Effects of uroguanylin and guanylin against antigen-induced bronchoconstriction and airway microvascular leakage in sensitized guinea-pigs

Uroguanylin and guanylin are isolated mainly from the gastrointestinal tract and are activators of guanylyl cyclase C receptor (GC-C), which mediates the production of intracellular cyclic guanosine 3',5'-monophosphate (cyclic GMP). The bronchodilator effects of agents that raise cyclic GMP levels, such as atrial natriuretic peptide, have been reported, and uroguanylin mRNA has recently been detected in extra-gastrointestinal tissues, including the lung, suggesting their role in pulmonary activity. In the first step of this study, we examined the relaxant effects of uroguanylin and guanylin on isolated tracheal smooth muscle of guinea-pigs, and measured tissue cyclic GMP levels by means of enzymeimmunoassay. Uroguanylin produced concentration-dependent relaxant effects on resting tone and significant elevated cyclic GMP levels. Guanylin produced the same, but less potent, effects. In this study, we first investigated the effects of uroguanylin and guanylin on antigen-induced bronchoconstriction and airway microvascular leakage in actively sensitized guinea-pigs. Anesthetized male guinea-pigs, ventilated via a tracheal cannula, were placed in a plethysmograph to measure pulmonary mechanics for 10 min after challenging with 1 mg/kg of ovalbumin. Evans blue dye was then extravasated into their airway tissues to measure microvascular leakage. Intravenous pretreatment with uroguanylin significantly inhibited ovalbumin-induced bronchoconstriction and microvascular leakage in a dose-dependent manner. These inhibitory effects were mimicked by 8-bromoguanosine 3', 5'-cyclic monophosphate. This study is the first to show that uroguanylin not only had a potent bronchodilatory effect but also inhibited microvascular leakage. These results encouraged us to continue the above experimental and clinical studies in bronchial asthma.     

Steroid hormones and their receptors in the brain

Steroid hormones regulate several important functions of the brain by altering the expression of particular genes through their receptors. First in this paper the localization of glucocorticoid receptor immunoreactivity and mRNA in the brain was examined. Second biphasic effects of glucocorticoid on the hippocampus was described and particular emphasis was given on the apoptosis. Third the significance of estrogen receptor in the sexually dimorphic areas was discussed. These results suggest that steroids modulate the gene expression along with the alteration of cell structures in a different manner in a tissue-specific pattern.     

Comparison of effects of uroguanylin, guanylin, and Escherichia coli heat-stable enterotoxin STa in mouse intestine and kidney: evidence that uroguanylin is an intestinal natriuretic hormone

BACKGROUND: Uroguanylin and guanylin are intestinal peptides that activate a receptor-guanylate cyclase, which is also a receptor for Escherichia coli heat-stable enterotoxin (STa). These peptides may have a role in the body's regulation of fluid and electrolytes. METHODS: STa, bioactive guanylin, and bioactive uroguanylin were evaluated for effects in: 1) the suckling mouse intestinal fluid secretion assay; 2) an in vitro suckling mouse intestinal loop assay; 3) an intestinal receptor autoradiography assay; 4) a control or agonist-stimulated assay for cGMP response in T84 cells; and 5) an in vivo renal function assay in mice. RESULTS: In vivo, orally administered uroguanylin and STa but not guanylin, stimulated intestinal fluid secretion. All three peptides activated intestinal guanylate cyclase and had common intestinal receptors. In vitro, after pretreatment with chymotrypsin, only uroguanylin and STa retained agoinst activity. Chymostatin preserved guanylin activity. STa and uroguanylin induced diuresis, natriuresis, and kaliuresis. Guanylin was less potent than uroguanylin and STa. CONCLUSIONS: The results suggest that the endogenous intestinal peptides, uroguanylin and guanylin, regulate water and electrolyte homeostasis both through local effects on intestinal epithelia and endocrine effects on the kidney.     

The uroguanylin gene (Guca1b) is linked to guanylin (Guca2) on mouse chromosome 4

PURPOSE: To evaluate how anode-filter combinations influence image quality in and mean glandular dose to breasts of different thicknesses and compositions. MATERIALS AND METHODS: Mammograms were obtained with a molybdenum (Mo) anode and a Mo filter at 26 kVp, a Mo anode and a rhodium (Rh) filter at 27 kVp, or a tungsten (W) anode and a Rh filter at 26 kVp in 965 women. One anode-filter-tube voltage combination was used in the right breast and another in the left. The mean glandular dose to each breast was calculated. RESULTS: Image contrast was highest in the Mo-Mo mammograms. However, depiction of the glandular tissue, pectoral muscle, and skin and subcutis was significantly (P < .001) better with the Mo-Rh and the W-Rh than with the Mo-Mo combination. The average mean absorbed doses to the glandular tissue for W-Rh and Mo-Rh were 50% and 75%, respectively, of that for Mo-Mo. CONCLUSION: Breast thickness is the most important parameter in selection of an anode-filter-tube voltage combination. Compared with Mo-Mo, both Mo-Rh and W-Rh gave good image quality of the mammary gland and a considerably lower absorbed dose. Mo-Rh-27 kVp is recommended for breast thicknesses of 60 mm or less; W-Rh-26 kVp, for breast thicknesses of greater than 60 mm.     

Plasma and urine levels of uroguanylin, a new natriuretic peptide, in nephrotic syndrome

PURPOSE: The aim of this study was to determine the strength of periosteal and galeal adhesiveness at particular intervals after subperiosteal and subperiosteal-subgaleal forehead lifting in a rodent model. MATERIALS AND METHODS: Sixty mice underwent a subperiosteal or subperiosteal-subgaleal coronal forehead lift procedure. Necropic and histologic examination of the periosteal, galeal, and bone interface was performed on postoperative days 2, 4, 6, 8, and 10, and the strength of the elevated flap reattachment to underlying tissues was measured. RESULTS: Tension analysis in the early postoperative period showed a higher avulsive force was required to re-elevate subgaleal-subperiosteal flaps than subperiosteal flaps. However, subperiosteal flap adhesiveness appeared to increase rapidly between postoperative days 4 and 8. By day 10, the force required to re-elevate subperiosteal flaps was significantly higher than that required for subgaleal-subperiosteal flaps (P < or = .0001). Histologic analysis showed an inflammatory response at the periosteum-bone interface, which maximized at postoperative day 6. CONCLUSIONS: In the early postoperative period, subgaleal-subperiosteal flaps had higher adhesiveness than subperiosteal flaps. However, by postoperative day 10, subperiosteal forehead flaps were substantially more adherent in this rodent model.     

TNF-related ligands and their receptors

Multicellular organisms have the challenging task of coordinating the activities of many distinct cell types. This coordination is accomplished largely by cell-associated and soluble signalling molecules that act locally or distantly to alter target-cell physiology. The tumour necrosis factor family of cytokines are type II transmembrane proteins that are important regulators of homeostasis and have been implicated as mediators of disease. These molecules serve as ligands for a family of cell-surface receptors termed the tumour necrosis factor/nerve growth factor (TNF/NGF) receptor family. The receptors are type I transmembrane proteins capable of mediating a wide range of responses in vitro and in vivo. Signal transduction is mediated by several newly discovered cytoplasmic proteins that couple these receptors to downstream signalling events. The elucidation and use of spontaneously occurring mutants in TNF-related ligands and receptors in addition to gene-targeting experiments have begun to clarify the diverse biological effects mediated by this superfamily of cytokines.     

Insect neurotransmission: neurotransmitters and their receptors

The roles of acetylcholine, dopamine, octopamine, tyramine, 5-hydroxytryptamine, histamine, glutamate, 4-aminobutanoic acid (gamma-aminobutyric acid) and a range of peptides as insect neurotransmitters are evaluated in terms of the criteria used to identify transmitters. Of the biogenic amines considered, there is good evidence that acetylcholine, dopamine, octopamine, 5-hydroxytryptamine, and histamine should be considered to be neurotransmitters, but the case for tyramine is less convincing at the moment. The evidence supporting neurotransmitter roles for glutamate and gamma-aminobutyric acid at specific insect synapses is overwhelming, but much work remains to be undertaken before the full significance of these molecules in the insect nervous system is appreciated. Attempts to characterise biogenic amine and amino acid receptors using pharmacological and molecular biological techniques have revealed considerable differences between mammalian and insect receptors. The number of insect neuropeptides isolated and identified has increased spectacularly in recent years, but genuine physiological or biochemical functions can be assigned to very few of these molecules. Of these, only proctolin fulfills the criteria expected of a neurotransmitter, and the recent discovery of proctolin receptor antagonists should enable the biology of this pentapeptide to be explored fully.     

Uterine relaxation responses to calcitonin gene-related peptide and calcitonin gene-related peptide receptors decreased during labor in rats

OBJECTIVES: Our purpose was to investigate (1) whether uterine relaxation responses to calcitonin gene-related peptide are differentially regulated during pregnancy and labor, (2) the involvement of nitric oxide in smooth muscle relaxant action of calcitonin gene-related peptide in the rat uterus, (3) whether receptors for calcitonin gene-related peptide are expressed in rat uterus, and if so (4) whether the concentrations of these receptors are differently regulated during pregnancy and labor. STUDY DESIGN: Rats were killed on day 18 of gestation, at the time of spontaneous labor, or postpartum day 2. The uteri were removed for in vitro contractility measurements, nitric oxide production, and calcitonin gene-related peptide receptor binding assay. RESULTS: (1) Calcitonin gene-related peptide induced a dose-dependent relaxation in spontaneously contracting uterine strips from pregnant rats on day 18 of gestation; (2) the relaxation effects of calcitonin gene-related peptide on the uterus were decreased during spontaneous delivery at term and post partum compared with that during pregnancy; (3) calcitonin gene-related peptide-induced relaxation was inhibited by pretreatment of the uterine tissue with a calcitonin gene-related peptide receptor antagonist, calcitonin gene-related peptide(8-37); (4) nitric oxide synthesis inhibitor (N(G)-nitro-L-arginine methyl ester) and soluble guanylate cyclase inhibitor (LY83583) significantly decreased calcitonin gene-related peptide-induced relaxation of the rat uterus during pregnancy; (5) calcitonin gene-related peptide increased the uterine nitric oxide production in pregnant rats, and this increase was obliterated in the presence of calcitonin gene-related peptide(8-37); and (6) calcitonin gene-related peptide receptors are present in rat uterus, and the concentration of these receptors dramatically increases during pregnancy and decreases during labor at term. CONCLUSIONS: Calcitonin gene-related peptide inhibits uterine spontaneous contractions in rats during pregnancy but not during labor and post partum. The inhibitory effects of calcitonin gene-related peptide on uterine contractility appear to be modulated, at least in part, by the activation of nitric oxide generation in the rat uterus. Changes in calcitonin gene-related peptide receptors could contribute to the changes in calcitonin gene-related peptide-mediated uterine relaxation during pregnancy and labor.     

The expression of cytokines and their receptors in normal and mildly reactive human brain

This article reviews the currently available data on the role of peroxisomal function in relation to the processes of cell differentiation and carcinogenesis. In regard to tumourigenesis, both genotoxic and non-genotoxic processes have been considered, and the peroxisomal relationships with these phenomena and with differentiation are described at the level of organelle characteristics, enzyme contents, and the involvement of retinoids, steroid hormones, oxygen free radicals, growth factors, apoptosis, omega-3 polyunsaturated fatty acids and the cellular signalling networks. Overall these data serve to illustrate the unique and distinctive role of the peroxisome in differentiation and carcinogenesis, and point to the advantages of considering the peroxisomal involvement in the holistic context of the differentiation dedifferentiation continuum rather than the narrower focus of non-genotoxic carcinogenesis. The review also outlines the potential for medical benefit arising from a fuller understanding of these peroxisomal affiliations.     

Human fetal pituitary expresses functional growth hormone-releasing peptide receptors

We have demonstrated that transferrin binding protein (TfBP), ferritin, and iron, are specifically localized in Bergmann glia, while the transferrin receptor is confined to Purkinje cells in the chicken cerebellum. The results of this study suggest that Bergmann glia have previously undescribed functions related to iron regulation such as sequestration of iron and the maintenance of iron homeostasis in the cerebellum.     

Death domain receptors and their role in cell demise

Apoptotic signals are transduced by five death domain-containing receptors--TNFR1, Fas, DR3, DR4, and DR5--by binding to their ligands. The intracellular portion of all these receptors contains a region, approximately 80 amino acids long, referred to as the "death domain" (DD). On activation by its ligand, the DD recruits various proteins that mediate cell death. These proteins, in turn, recruit other proteins via their DDs or death effector domains (DED). The actual destruction of the cell, however, is accomplished by serial activation of a family of proteases referred to as caspases. Cell death is, in part, regulated by transmembrane decoy receptors that contain either none of or only part of the DD. This article briefly reviews what is known about the receptors and other proteins involved in apoptosis. In addition, because numerous proteins that mediate apoptosis have been discovered independently and simultaneously and thus are known by many different names, a comprehensive cross-referenced list of these proteins is provided.     

Cyclic guanosine monophosphate responses to atrial natriuretic factor, brain natriuretic peptide, but not C-type natriuretic peptide, and the characterization of their receptors in rat medullary thick ascending limb

The effects of atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) on renal medullary thick ascending limb (mTAL) have not been fully understood. The aim of this study is to examine the second-messenger responses of rat mTAL to ANF, BNP, and CNP. Characterizations of the ANF, BNP, and CNP receptors in mTAL were also performed by radioligand studies. Results showed that ANF and BNP were both capable of eliciting cyclic guanosine monophosphate (cGMP) responses in mTAL. Conversely, no cGMP response was observed upon stimulation by CNP in mTAL. The presence of ANF receptors was demonstrated by radioligand studies. One receptor site was found, and the Kd and maximum binding capacity were 4.0 +/- 0.45 nmol/L and 277.8 +/- 47.7 fmol/mg protein, respectively. BNP receptors were also found in mTAL, and ANF and BNP were sharing the same receptor. On the contrary, no CNP receptor could be shown by radioligand studies. These results suggest that guanylyl cyclase-coupled receptors (atrial natriuretic peptide receptor-A [ANPR-A]) specific for ANF and BNP are present in rat mTAL, while those for CNP (ANPR-B) are absent. ANF and BNP but not CNP act on mTAL to control water excretion.