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CHARACTERIZATION OF ANGIOTENSIN-II RECEPTOR SUBTYPES IN RAT-HEART
No full textAngiotensin II exerts positive inotropic and chronotropic effects on the mammalian heart by binding to specific membrane receptors. Recently, two subtypes of angiotensin II receptors (AT1 and AT2) have been distinguished by using the nonpeptide antagonists losartan (previously known as DuP 753) and PD123177. To evaluate the tissue distribution and subtypes of angiotensin II receptors in rat heart, we performed a I-125-[Sar1,Ile8]angiotensin II in situ binding assay on tissue sections obtained from adult Sprague-Dawley rats (10 and 14 weeks old). Binding specificity was verified by competition with unlabeled [Sar1]angiotensin II. Distribution of AT1 and AT2 receptors was determined by competition with losartan and PD123177, respectively, and the density of the receptors was quantified by emulsion autoradiography. Angiotensin II receptors were widely distributed throughout the heart, with each receptor subtype accounting for approximately 50% of the specific binding. Binding density was comparable in the atria, right and left ventricles, intraventricular septum, and sinoatrial node, whereas it was significantly greater in the atrioventricular node. The AT1 receptor appears to interact with guanidine nucleotide regulatory proteins, because GTP-gamma-S causes dissociation of the radioligand from this receptor. In contrast, the AT2 receptor does not appear to directly interact with guanine nucleotide regulatory proteins, inasmuch as radioligand dissociation from this receptor subtype is not affected by GTP-gamma-S. Because angiotensin II has been reported to have growth-potentiating effects in several tissues, we examined angiotensin II receptors in fetal (embryonic days 16 and 19) and neonatal (1-, 2-, 3-, and 10-day-old) rats. A twofold increase in the density of both receptor subtypes was found immediately after birth, reaching a maximum on day 2 and decreasing toward prenatal values thereafter. Thus, in rat heart, AT1 and AT2 receptors are equally distributed over the myocardium. The density of these angiotensin II receptors is developmentally regulated
Activation and internalization of the mu-opioid receptor by the newly discovered endogenous agonists, endomorphin-1 and endomorphin-2
No full textThe multiple effects of opiate alkaloids, important therapeutic drugs used for pain control, are mediated by the neuronal miro-opioid receptor. Among the side effects of these drugs is a profound impairment of gastrointestinal transit. Endomorphins are opioid peptides recently isolated from the nervous system, which have high affinity and selectivity for micro-opioid receptors. Since the miro-opioid receptor undergoes ligand-induced receptor endocytosis in an agonist-dependent manner, we compared the ability of endomorphin-1, endomorphin-2 and the micro-opioid receptor peptide agonist, [D-Ala2,MePhe4,Gly-ol5]-enkephalin (DAMGO), to induce receptor endocytosis in cells transfected with epitope-tagged micro-opioid receptor complementary DNA, and in myenteric neurons of the guinea-pig ileum, which naturally express this receptor. Immunohistochemistry with antibodies to the FLAG epitope or to the native receptor showed that the micro-opioid receptor was mainly located at the plasma membrane of unstimulated cells. Endomorphins and DAMGO induced micro-opioid receptor endocytosis into early endosomes, a process that was inhibited by naloxone. Quantification of surface receptors by flow cytometry indicated that endomorphins' and DAMGO stimulated endocytosis with similar time-course and potency. They inhibited with similar potency electrically induced cholinergic contractions in the longitudinal muscle-myenteric plexus preparation through an action antagonized by naloxone. The apparent affinity estimate of naloxone (pA2 approximately 8.4) is consistent with antagonism at the micro-opioid receptor in myenteric neurons. These results indicate that endomorphins directly activate the micro-opioid receptor in neurons, thus supporting the hypothesis that they are ligands mediating opioid actions in the nervous system. Endomorphin-induced micro-opioid receptor activation can be visualized by receptor endocytosi
INSULIN-RECEPTOR CONCENTRATION AND GENE-EXPRESSION ARE MODULATED BY SODIUM-INTAKE IN THE RAT-KIDNEY
No full textCHARACTERIZATION OF ANGIOTENSIN-II RECEPTOR SUBTYPES IN THE RAT-KIDNEY AND HEART USING THE NONPEPTIDE ANTAGONISTS DUP-753 AND PD-123-177
No full textTISSUE-SPECIFIC REGULATION OF INSULIN-RECEPTOR MESSENGER-RNA LEVELS IN RATS WITH STZ-INDUCED DIABETES-MELLITUS
No full textIn rats with STZ-induced diabetes mellitus, a reduction in insulin secretion is associated with increased insulin binding in the liver, muscle, fat, and kidney, but not in the brain. To test the hypothesis that tissue-specific modulation of insulin receptors (IRs) in STZ-induced diabetes occurs at the level of mRNA, IR mRNA levels were measured in the liver, kidney, and brain of Sprague-Dawley rats 15 days after intravenous administration of STZ (60 mg/kg body weight) and compared with those of control rats. Diabetic rats were either left untreated or given differing insulin regimens that were designed to achieve varying degrees of metabolic control. IR mRNA levels were measured by slot blot hybridization with a P-32-labeled rIR probe and standardized by 28S ribosomal RNA determination. Hepatic IR mRNA levels were increased significantly in both untreated diabetic rats and in those that received low-dose (2 U/day) insulin therapy. In contrast, hepatic IR mRNA levels did not differ significantly from controls in those that received moderate doses of insulin (3-8 U/day) and were significantly less than controls in those that received the highest doses (6-10 U/day). Renal IR mRNA levels also were increased significantly in the untreated diabetic rats but not in those that received low- or moderate-dose insulin therapy, and were significantly less than controls in those that received the highest doses. A highly significant negative correlation was observed between the level of hepatic (r = -0.84, P < 0.001) and renal (r = -0.64, P < 0.001) IR mRNA, and the plasma concentration of insulin obtained at the time of death. No significant difference was observed in brain IR mRNA levels between untreated diabetic and control rats. Thus, in rats with insulin deficiency, modulation of insulin binding in the liver and kidney can be attributed, at least in part, to a change in steady-state IR mRNA levels
DISTRIBUTION OF ANGIOTENSIN-II RECEPTOR SUBTYPES IN RAT AND HUMAN KIDNEY
No full textAngiotensin II initiates a variety of physiological effects in the kidney by binding to high-affinity receptors on plasma membranes. Recently, two subtypes of angiotensin II receptors have been distinguished on the basis of differences in signal transduction mechanisms, binding affinity to agonists and antagonists, and inhibition of binding by dithiothreitol. To evaluate the density and distribution of these receptor subtypes in the kidney, we performed an in situ autoradiographic study on frozen tissue sections obtained from rat and human kidneys. Sections were incubated with I-125-[Sar1,Ile8]angiotensin II and binding specificity was verified by competition with unlabeled [Sar1]angiotensin II. Angiotensin II receptor subtypes were characterized by competition with the nonpeptide receptor antagonists, DuP 753 (type 1) and PD123177 (type 2). Both rat and human kidney exhibited a high concentration of angiotensin II receptors in glomeruli and in the longitudinal bands traversing the outer portion of the medulla, corresponding to the medullary vascular bundles. Binding affinity (K(d) = 0.6 +/- 0.4 nM), determined in rat kidney, was similar to that reported previously in isolated glomeruli and membrane vesicles prepared from renal tubules. Angiotensin II binding was almost completely inhibited by DuP 753, whereas PD123177 had little effect. Thus the predominant angiotensin II receptor subtype in both rat and human kidney is type 1. The distribution of angiotensin II receptors correlates well with the intrarenal sites at which the peptide has its major physiological effects
EXPRESSION OF AT2-RECEPTORS IN THE DEVELOPING RAT FETUS
No full textAngiotensin II is known primarily for its effects on blood pressure and electrolyte homeostasis, but recent studies suggest that angiotensin II may play a role in the regulation of cellular growth. This study was undertaken to identify the angiotensin II receptor subtypes expressed during fetal and neonatal development and to characterize their cellular localization. Using an in situ receptor binding assay on sagittal frozen sections of fetal and neonatal rats, bound I-125-[Sar1, Ile8]-angiotensin II was visualized by film and emulsion autoradiography. Bound radioligand was detected by E11 (embryonic day 11) and maximal binding occurred by E19-21. Radioligand binding remained unaltered 30 min after birth, whereas a noticeable and stable decrease was observed 12 h postparturition. The highly abundant angiotensin II receptors were shown to be AT2 by the marked reduction in radioligand binding achieved with PD123177 (10(-7) M), a specific AT2 receptor antagonist, whereas DuP 753 (10(-5) M), an AT1 receptor antagonist, had little effect. Emulsion autoradiography showed radioligand binding in the undifferentiated mesenchyme of the submucosal layers of the intestine and stomach, connective tissue and choroid surrounding the retina, subdermal mesenchyme adjacent to developing cartilage, diaphragm, and tongue. Residual AT2 receptors were found on the dorsal subdermal region of the tongue 72 h after birth. AT1 receptors were detected in the placenta at E13 and in the aorta, kidney, lung, liver, and adrenal gland at E19-21, consistent with an adult distribution. The transient expression of AT2 receptors in the mesenchyme of the fetus suggests a role of angiotensin II in fetal development
Deletion of Neutral Endopeptidase exacerbates intestinal inflammation induced by Clostridium difficile Toxin A
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Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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