Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Dahl strain of genetically salt resistant (R) and salt sensitive (S) rats affords an opportunity to explore mechanisms for salt resistance and sensitivity. Because of the evidence that opioid peptides and their receptors can be involved in cardiovascular regulation, the objective of this study was to test the hypothesis that proopiomelanocortin (POMC), the precursor of beta-endorphin, is involved in the development of hypertension, through the determination of POMC mRNA in the pituitary. Three-week-old inbred Dahl R and S rats were maintained on a high salt diet (8% NaCl) or low salt diet (0.4% NaCl) for 6 weeks. POMC mRNA and for comparison preproenkephalin A (preproENK) mRNA were examined from tissues of Dahl R and S rats as determined by Northern blot analysis using beta-actin as an internal standard. POMC mRNA was abundant in the pituitary tissues. There was more POMC mRNA in the pituitary tissue of R rats compared with that of S rats on the high salt diet. Differences in POMC mRNA in the pituitary were not observed between R and S on the low salt diet. There were no differences in the levels of preproENK mRNA in the pituitary tissues of R and S rats on high or low salt diet. From these data, we propose that inefficient production of POMC mRNA is a characteristic of the Dahl S rat on a high salt diet.
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PMID:Differences in pituitary expression of proopiomelanocortin in Dahl salt-resistant and salt-sensitive rats on a high salt diet. 890 76

Twenty-one hydroxylase (21-OH)-deficient classic adrenal hyperplasia (CAH) and nonclassic adrenal hyperplasia (NCAH) are two of the most common genetic disorders known to man, yet the mechanism(s) resulting in steroid excess remains unclear. Overactivation of the hypothalamic-pituitary-adrenal (HPA) axis and increased ACTH secretion appear to be important mechanisms resulting in steroid excess in untreated patients, at least in the classic forms of the disorder. Nonetheless, most NCAH patients do not demonstrate overactivity of the HPA axis. A few of these patients may demonstrate a mild degree of ACTH hyper-responsiveness to corticotropin-releasing hormone stimulation, and up to 40% have radiologic evidence of adrenocortical hyperplasia and/or isolated adenomas, suggesting that some degree of chronic ACTH excess is present. Another mechanism resulting in adrenocortical excess in adrenal hyperplasia, and primarily in NCAH, follows the alteration in enzyme kinetics resulting from the mutation of 21-OH. The mutated enzyme product is less efficient than the wild type, resulting in an increased precursor to product ratio, independent of ACTH levels. Hence, progesterone (P4) and 17-hydroxyprogesterone (17-HP) levels in these patients may remain above normal even in the presence of excess glucocorticoid administration. Overactivity of the renin-angiotensin system may also be important in stimulating adrenocortical steroidogenesis in patients with salt-wasting and in some with simple virilizing CAH. Alterations in ovarian and gonadotropic function, with the appearance of a polycystic ovary-like picture, also contribute to the androgen excess of these patients. Functional ovarian abnormalities in patients with CAH or NCAH may relate to a number of causes, including prenatal masculinization of the hypothalamic-pituitary-ovarian (HPO) axis by adrenal androgens, continued disruption of the HPO axis by persistently elevated P4 or androgen levels, and/or a direct glucocorticoid effect. Finally, these data suggest that the measurement of P4 or 17-HP may not be the most accurate marker of therapeutic efficacy, and suppression of both the ovaries and adrenals may be necessary for optimum steroidogenic control.
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PMID:The 21-hydroxylase-deficient adrenal hyperplasias: more than ACTH oversecretion. 892 12

17beta-Estradiol (E2) rapidly (<20 min) attenuates the ability of mu-opioids to hyperpolarize guinea pig hypothalamic (beta-endorphin) neurons. In the current study, we used intracellular recordings from guinea pig hypothalamic slices to characterize the receptor and intracellular effector system mediating the rapid effects of E2. E2 acted stereospecifically with physiologically relevant concentration dependence (EC50 = 8 nM) to cause a 4-fold reduction in the potency of a mu-opioid agonist to activate an inwardly rectifying K+ conductance. Using Schild analysis to estimate the affinity of the mu-opioid receptor for an antagonist (naloxone), we found that estrogen did not compete for the mu-opioid receptor or alter the affinity of the mu receptor. Both the nonsteroidal estrogen diethylstilbestrol and the "pure" antiestrogen ICI 164,384 blocked the actions of E2, the latter with a subnanomolar affinity. The protein synthesis inhibitor cycloheximide did not block the estrogenic uncoupling of the mu-opioid receptor from its K+ channel, implying a nongenomic mechanism of action by E2. The actions of E2 were mimicked by the protein kinase A (PKA) activators forskolin and cAMP, Sp-isomer triethylammonium salt. Furthermore, the selective PKA antagonists cAMP, Rp-isomer triethylammonium salt and KT5720, which have different chemical structures and modes of action, both blocked the effects of E2. Thus, estrogen binds to a specific receptor that activates PKA to rapidly uncouple the mu-opioid receptor from its K+ channel. Because we have previously shown that gamma-aminobutyric acidB receptors are also uncoupled by estrogen, this mechanism of action has the potential to alter synaptic transmission via G protein-coupled receptors throughout the brain.
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PMID:Modulation of G protein-coupled receptors by an estrogen receptor that activates protein kinase A. 910 25

The data reviewed establish the presence and important role in body fluid homeostasis of brain atrial natriuretic peptide (ANP) in all vertebrate-species examined. The peptide is localized in neurons in hypothalamic and brain stem areas involved in body fluid volume and blood pressure regulation, and its receptors are located in regions that contain the peptide. Most, if not all, of the actions of ANP are mediated by activation of particulate guanylyl cyclase with generation of guanosine 3',5'-cyclic monophosphate, which mediates its actions in brain as in the periphery. Although atrial stretch releases ANP from cardiac myocytes, the experiments indicate that the response to acute blood volume expansion is markedly reduced after elimination of neural control. Volume expansion distends baroreceptors in the right atria, carotid-aortic sinuses, and kidney, altering afferent input to the brain stem and hence the hypothalamus, resulting in stimulation via ANPergic neurons in the hypothalamus of oxytocin release from the neurohypophysis that circulates to the right atrium to stimulate ANP release. The ANP circulates to the kidney and induces natriuresis. Atrial natriuretic peptide also induces vasodilation compensating rapidly for increased blood volume by increased vascular capacity. Atrial natriuretic peptide released into hypophysial portal blood vessels inhibits release of adrenocorticotropic hormone (ACTH), thereby decreasing aldosterone release and enhancing natriuresis. Furthermore, the ANP neurons inhibit AVP release leading to diuresis and decreased ACTH release. Activation of hypothalamic ANPergic neurons via volume expansion also inhibits water and salt intake. These inhibitory actions may be partially mediated via ANP neurons in the olfactory system altering salt taste. Atrial natriuretic peptide neurons probably also alter fluid movement in the choroid plexus and in other brain vascular beds. Therefore, brain ANP neurons play an important role in modulating not only intake of body fluids, but their excretion to maintain body fluid homeostasis.
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PMID:Atrial natriuretic peptide in brain and pituitary gland. 911 21

Novel subtype of corticotropin-releasing hormone receptor (CRHR), designated type-2 CRHR (CRHR-2), mRNA was expressed not only in the central nervous system but also in the peripheral tissues such as the heart and skeletal muscle. The previous finding that type-1 CRHR mRNA is not detected in heart leads us to speculate that systemic administration of CRH induces hypotensive effects through CRHR-2, and that alterations in CRHR-2 in the heart may be implicated in blood pressure regulation. Therefore we examined CRHR-2 mRNA expression in the heart (at the level of ventricle) in spontaneously hypertensive rats (SHR) or DOCA-salt hypertensive rats (DOCA) using in situ hybridization histochemistry, compared to age-matched normotensive control rats. CRHR-2 mRNA levels in the heart were significantly higher in 7-week-old SHR than in 12-week-old SHR. Furthermore, CRHR-2 mRNA levels in SHR heart were significantly higher than those in normotensive controls, Wistar-Kyoto rats (WKY), at both 7 and 12 weeks of age. In contrast, CRHR-2 mRNA levels in DOCA heart were significantly lower than that of sham-operated controls after 6-weeks of treatment. Thus, alterations of CRHR-2 mRNA are dependent on the strain or experimental condition rather than as a consequence of hypertension. Plasma CRH levels in SHR or DOCA were not different from their normotensive control rats. CRH content in the ventricular heart of SHR or DOCA were also similar to normotensive controls. These results suggest that heart CRHR-2 mRNA levels are not influenced by circulating or locally existing CRH. Since alterations in heart CRHR-2 mRNA, as seen in SHR and DOCA, were bi-directional, the role of heart CRHR-2 in the regulation of hypertension remains to be elucidated.
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PMID:Type 2 corticotropin-releasing hormone receptor mRNA expression in the heart in hypertensive rats. 946 63

The cloning of melanocortin receptors opened new avenues to identify selective ligands for this receptor family. gamma-MSH was characterized as a melanocortin-3 receptor selective agonist, [D-Arg8]ACTH-(4-10) and [Pro8,10, Gly9]ACTH-(4-10) were characterized as melanocortin-4 receptor antagonists. The application of these ligands in vivo revealed that melanocortin-4 receptors mediate melanocortin-induced grooming behaviour in the rat. Since we still lack potent and selective melanocortin receptor ligands, we performed homology modelling and site directed mutagenesis of the melanocortin-4 receptor, in order to understand how melanocortins bind melanocortin receptors. A histidine at position 260 in the melanocortin-4 receptor is important for normal receptor function. However this residue is not forming a salt bridge with a glutamate at position 92 to keep the receptor in an inactive conformation, nor with the glutamate in the melanocortin peptides as had been suggested before.
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PMID:Molecular pharmacology of neural melanocortin receptors. 960 26

In vitro and in vivo cadmium toxicity studies focus almost exclusively on CdCl2 effects. Only a few studies have used adrenocortical cells and tissue to determine cadmium salt effects during stress of adrenocorticotropin stimulation. Because several biologically relevant water-soluble cadmium salts exist, this study extended work with CdCl2 to evaluate the acute adrenocortical cell steroid secretory responses to non-lethal cadmium acetate (CdAc2) and CdSO4 concentrations. Control or ACTH-stimulated cultured Y-1 mouse adrenal tumor cells (ATCC) which secrete 20alpha-dihydroprogesterone (20-DHP) were incubated for 0.5 h in serum-free medium (FMEM) with or without 0.5, 1.0, 5.0, 10.0, 50.0, 100.0, 500.0 and 1000.0 microg CdAc2 or CdSO4/ml FMEM (1.9, 3.8, 19.0, 38.0, 190.0, 380.0 and 1900.0 micromol/L, respectively). For each salt, cell viability was measured at the end of the incubation using live cell trypan blue exclusion. In addition, cumulative CdAc2 effects during 4 h incubations and effect reversibility were determined for control and stimulated cells. After each experimental incubation, the 20-DHP secreted into the medium was determined by radioimmunoassay. Over 80% of all control or ACTH-stimulated cells were viable after incubation in the presence or absence of various CdAc2 or CdSO4 concentrations. Cadmium acetate and sulfate inhibited basal and ACTH-stimulated steroid secretion in a dose-dependent manner. For basal steroid secretion the CdAc2 concentration that first significantly inhibited was 0.5 microg/ml medium (1.9 micromol/L); stimulated secretion was significantly inhibited beginning at 5.0 microg/ml (19.0 micromol/L) and the concentration reducing stimulated 20-DHP secretion by 50% (IC50) was 5.6 microg/ml (21.3 micromol/L). Similarly, the first CdSO4 concentration to significantly inhibit basal and ACTH-stimulated steroid secretion was 10.0 microg/ml medium (39.0 micromol/L); the IC50 was 7.8 microg/ml (29.8 micromol/L). Except that basally secreting Cd2+-treated cells almost doubled 20-DHP secretion after Cd2+ removal and subsequent incubation with ACTH, all basal and ACTH-stimulated steroid secretion was irreversibly inhibited by every CdAc2 concentration. All CdAc2 concentrations initiated and maintained cumulative inhibitory effects on basal and ACTH-stimulated steroid secretion over a 4 h period. Reversibility and cumulative CdSO4 treatment studies were not conducted. Based on the results from the present studies, both CdAc2 and CdSO4 appeared to incrementally inhibit control and ACTH-stimulated steroidogenesis without affecting cell viability and to be more potent inhibitors of adrenocortical cell steroid secretion than CdCl2. Finally, CdAc2 effects on control and stimulated cells were cumulative and irreversible.
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PMID:Modulation of adrenal cell functions by cadmium salts. 5. Cadmium acetate and sulfate effects on basal and ACTH-stimulated steroidogenesis. 973 85

The present study was designed to investigate the role of nitric oxide (NO) in the regulation of adrenocortical function. Different NO donors, such as sodium nitroprusside (SNP), S-nitroso-L-acetyl penicillamine, diethylamine/NO complex sodium salt and diethylenetriamine NO adduct, significantly decreased corticosterone production both in unstimulated and in corticotropin-stimulated zone fasciculata adrenal cells, in a dose-dependent manner. The effect of SNP was reversed by ferrous hemoglobin. A selective inhibitor of NO synthase, L-NG-nitro-arginine significantly increased corticosterone secretion. The effect of SNP was not mediated by cGMP as permeable cGMP analogs did not reproduce its inhibitory effect. SNP significantly inhibited the steroidogenesis stimulated by 8Br-cAMP and 22(R)-OH-cholesterol, but was ineffective when corticosterone was produced in the presence of exogenously added pregnenolone. Moreover, the conversion of [3H]cholesterol to [3H]pregnenolone and the production of pregnenolone or progesterone (assessed by RIA) were significantly decreased by SNP. Taken together, these results suggest that NO may be a negative modulator of adrenal zona fasciculata steroidogenesis.
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PMID:Effect of nitric oxide on rat adrenal zona fasciculata steroidogenesis. 977 63

Sodium is an essential nutrient for life, and its level in the body is tightly regulated. When sodium deficient, some mammals alter their behavior towards salt by avidly consuming it, even at concentrations animals typically choose to avoid. This change in acceptance is accompanied by a reduction in the response of the gustatory chorda tympani nerve to sodium solutions. More specifically, the response rate of the sodium-specialist units to NaCl stimulation is reduced following sodium deficiency or adrenalectomy. The initial transduction of the chemical signal is mediated, in part, by Na+ influx through epithelial Na+ channels in the apical membrane of taste cells that synapse with the specialist neurons. Circulating hormones like angiotensin II and adrenocorticotropin hormone, which are released in response to sodium deficiency and adrenalectomy, could regulate the activity of Na+ channels through G-protein linked second-messenger systems. These putative pathways are of interest because they have been described in mammalian taste receptor cells. The present review will summarize evidence linking some hormones of fluid homeostasis with the apparent attenuation of input from sodium-specialist neurons.
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PMID:Potential mechanisms for functional changes in taste receptor cells following sodium deficiency in mammals. 986 15

Two potent hypotensive peptides, adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP), are encoded by the adrenomedullin gene. AM stimulates nitric oxide production by endothelial cells, whereas PAMP acts presynaptically to inhibit adrenergic nerves that innervate blood vessels. Complementary, but mechanistically unique, actions also occur in the anterior pituitary gland where both peptides inhibit adrenocorticotropin release. In the adrenal gland both AM and PAMP inhibit potassium and angiotensin II-stimulated aldosterone secretion. Natriuretic and diuretic actions of AM reflect unique actions of the peptide on renal blood flow and tubular function. In the brain AM inhibits water intake and, in a physiologically relevant manner, salt appetite. Both AM and PAMP act in the brain to elevate sympathetic tone, effects that mirror the positive inotropic action of AM in the heart. Cardioprotective actions in the brain and heart may be important counter-regulatory actions that buffer the extreme hypotensive actions of the peptides when released in sepsis. Thus the biologic actions of the proadrenomedullin-derived peptides seem well coordinated to contribute to the physiologic regulation of volume and electrolyte homeostasis.
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PMID:Adrenomedullin and the control of fluid and electrolyte homeostasis. 1009 93


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