of PRL. The EB or ES significantly decreased AP and serum concentrations of LH. ES given simultaneously with EB further decreased AP and serum concentrations of LH. After administration of either ES or EB, AP contents of cAMP and cGMP were significantly increased. An additive effect of these estrogens on the cGMP content was found. ES given simultaneously with EB further increased cGMP content in the AP but partially inhibited the effect of EB on the AP cAMP content. The present results demonstrate that the effects of ES on the AP content of PRL, LH, cAMP, and cGMP differ from the effects of EB. Whether this is due to lower levels of estradiol after the administration of ES secondary to its different absorption when compared to EB is unknown. Thus, our data support the concept that the ES has a lesser estrogenic effect on the AP function.

Animals↗
PubMed1997

Chronic blockade of nitric oxide synthesis elevates plasma levels of catecholamines and their metabolites at rest and during stress in rats.

Formation of nitric oxide, and endothelium-derived relaxing factor, can be inhibited by administration of N-nitro-L-arginine methylesther (L-NAME). In the present study, the activity of the sympathoadrenal system in rats with blood pressure (BP) elevation induced by L-NAME was investigated. L-NAME was administered in a dose of 50 mg/kg, i.p. every 12 h for 4 days. Blood samples were collected via chronically inserted arterial catheters in conscious, freely moving rats at rest and during immobilization stress. Plasma epinephrine (EPI), norepinephrine (NE), and dopamine (DA), as well as catecholamine metabolites dihydroxyphenylglycol (DHPG) and dihydroxyphenylacetic acid (DOPAC) were measured by HPLC method. In L-NAME treated animals, which slowed a significant increase in BP, plasma EPI levels were markedly elevated both before and during stress. Plasma NE levels were not significantly increased, however, DHPG levels, which indicate NE turnover and reuptake, were highly elevated. Plasma DA levels were not changed after L-NAME administration but DA metabolite DOPAC showed a significant elevation both under basal conditions and during stress. Thus, the present results indicate that the prolonged blockade of nitric oxide synthesis that causes arterial hypertension is associated with an activation of the sympathoadrenal system.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1996

Triiodothyronine attenuates estradiol-induced increases in dopamine D-2 receptor number in rat anterior pituitary.

Estrogens promote adenohypophyseal enlargement and tumor transformation, and thyroid hormones antagonize these effects. Hormone-induced pituitary enlargement may be mediated by alterations in pituitary dopaminergic function. The present study examined the effects of chronic (20 days) administration of estradiol benzoate (EB), triiodothyronine (T3), or EB and T3 (T3 + EB) on dopamine (D-2) receptors in rat anterior pituitary. D-2 receptor number increased after EB without altered receptor affinity. T3 alone did not affect D-2 receptor number in the anterior pituitary but significantly attenuated the effect of EB. T3 administration also inhibited EB-induced anterior pituitary hyperplasia. D-2 receptor upregulation by EB more likely could reflect a compensatory response to decreased receptor occupation. The present results suggest that D-2 receptors could play an important role in estrogen-induced adenohypophyseal tumor formation and hyperprolactinemia and that thyroid hormones may inhibit estrogen-induced pituitary tumor development via adenohypophyseal D-2 receptors.

Animals↗