FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2068533848> ?p ?o ?g. }

• W2068533848 endingPage "S28" @default.
• W2068533848 startingPage "S22" @default.
• W2068533848 abstract "Localization and interactions of vasoactive peptide receptors in renomedullary interstitial cells of the kidney. Vasoactive peptides regulate renal medullary microcirculation and tubular function, but the localization of their receptors and mechanisms of actions are currently unknown. Using electron microscopic autoradiography, we have mapped the receptors for angiotensin II (Ang II [AT1 and AT2]), endothelin (ETA and ETB), and bradykinin (B2) in the rat renal medulla. Although these peptide receptors show distinct vascular and tubular distributions, they overlap strikingly in renomedullary interstitial cells (RMICs) of the inner stripe and the papilla. Using reverse transcription-polymerase chain reaction (RT-PCR) and Southern analysis, mRNAs for AT1A, ETA, and B2 receptors were detected in cultured adult RMICs. Ang II increases intracellular inositol 1,4,5-triphosphate (IP3) and [Ca2+]i and stimulates [3H]thymidine incorporation and extracellular matrix (ECM) synthesis via AT1A receptors. Endothelin and bradykinin also stimulate cell proliferation and ECM synthesis in RMICs through ETA and B2 receptors, respectively, but the actions of endothelin are modulated by concurrent nitric oxide production. By contrast, AT2 receptor mRNA was detected only in embryonic RMICs, in which Ang II inhibits cell proliferation through this receptor. These results suggest that multiple vasoactive peptides may interact with RMICs to exert endocrine and/or paracrine influences on renal medullary microcirculation and tubular function. Localization and interactions of vasoactive peptide receptors in renomedullary interstitial cells of the kidney. Vasoactive peptides regulate renal medullary microcirculation and tubular function, but the localization of their receptors and mechanisms of actions are currently unknown. Using electron microscopic autoradiography, we have mapped the receptors for angiotensin II (Ang II [AT1 and AT2]), endothelin (ETA and ETB), and bradykinin (B2) in the rat renal medulla. Although these peptide receptors show distinct vascular and tubular distributions, they overlap strikingly in renomedullary interstitial cells (RMICs) of the inner stripe and the papilla. Using reverse transcription-polymerase chain reaction (RT-PCR) and Southern analysis, mRNAs for AT1A, ETA, and B2 receptors were detected in cultured adult RMICs. Ang II increases intracellular inositol 1,4,5-triphosphate (IP3) and [Ca2+]i and stimulates [3H]thymidine incorporation and extracellular matrix (ECM) synthesis via AT1A receptors. Endothelin and bradykinin also stimulate cell proliferation and ECM synthesis in RMICs through ETA and B2 receptors, respectively, but the actions of endothelin are modulated by concurrent nitric oxide production. By contrast, AT2 receptor mRNA was detected only in embryonic RMICs, in which Ang II inhibits cell proliferation through this receptor. These results suggest that multiple vasoactive peptides may interact with RMICs to exert endocrine and/or paracrine influences on renal medullary microcirculation and tubular function. The renal medulla plays an important role in maintaining body fluid and electrolyte balance and blood pressure homeostasis through actions of various humoral and paracrine/autocrine factors on renal medullary hemodynamics, tubular reabsorption, and urine concentration1.Cowley Jr, A.W. Mattson D.L. Lu S.H. Roman R.J. The renal medulla and hypertension.Hypertension. 1995; 25: 663-673Crossref PubMed Google Scholar. Angiotensin II (Ang II), endothelin (ET), and bradykinin (BK) are vasoactive peptides that have been implicated in the regulation of renal medullary function1.Cowley Jr, A.W. Mattson D.L. Lu S.H. Roman R.J. The renal medulla and hypertension.Hypertension. 1995; 25: 663-673Crossref PubMed Google Scholar,2.Navar L.G. Inscho E.W. Majid D.S.A. Imig J.D. Harrison-Bernard L.M. Mitchell K.D. Paracrine regulation of the renal microcirculation.Physiol Rev. 1996; 76: 425-536PubMed Google Scholar. In the renal medulla, physiological studies have shown that these vasoactive peptides either act alone or interact with each other to influence medullary/papillary blood flow and urinary water and sodium excretion1.Cowley Jr, A.W. Mattson D.L. Lu S.H. Roman R.J. The renal medulla and hypertension.Hypertension. 1995; 25: 663-673Crossref PubMed Google Scholar,3.Chou S.-Y. Porush J.G. Faubert P.F. Renal medullary circulation: Hormonal control.Kidney Int. 1990; 37: 1-13Abstract Full Text PDF PubMed Scopus (90) Google Scholar. However, the precise sites and cellular mechanisms of actions of the vasoactive peptide receptors in the renal medulla are not fully understood. The aim of this article is to review current understanding of the cellular localization of the receptors for Ang II (AT1), ET (ETA and ETB), and BK (B2) and their actions in type I renomedullary interstitial cells (RMICs) and other cellular structures in the rat renal medulla. Evidence that Ang II may regulate renal medullary and papillary microcirculation and countercurrent exchange mechanisms came from early physiological studies showing medullary blood flow and/or papillary blood flow to be reduced markedly by sodium restriction and/or depletion or by infusion of exogenous Ang II1.Cowley Jr, A.W. Mattson D.L. Lu S.H. Roman R.J. The renal medulla and hypertension.Hypertension. 1995; 25: 663-673Crossref PubMed Google Scholar,3.Chou S.-Y. Porush J.G. Faubert P.F. Renal medullary circulation: Hormonal control.Kidney Int. 1990; 37: 1-13Abstract Full Text PDF PubMed Scopus (90) Google Scholar. Conversely, angiotensin converting enzyme (ACE) inhibitors, or Ang II receptor antagonists, exerts opposite effects1.Cowley Jr, A.W. Mattson D.L. Lu S.H. Roman R.J. The renal medulla and hypertension.Hypertension. 1995; 25: 663-673Crossref PubMed Google Scholar,3.Chou S.-Y. Porush J.G. Faubert P.F. Renal medullary circulation: Hormonal control.Kidney Int. 1990; 37: 1-13Abstract Full Text PDF PubMed Scopus (90) Google Scholar. However, little is known about either the mechanisms responsible for the regulation of these physiological processes at the receptor level or the precise cellular location of Ang II receptors in the renal medulla. We therefore evaluated the cellular localization of AT1 receptors in the inner stripe of the outer medulla using high-resolution light and electron microscopic autoradiography4.Zhuo J. Alcorn D. Allen A.M. Mendelsohn F.A. High-resolution localization of angiotensin II receptors in rat renal medulla.Kidney Int. 1992; 42: 1372-1380Abstract Full Text PDF PubMed Scopus (71) Google Scholar. Fresh tissue slices were dissected from the inner stripe of the outer medulla instead of using frozen tissue sections4.Zhuo J. Alcorn D. Allen A.M. Mendelsohn F.A. High-resolution localization of angiotensin II receptors in rat renal medulla.Kidney Int. 1992; 42: 1372-1380Abstract Full Text PDF PubMed Scopus (71) Google Scholar. This technique permits localization of AT1 receptor at the cellular and subcellular levels while preserving cellular morphology. Light microscopy confirmed that a high density of AT1 receptor binding occurs in the inner stripe, where silver grains are found outlining, but distinct from, renal tubules and the vasa recta bundles Figure 1a. Cellular identification was confirmed by electron microscopic autoradiography, where the distribution of silver grains is seen almost exclusively on RMICs situated between the vasa recta and tubules Figure 2a. No appreciable binding is observed over the cells of the descending thin limb and ascending thick limb of the loop of Henle, the medullary collecting duct, or the vasa recta4.Zhuo J. Alcorn D. Allen A.M. Mendelsohn F.A. High-resolution localization of angiotensin II receptors in rat renal medulla.Kidney Int. 1992; 42: 1372-1380Abstract Full Text PDF PubMed Scopus (71) Google Scholar. At high magnification, these AT1 receptor-bearing interstitial cells show long cytoplasmic projections, lipid droplets, cisternae of rough endoplasmic reticulum, free ribosomes, lysosomes, and vacuoles in the cytoplasm, along with small bundles of microfilaments4.Zhuo J. Alcorn D. Allen A.M. Mendelsohn F.A. High-resolution localization of angiotensin II receptors in rat renal medulla.Kidney Int. 1992; 42: 1372-1380Abstract Full Text PDF PubMed Scopus (71) Google Scholar. These histological characteristics resemble those of type I interstitial cells5.Bohman S.O. The ultrastructure of the renal medulla and the interstitial cells,.in: Mandel A.K. Bohman S.O. The Renal Papilla and Hypertension. Plenum, New York1980: 7-33Crossref Google Scholar.Figure 2Electron microscopic localization of angiotensin II receptor (AT1) (A), endothelin (ET)B (B), and bradykinin (B)2receptors (C) in rat RMICs. Abbreviations are: DT, distal tubule; IC; RMIC, renomedullary interstitial cells; CD, collecting duct; CP, cell process; EC, peritubular capillary endothelial cells. Stain: Uranyl acetate, lead citrate. Magnification is (A) ×7200; (B) ×12000; (C)×9600.View Large Image Figure ViewerDownload (PPT) AT1 receptors on RMICs of the inner stripe of the outer medulla appear to be regulated physiologically in a similar manner to those in glomerular mesangial cells6.Zhuo J. Alcorn D. Mc Causland J. Casley D. Mendelsohn F.A. In vivo occupancy of angiotensin II subtype 1 receptors in rat renal medullary interstitial cells.Hypertension. 1994; 23: 838-843Crossref PubMed Scopus (25) Google Scholar. Parallel changes in AT1 receptor binding occur in both the glomerulus and the inner stripe during altered dietary sodium intake6.Zhuo J. Alcorn D. Mc Causland J. Casley D. Mendelsohn F.A. In vivo occupancy of angiotensin II subtype 1 receptors in rat renal medullary interstitial cells.Hypertension. 1994; 23: 838-843Crossref PubMed Scopus (25) Google Scholar. Although these changes might result directly from altered AT1 receptor mRNA expression7.Schmid C. Castrop H. Reitbauer J. Bruna R.D. Kurtz A. Dietary salt intake modulates angiotensin II type 1 receptor gene expression.Hypertension. 1997; 29: 923-929Crossref PubMed Scopus (58) Google Scholar, in vivo occupancy of these receptors by both circulating and intrarenally formed Ang II might also contribute to this receptor regulation6.Zhuo J. Alcorn D. Mc Causland J. Casley D. Mendelsohn F.A. In vivo occupancy of angiotensin II subtype 1 receptors in rat renal medullary interstitial cells.Hypertension. 1994; 23: 838-843Crossref PubMed Scopus (25) Google Scholar. This proposition is supported by a striking difference in cortical and medullary AT1 receptor binding in rats following in vitro and in vivo labeling6.Zhuo J. Alcorn D. Mc Causland J. Casley D. Mendelsohn F.A. In vivo occupancy of angiotensin II subtype 1 receptors in rat renal medullary interstitial cells.Hypertension. 1994; 23: 838-843Crossref PubMed Scopus (25) Google Scholar,8.Zhuo J. Alcorn D. Harris P.J. Mendelsohn F.A.O. Localization and properties of angiotensin II receptors in rat kidney.Kidney Int. 1993; 44: S40-S46Google Scholar. Although AT1 receptors in glomeruli and proximal tubules are labeled similarly by both techniques, the binding sites in the inner stripe of the outer medulla, as visualized by in vitro autoradiography, are not readily labeled in vivo by the vascularly delivered radioligands, 125I-Ang II or its antagonist analogue 125I-[Sar1,Ile8]Ang II8.Zhuo J. Alcorn D. Harris P.J. Mendelsohn F.A.O. Localization and properties of angiotensin II receptors in rat kidney.Kidney Int. 1993; 44: S40-S46Google Scholar. This lack of AT1 receptor binding in the inner stripe following systemic delivery of the radioligands appears not to be due to Ang II-induced renal vasoconstriction, because prior renal vasodilatation induced by sodium nitroprusside fails to increase AT1 receptor labeling in RMICs of the inner stripe. In contrast, chronic salt loading or inhibition of ACE with perindopril both significantly increases AT1 receptor binding to the type 1 RMICs in vivo8.Zhuo J. Alcorn D. Harris P.J. Mendelsohn F.A.O. Localization and properties of angiotensin II receptors in rat kidney.Kidney Int. 1993; 44: S40-S46Google Scholar. These findings may be explained by the observation that intrarenal Ang II levels are much higher than circulating Ang II under physiological conditions9.Mendelsohn F.A.O. Angiotensin: Evidence for its role as an intrarenal hormone.Kidney Int. 1982; 22: S78-S81Google Scholar. A recent study using in vivo microdialysis, in which nanomolar levels of Ang II were reported in the renal interstitial fluid, lends further support to our interpretation10.Siragy H.M. Howell N.L. Ragsdale N.V. Carey R.M. Renal interstitial fluid angiotensin: Modulation by anesthesia, epinephrine, sodium depletion, and renin inhibition.Hypertension. 1995; 25: 1021-1024Crossref PubMed Scopus (119) Google Scholar. Although the physiological significance of this in vivo occupancy of AT1 receptors in RMICs is unclear, endogenous interstitial Ang II may interact with RMICs to modulate indirectly renal cortical and medullary hemodynamics and tubular function under certain physiological and pathophysiological states. High-affinity Ang II receptor binding sites have been reported previously in cultured rabbit RMICs in which Ang II stimulates prostaglandin (PG) synthesis11.Brown C.A. Zusman R.M. Haber E. Identification of an angiotensin receptor in rabbit renomedullary interstitial cells in tissue culture: Correlation with prostaglandin biosynthesis.Circ Res. 1980; 46: 802-807Crossref PubMed Scopus (47) Google Scholar. We recently showed that cultured rat RMICs also express AT1 receptors12.Zhuo J. Alcorn D. Mc Causland J. Mendelsohn F.A.O. Localization and regulation of angiotensin II receptors in renomedullary interstitial cells.Kidney Int. 1994; 46: 1483-1485Abstract Full Text PDF PubMed Scopus (22) Google Scholar,13.Maric C. Aldred G.P. Antoine A.M. Dean R.G. Eitle E. Mendelsohn F.A.O. Williams D.A. Harris P.J. Alcorn D. Effects of angiotensin II on cultured rat renomedullary interstitial cells are mediated by AT1A receptors.Am J Physiol. 1996; 271: F1020-F1028PubMed Google Scholar. Using reverse transcription-polymerase chain reaction (RT-PCR) and Southern blot analysis, we subsequently confirmed that the AT1 receptors on cultured RMICs are exclusively the AT1A subtype: no AT1B receptor mRNA was detected13.Maric C. Aldred G.P. Antoine A.M. Dean R.G. Eitle E. Mendelsohn F.A.O. Williams D.A. Harris P.J. Alcorn D. Effects of angiotensin II on cultured rat renomedullary interstitial cells are mediated by AT1A receptors.Am J Physiol. 1996; 271: F1020-F1028PubMed Google Scholar. In contrast, the whole rat kidney expresses both AT1A and AT1B receptors, with the former predominating12.Zhuo J. Alcorn D. Mc Causland J. Mendelsohn F.A.O. Localization and regulation of angiotensin II receptors in renomedullary interstitial cells.Kidney Int. 1994; 46: 1483-1485Abstract Full Text PDF PubMed Scopus (22) Google Scholar. In cultured RMICs, we have demonstrated that these cells respond to Ang II to increase [3H]thymidine incorporation in a time- and dose-dependent manner with a maximal response achieved at 1 μmFigure 3a. The Ang II-induced DNA synthesis in cultured RMICs does not require the presence of insulin, but other growth factors may play a synergistic role because treatment of RMICs with insulin-depleted serum produces greater increase in DNA synthesis13.Maric C. Aldred G.P. Antoine A.M. Dean R.G. Eitle E. Mendelsohn F.A.O. Williams D.A. Harris P.J. Alcorn D. Effects of angiotensin II on cultured rat renomedullary interstitial cells are mediated by AT1A receptors.Am J Physiol. 1996; 271: F1020-F1028PubMed Google Scholar. In addition, Ang II potently stimulates extracellular matrix (ECM) synthesis as detected by trans-35S incorporation. Although the signal transduction pathways of Ang II actions on RMICs are not fully understood, our studies suggest that increases in intracellular inositol 1,4,5-triphosphate (IP3) followed by intracellular Ca2+ ([Ca2+]i) mobilization may be involved12.Zhuo J. Alcorn D. Mc Causland J. Mendelsohn F.A.O. Localization and regulation of angiotensin II receptors in renomedullary interstitial cells.Kidney Int. 1994; 46: 1483-1485Abstract Full Text PDF PubMed Scopus (22) Google Scholar. Indeed, Ang II induces marked increases in IP3 and [Ca2+]i but does not appear to alter either basal or forskolin-induced intracellular cAMP13.Maric C. Aldred G.P. Antoine A.M. Dean R.G. Eitle E. Mendelsohn F.A.O. Williams D.A. Harris P.J. Alcorn D. Effects of angiotensin II on cultured rat renomedullary interstitial cells are mediated by AT1A receptors.Am J Physiol. 1996; 271: F1020-F1028PubMed Google Scholar. All of these cellular responses to Ang II in cultured RMICs are completely inhibited by the AT1 receptor antagonist, losartan, but not by the AT2 receptor antagonist PD 12331913.Maric C. Aldred G.P. Antoine A.M. Dean R.G. Eitle E. Mendelsohn F.A.O. Williams D.A. Harris P.J. Alcorn D. Effects of angiotensin II on cultured rat renomedullary interstitial cells are mediated by AT1A receptors.Am J Physiol. 1996; 271: F1020-F1028PubMed Google Scholar. Thus, our studies indicate that the type 1 RMICs are the primary sites for AT1A receptors in the inner stripe of the outer medulla, and this subtype of AT1 receptors may mediate Ang II stimulation of intracellular IP3 and [Ca2+]i and cell proliferation in RMICs. In contrast, AT2 receptor binding or mRNA is not detected in RMICs isolated and cultured from the adult rat kidney, but they occur in embryonic RMICs14.Maric C. Aldred G.P. Harris P.J. Alcorn D. An antiproliferative action of angiotensin II mediated by AT2 receptors in embryonic renomedullary interstitial cells.Proc 18th Annu Scientific Meeting High Blood Pressure Research Council of Australia. 1996; 18 (abstract): 105Google Scholar. In embryonic RMICs, we have observed recently that Ang II inhibits basic fibroblast growth factor-induced DNA synthesis and that this effect is mediated by AT2 receptors14.Maric C. Aldred G.P. Harris P.J. Alcorn D. An antiproliferative action of angiotensin II mediated by AT2 receptors in embryonic renomedullary interstitial cells.Proc 18th Annu Scientific Meeting High Blood Pressure Research Council of Australia. 1996; 18 (abstract): 105Google Scholar. These results suggest that, as in coronary endothelial cells15.Stoll M. Steckelings U.M. Paul M. Bottari S.P. Metzger R. Unger T. The angiotensin AT2-receptor mediates inhibition of cell proliferation in coronary endothelial cells.J Clin Invest. 1995; 95: 651-657Crossref PubMed Google Scholar, Ang II may exert a dual role in the regulation of cell proliferation with a stimulation of the cell growth by AT1 receptors and an antiproliferative effect mediated by AT2 receptors. ETs, a family of three isopeptides (ET-1, ET-2, and ET-3), initially isolated from cultured porcine aortic endothelial cells16.Yanagisawa M. Kurihara H. Kumura S. Tomobe Y. Kobayashi M. Mitsui Y. Goto K. Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells.Nature. 1988; 332: 441-445Crossref Scopus (9964) Google Scholar, are well recognized as potent paracrine and autocrine factors in the kidney17.Nord E.P. Renal actions of endothelin.Kidney Int. 1995; 44: 451-463Abstract Full Text PDF Scopus (48) Google Scholar,19.Chow L.H. Subramanian S. Nuovo G.J. Miller F. Nord E.P. Endothelin receptor mRNA expression in renal medulla identified by in situ RT-PCR.Am J Physiol. 1995; 269: F449-F457PubMed Google Scholar. Several renal cell types, including vascular endothelial cells, cultured mesangial cells, and tubular epithelial cells, express mRNA for ET-1 and its receptor subtypes, ETA and ETB17.Nord E.P. Renal actions of endothelin.Kidney Int. 1995; 44: 451-463Abstract Full Text PDF Scopus (48) Google Scholar,18.Kon V. Badr K. Biological actions and pathophysiologic significance of endothelin in the kidney.Kidney Int. 1991; 40: 1-12Abstract Full Text PDF PubMed Scopus (174) Google Scholar. In the kidney, ET-1 is a potent vasoconstrictor and decreases glomerular filtration rate and renal plasma flow and sodium and water excretion17.Nord E.P. Renal actions of endothelin.Kidney Int. 1995; 44: 451-463Abstract Full Text PDF Scopus (48) Google Scholar,18.Kon V. Badr K. Biological actions and pathophysiologic significance of endothelin in the kidney.Kidney Int. 1991; 40: 1-12Abstract Full Text PDF PubMed Scopus (174) Google Scholar. However, at low doses, ET-1 may vasodilate in the kidney, leading to diuresis and natriuresis probably mediated by interaction with nitric oxide (NO)17.Nord E.P. Renal actions of endothelin.Kidney Int. 1995; 44: 451-463Abstract Full Text PDF Scopus (48) Google Scholar,18.Kon V. Badr K. Biological actions and pathophysiologic significance of endothelin in the kidney.Kidney Int. 1991; 40: 1-12Abstract Full Text PDF PubMed Scopus (174) Google Scholar. Two subclasses of ET-1 receptors are thought to mediate the physiological responses to ET-1, and the receptors and their mRNAs have been identified and characterized in different structures of the renal medulla by radioreceptor assays, in vitro autoradiography, or RT-PCR19.Chow L.H. Subramanian S. Nuovo G.J. Miller F. Nord E.P. Endothelin receptor mRNA expression in renal medulla identified by in situ RT-PCR.Am J Physiol. 1995; 269: F449-F457PubMed Google Scholar,20.Dean R. Zhuo J. Alcorn D. Casley D. Mendelsohn F.A.O. Cellular localization of endothelin receptor subtypes in the rat kidney following in vitro labelling.Clin Exp Pharmacol Physiol. 1996; 23: 524-531Crossref PubMed Scopus (29) Google Scholar. A high density of ET-1 receptor binding occurs primarily in the inner medulla and glomeruli, with moderate-to-low levels in the inner stripe of the outer medulla and the interglomerular region of the cortex, which corresponds to the proximal convoluted tubules20.Dean R. Zhuo J. Alcorn D. Casley D. Mendelsohn F.A.O. Cellular localization of endothelin receptor subtypes in the rat kidney following in vitro labelling.Clin Exp Pharmacol Physiol. 1996; 23: 524-531Crossref PubMed Scopus (29) Google Scholar. However, ET receptor binding has not yet been localized at the cellular level in the kidney. Using electron microscopic autoradiography, we thus localized ET-1 receptors in the rat kidney following in vivo labeling with 125I-ET-1, analogous to the technique used for localization of AT1 receptors12.Zhuo J. Alcorn D. Mc Causland J. Mendelsohn F.A.O. Localization and regulation of angiotensin II receptors in renomedullary interstitial cells.Kidney Int. 1994; 46: 1483-1485Abstract Full Text PDF PubMed Scopus (22) Google Scholar. Specific ET-1 receptor binding is almost exclusively localized to the fenestrated endothelial cells of glomerular capillaries and peritubular capillaries in both cortex and medulla, and there is no appreciable binding in cells of glomerular mesangium, renal tubules, and the interstitium21.Dean R. Zhuo J. Alcorn D. Casley D. Mendelsohn F.A.O. Cellular distribution of 125I-endothelin-1 binding in rat kidney following in vivo labeling.Am J Physiol. 1994; 267: F845-F852PubMed Google Scholar. Because ET-1 receptor binding has been shown in cultured mesangial cells and RMICs and microdissected renal tubules by binding assays in vitro17.Nord E.P. Renal actions of endothelin.Kidney Int. 1995; 44: 451-463Abstract Full Text PDF Scopus (48) Google Scholar, 18.Kon V. Badr K. Biological actions and pathophysiologic significance of endothelin in the kidney.Kidney Int. 1991; 40: 1-12Abstract Full Text PDF PubMed Scopus (174) Google Scholar, 22.Wilkes B.M. Ruston A.S. Mento T. Giarrdi E. Hart D. Molen M.V. Barnett R. Nord E.P. Characterization of endothelin-1 receptor and signal transduction mechanisms in rat medullary interstitial cells.Am J Physiol. 1991; 260: F579-F589PubMed Google Scholar, we reasoned that the lack of ET-1 receptor binding in these cells in vivo could be due to the physical barrier that prevents penetration of the circulating radioligand into these structures. ET-1 receptor subtypes were thus mapped in fresh thin sections of kidney to investigate whether other renal components also possess ET-1 receptor binding20.Dean R. Zhuo J. Alcorn D. Casley D. Mendelsohn F.A.O. Cellular localization of endothelin receptor subtypes in the rat kidney following in vitro labelling.Clin Exp Pharmacol Physiol. 1996; 23: 524-531Crossref PubMed Scopus (29) Google Scholar. Tissues were incubated with the radioligand in the presence or absence of ET-1 receptor subtype-selective ligands to determine ET-1 receptor subtypes. High densities of ETB receptors were found in the glomerulus, proximal tubule, and the outer and inner medulla, whereas ETA receptor binding is much lower throughout the kidney Figure 1b20.Dean R. Zhuo J. Alcorn D. Casley D. Mendelsohn F.A.O. Cellular localization of endothelin receptor subtypes in the rat kidney following in vitro labelling.Clin Exp Pharmacol Physiol. 1996; 23: 524-531Crossref PubMed Scopus (29) Google Scholar. At the electron microscopic level, as for in vivo labeling, ET-1 receptor binding is localized primarily to the fenestrated endothelium of glomerular capillaries and peritubular capillaries of the cortex, inner stripe of the outer medulla, and the inner medulla. However, ET-1 receptor binding also occurs in RMICs of the inner medulla and to a lesser extent in the inner stripe Figure 2b. The ETB receptor-selective agonist, sarafotoxin 6c (S6c), almost completely abolishes ET-1 receptor binding in the vascular endothelium throughout the kidney, whereas the ETA receptor selective antagonist, BQ123, is without effect20.Dean R. Zhuo J. Alcorn D. Casley D. Mendelsohn F.A.O. Cellular localization of endothelin receptor subtypes in the rat kidney following in vitro labelling.Clin Exp Pharmacol Physiol. 1996; 23: 524-531Crossref PubMed Scopus (29) Google Scholar. Interestingly, both BQ123 and S6c partially inhibit the binding in RMICs in the medulla. These results indicate that in the endothelium of the glomerular and peritubular capillaries, ET-1 binds to ETB receptors, whereas both ETA and ETB are present in RMICs20.Dean R. Zhuo J. Alcorn D. Casley D. Mendelsohn F.A.O. Cellular localization of endothelin receptor subtypes in the rat kidney following in vitro labelling.Clin Exp Pharmacol Physiol. 1996; 23: 524-531Crossref PubMed Scopus (29) Google Scholar. Cultured RMICs contain high-affinity binding sites that are selective for ET-1 and ET-222.Wilkes B.M. Ruston A.S. Mento T. Giarrdi E. Hart D. Molen M.V. Barnett R. Nord E.P. Characterization of endothelin-1 receptor and signal transduction mechanisms in rat medullary interstitial cells.Am J Physiol. 1991; 260: F579-F589PubMed Google Scholar. In these cells, ET-1 stimulates phosphatidylinositol hydrolysis, which results in increases in intracellular IP3 and [Ca2+]i, and activates phospholipase A2 to increase PG E2 production22.Wilkes B.M. Ruston A.S. Mento T. Giarrdi E. Hart D. Molen M.V. Barnett R. Nord E.P. Characterization of endothelin-1 receptor and signal transduction mechanisms in rat medullary interstitial cells.Am J Physiol. 1991; 260: F579-F589PubMed Google Scholar. In addition, ET-1 contracts RMICs accompanied by increased F-actin microfilament staining, which may play a role in modifying renal medullary function including the microcirculation and urinary concentration23.Hughes A.K. Barry W.H. Kohan D.E. Identification of a contractile function for renal medullary interstitial cells.J Clin Invest. 1995; 96: 411-416Crossref PubMed Scopus (27) Google Scholar. However, it remains unclear which ET receptor subtype is involved in these cellular responses, because subtype-selective antagonists were not used in these studies22.Wilkes B.M. Ruston A.S. Mento T. Giarrdi E. Hart D. Molen M.V. Barnett R. Nord E.P. Characterization of endothelin-1 receptor and signal transduction mechanisms in rat medullary interstitial cells.Am J Physiol. 1991; 260: F579-F589PubMed Google Scholar,23.Hughes A.K. Barry W.H. Kohan D.E. Identification of a contractile function for renal medullary interstitial cells.J Clin Invest. 1995; 96: 411-416Crossref PubMed Scopus (27) Google Scholar. Recently, we have examined the effects of ET on cell proliferation and ECM synthesis in cultured RMICs and determined the receptor subtypes involved24.Maric C. Dean R.G. Aldred G.P. Mendelsohn F.A.O. Ryan G.B. Harris P.J. Alcorn D. Proliferation of cultured rat renomedullary interstitial cells and matrix synthesis is stimulated by endothelin 1.J Hypertens. 1996; 14 (abstract): S148Google Scholar. Although [3H]thymidine incorporation and ECM synthesis are not altered by ET-1 alone, they both increase in response to ET-1 when NO synthesis is blocked24.Maric C. Dean R.G. Aldred G.P. Mendelsohn F.A.O. Ryan G.B. Harris P.J. Alcorn D. Proliferation of cultured rat renomedullary interstitial cells and matrix synthesis is stimulated by endothelin 1.J Hypertens. 1996; 14 (abstract): S148Google Scholar. These cellular responses are completely inhibited by the ETA receptor antagonist, BQ123 (1 μm), but not the ETB receptor agonist S6c (1 μm), consistent with the presence of ETA receptors and mRNA in these cells Figure 3b. In contrast, the role of ETB receptor binding, as detected by electron microscopic autoradiography, is currently unknown, although renal vascular effects including vasoconstriction and dilatation and tubular actions have been described for ETB receptors18.Kon V. Badr K. Biological actions and pathophysiologic significance of endothelin in the kidney.Kidney Int. 1991; 40: 1-12Abstract Full Text PDF PubMed Scopus (174) Google Scholar. More studies are thus needed to characterize further the paracrine and autocrine roles of ET and its receptor subtypes in the regulation of renal physiological processes and in pathogenesis of renal disease. The major effector of the renal kallikrein-kinin system, BK, is an important intrarenal paracrine and/or autocrine factor implicated in the regulation of renal hemodynamics and tubular electrolyte fluxes and water transport2.Navar L.G. Inscho E.W. Majid D.S.A. Imig J.D. Harrison-Bernard L.M. Mitchell K.D. Paracrine regulation of the renal microcirculation.Physiol Rev. 1996; 76: 425-536PubMed Google Scholar,25.Regoli D. Barabe J. Pharmacology of bradykinin and related kinins.Pharmacol Rev. 1980; 32: 1-46Crossref PubMed Scopus (15) Google Scholar. In the kidney, BK is a potent vasodilator, reducing renal vascular resistance, increasing renal blood flow, and causing diuresis, natriuresis, and lower urine osmolarity2.Navar L.G. Inscho E.W. Majid D.S.A. Imig J.D. Harrison-Bernard L.M. Mitchell K.D. Paracrine regulation of the renal microcirculation.Physiol Rev. 1996; 76: 425-536PubMed Google Scholar,25.Regoli D. Barabe J. Pharmacology of bradykinin and related kinins.Pharmacol Rev. 1980; 32: 1-46Crossref PubMed Scopus (15) Google Scholar. BK also produces many renal responses indirectly by interacting with local PGs or the renin-angiotensin system2.Navar L.G. Inscho E.W. Majid D.S.A. Imig J.D. Harrison-Bernard L.M. Mitchell K.D. Paracrine regulation of the renal microcirculation.Physiol Rev. 1996; 76: 425-536PubMed Google Scholar,25.Regoli D. Barabe J. Pharmacology of bradykinin and related kinins.Pharmacol Rev. 1980; 32: 1-46Crossref PubMed Scopus (15) Google Scholar. BK receptors in the kidney have been studied previously at the light microscopic level, where they are found in the inner stripe of the outer medulla, inner medulla, and the pelvic capsule26.Figueroa C.D. Gonzalez C.B. Grigoriev S. Alla S.A. Haasemann M. Jarnagin K. Muller-Esterl W. Probing for the bradykinin B2 receptor in rat kidney by antipeptide and anti-ligand antibodies.J Histochem Cytochem. 1995; 43: 137-148Crossref PubMed Scopus (116) Google Scholar,27.Manning D.C. Snyder S.H. Bradykinin receptors localized by quantitative autoradiography in kidney, ureter, and bladder.Am J Physiol. 1989; 256: F909-F915PubMed Google Scholar. The cellular localization of the B2 receptors is, however, not known. To help elucidate the mechanisms of renal actions of BK, we localized B2 binding sites in the rat kidney using in vitro autoradiography and high-resolution electron microscopic autoradiography following i.v. administration of a radiolabeled ligand, 125I-HPP-HOE 140, a derivative of the highly selective B2 receptor antagonist, HOE 140 (3 to 4-hydroxyphenol-propionyl-DArg0-[Hyp3-Thi5-D-Tic7-Oic8]-BK)26.Figueroa C.D. Gonzalez C.B. Grigoriev S. Alla S.A. Haasemann M. Jarnagin K. Muller-Esterl W. Probing for the bradykinin B2 receptor in rat kidney by antipeptide and anti-ligand antibodies.J Histochem Cytochem. 1995; 43: 137-148Crossref PubMed Scopus (116) Google Scholar,28.Dean R. Murone C. Lew R.A. Zhuo J. Casley D. Muller-Esterl W. Alcorn D. Mendelsohn F.A.O. Localization of bradykinin B2 binding sites in rat kidney following chronic ACE inhibitor treatment.Kidney Int. 1997; 52: 1261-1270Abstract Full Text PDF PubMed Scopus (17) Google Scholar. B2 receptor binding is present throughout the entire renal medulla, with the highest density in the inner medulla and in longitudinal bands traversing the inner stripe of the outer medulla. Little binding is observed in the cortex Figure 1c. At the electron microscopic level, B2 binding is widely distributed, including distal tubules, thin limbs of the loop of Henle, collecting ducts, and peritubular capillary endothelium Figure 2c. Interestingly, B2 receptor binding also occurs in RMICs throughout the inner stripe of the outer medulla and the inner medulla Figure 2c28.Dean R. Murone C. Lew R.A. Zhuo J. Casley D. Muller-Esterl W. Alcorn D. Mendelsohn F.A.O. Localization of bradykinin B2 binding sites in rat kidney following chronic ACE inhibitor treatment.Kidney Int. 1997; 52: 1261-1270Abstract Full Text PDF PubMed Scopus (17) Google Scholar. In HPLC studies in rats pretreated with the ACE inhibitor, perindopril, to reduce degradation of the radioligand in vivo, B2 receptor binding persisted at the sites described earlier here, but cortical binding was abolished. This indicates that the cortical binding following in vivo labeling is due to tubular uptake of the degraded radioligand, whereas authentic B2 receptors occur predominantly in the renal tubules, vascular endothelium, and RMICs in the medulla28.Dean R. Murone C. Lew R.A. Zhuo J. Casley D. Muller-Esterl W. Alcorn D. Mendelsohn F.A.O. Localization of bradykinin B2 binding sites in rat kidney following chronic ACE inhibitor treatment.Kidney Int. 1997; 52: 1261-1270Abstract Full Text PDF PubMed Scopus (17) Google Scholar. Binding assays28.Dean R. Murone C. Lew R.A. Zhuo J. Casley D. Muller-Esterl W. Alcorn D. Mendelsohn F.A.O. Localization of bradykinin B2 binding sites in rat kidney following chronic ACE inhibitor treatment.Kidney Int. 1997; 52: 1261-1270Abstract Full Text PDF PubMed Scopus (17) Google Scholar,29.Fredrick M.J. Abel F.C. Rightsel W.A. Muirhead E.E. Odya C.E. B2 bradykinin receptor-like binding in rat renomedullary interstitial cells.Life Sci. 1985; 37: 331-338Crossref PubMed Scopus (23) Google Scholar and RT-PCR analysis28.Dean R. Murone C. Lew R.A. Zhuo J. Casley D. Muller-Esterl W. Alcorn D. Mendelsohn F.A.O. Localization of bradykinin B2 binding sites in rat kidney following chronic ACE inhibitor treatment.Kidney Int. 1997; 52: 1261-1270Abstract Full Text PDF PubMed Scopus (17) Google Scholar show that cultured RMICs also express B2 receptor binding sites and mRNA. In cultured RMICs, BK significantly increases cAMP and cGMP levels, but the latter response is dependent on the production of NO. [3H]thymidine incorporation and ECM synthesis are also stimulated by BK, and these responses are abolished by the B2 receptor antagonist, HOE 140, whereas the B1 receptor antagonist, desArg9[Leu8]BK (1 μm) is without effect Figure 3c28.Dean R. Murone C. Lew R.A. Zhuo J. Casley D. Muller-Esterl W. Alcorn D. Mendelsohn F.A.O. Localization of bradykinin B2 binding sites in rat kidney following chronic ACE inhibitor treatment.Kidney Int. 1997; 52: 1261-1270Abstract Full Text PDF PubMed Scopus (17) Google Scholar. The presence and expression of B2 receptors in RMICs in culture and in vivo support an important role for BK in the regulation of renal medullary hemodynamics and urinary excretion of sodium and water through the B2 receptor. Various vasoactive peptides appear to interact physiologically at multiple intrarenal sites to influence renal hemodynamics and tubular function1.Cowley Jr, A.W. Mattson D.L. Lu S.H. Roman R.J. The renal medulla and hypertension.Hypertension. 1995; 25: 663-673Crossref PubMed Google Scholar,3.Chou S.-Y. Porush J.G. Faubert P.F. Renal medullary circulation: Hormonal control.Kidney Int. 1990; 37: 1-13Abstract Full Text PDF PubMed Scopus (90) Google Scholar. In the cortex, Ang II and ET act as vasoconstrictors to decrease renal blood flow and glomerular filtration rate, whereas BK causes vasodilatation and increases glomerular capillary permeability2.Navar L.G. Inscho E.W. Majid D.S.A. Imig J.D. Harrison-Bernard L.M. Mitchell K.D. Paracrine regulation of the renal microcirculation.Physiol Rev. 1996; 76: 425-536PubMed Google Scholar. In the medulla, Ang II and ET cause vasoconstriction of outer medullary descending vasa recta and thereby decrease vasa recta and papillary blood flow, whereas BK exerts opposite effects2.Navar L.G. Inscho E.W. Majid D.S.A. Imig J.D. Harrison-Bernard L.M. Mitchell K.D. Paracrine regulation of the renal microcirculation.Physiol Rev. 1996; 76: 425-536PubMed Google Scholar. These results suggest a functional interplay between these vasoactive peptides at multiple cellular sites of the kidney. In accordance with these functional interactions, receptor-mapping studies have revealed that the distributions of AT1, ETA and ETB, and B2 receptors closely overlap at several anatomical sites, including the renal vasculature, glomeruli, and the inner stripe of the outer medulla4.Zhuo J. Alcorn D. Allen A.M. Mendelsohn F.A. High-resolution localization of angiotensin II receptors in rat renal medulla.Kidney Int. 1992; 42: 1372-1380Abstract Full Text PDF PubMed Scopus (71) Google Scholar, 8.Zhuo J. Alcorn D. Harris P.J. Mendelsohn F.A.O. Localization and properties of angiotensin II receptors in rat kidney.Kidney Int. 1993; 44: S40-S46Google Scholar, 19.Chow L.H. Subramanian S. Nuovo G.J. Miller F. Nord E.P. Endothelin receptor mRNA expression in renal medulla identified by in situ RT-PCR.Am J Physiol. 1995; 269: F449-F457PubMed Google Scholar, 20.Dean R. Zhuo J. Alcorn D. Casley D. Mendelsohn F.A.O. Cellular localization of endothelin receptor subtypes in the rat kidney following in vitro labelling.Clin Exp Pharmacol Physiol. 1996; 23: 524-531Crossref PubMed Scopus (29) Google Scholar, 27.Manning D.C. Snyder S.H. Bradykinin receptors localized by quantitative autoradiography in kidney, ureter, and bladder.Am J Physiol. 1989; 256: F909-F915PubMed Google Scholar, 28.Dean R. Murone C. Lew R.A. Zhuo J. Casley D. Muller-Esterl W. Alcorn D. Mendelsohn F.A.O. Localization of bradykinin B2 binding sites in rat kidney following chronic ACE inhibitor treatment.Kidney Int. 1997; 52: 1261-1270Abstract Full Text PDF PubMed Scopus (17) Google Scholar. In the cortex, the distributions of AT1 and ETB receptors are similar in the glomeruli and superficial proximal tubules4.Zhuo J. Alcorn D. Allen A.M. Mendelsohn F.A. High-resolution localization of angiotensin II receptors in rat renal medulla.Kidney Int. 1992; 42: 1372-1380Abstract Full Text PDF PubMed Scopus (71) Google Scholar, 16.Yanagisawa M. Kurihara H. Kumura S. Tomobe Y. Kobayashi M. Mitsui Y. Goto K. Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells.Nature. 1988; 332: 441-445Crossref Scopus (9964) Google Scholar, 18.Kon V. Badr K. Biological actions and pathophysiologic significance of endothelin in the kidney.Kidney Int. 1991; 40: 1-12Abstract Full Text PDF PubMed Scopus (174) Google Scholar, 20.Dean R. Zhuo J. Alcorn D. Casley D. Mendelsohn F.A.O. Cellular localization of endothelin receptor subtypes in the rat kidney following in vitro labelling.Clin Exp Pharmacol Physiol. 1996; 23: 524-531Crossref PubMed Scopus (29) Google Scholar. In contrast, B2 receptor density is low in the cortex27.Manning D.C. Snyder S.H. Bradykinin receptors localized by quantitative autoradiography in kidney, ureter, and bladder.Am J Physiol. 1989; 256: F909-F915PubMed Google Scholar. AT1 receptors are predominantly in mesangial cells6.Zhuo J. Alcorn D. Mc Causland J. Casley D. Mendelsohn F.A. In vivo occupancy of angiotensin II subtype 1 receptors in rat renal medullary interstitial cells.Hypertension. 1994; 23: 838-843Crossref PubMed Scopus (25) Google Scholar,8.Zhuo J. Alcorn D. Harris P.J. Mendelsohn F.A.O. Localization and properties of angiotensin II receptors in rat kidney.Kidney Int. 1993; 44: S40-S46Google Scholar, whereas ETB receptors are present mainly in endothelial cells of glomerular capillaries20.Dean R. Zhuo J. Alcorn D. Casley D. Mendelsohn F.A.O. Cellular localization of endothelin receptor subtypes in the rat kidney following in vitro labelling.Clin Exp Pharmacol Physiol. 1996; 23: 524-531Crossref PubMed Scopus (29) Google Scholar,21.Dean R. Zhuo J. Alcorn D. Casley D. Mendelsohn F.A.O. Cellular distribution of 125I-endothelin-1 binding in rat kidney following in vivo labeling.Am J Physiol. 1994; 267: F845-F852PubMed Google Scholar. In the medulla, ETB and B2 receptors are very abundant in the inner medulla toward the tip of the papilla20.Dean R. Zhuo J. Alcorn D. Casley D. Mendelsohn F.A.O. Cellular localization of endothelin receptor subtypes in the rat kidney following in vitro labelling.Clin Exp Pharmacol Physiol. 1996; 23: 524-531Crossref PubMed Scopus (29) Google Scholar,28.Dean R. Murone C. Lew R.A. Zhuo J. Casley D. Muller-Esterl W. Alcorn D. Mendelsohn F.A.O. Localization of bradykinin B2 binding sites in rat kidney following chronic ACE inhibitor treatment.Kidney Int. 1997; 52: 1261-1270Abstract Full Text PDF PubMed Scopus (17) Google Scholar, whereas AT1 receptors are not readily detected in this region Figure 14.Zhuo J. Alcorn D. Allen A.M. Mendelsohn F.A. High-resolution localization of angiotensin II receptors in rat renal medulla.Kidney Int. 1992; 42: 1372-1380Abstract Full Text PDF PubMed Scopus (71) Google Scholar,8.Zhuo J. Alcorn D. Harris P.J. Mendelsohn F.A.O. Localization and properties of angiotensin II receptors in rat kidney.Kidney Int. 1993; 44: S40-S46Google Scholar. However, receptor binding sites for these vasoactive peptides all occur in the inner stripe of the outer medulla, where these receptors have been identified in rat type I RMICs or cultured rat RMICs Figure 24.Zhuo J. Alcorn D. Allen A.M. Mendelsohn F.A. High-resolution localization of angiotensin II receptors in rat renal medulla.Kidney Int. 1992; 42: 1372-1380Abstract Full Text PDF PubMed Scopus (71) Google Scholar, 11.Brown C.A. Zusman R.M. Haber E. Identification of an angiotensin receptor in rabbit renomedullary interstitial cells in tissue culture: Correlation with prostaglandin biosynthesis.Circ Res. 1980; 46: 802-807Crossref PubMed Scopus (47) Google Scholar, 13.Maric C. Aldred G.P. Antoine A.M. Dean R.G. Eitle E. Mendelsohn F.A.O. Williams D.A. Harris P.J. Alcorn D. Effects of angiotensin II on cultured rat renomedullary interstitial cells are mediated by AT1A receptors.Am J Physiol. 1996; 271: F1020-F1028PubMed Google Scholar, 19.Chow L.H. Subramanian S. Nuovo G.J. Miller F. Nord E.P. Endothelin receptor mRNA expression in renal medulla identified by in situ RT-PCR.Am J Physiol. 1995; 269: F449-F457PubMed Google Scholar, 21.Dean R. Zhuo J. Alcorn D. Casley D. Mendelsohn F.A.O. Cellular distribution of 125I-endothelin-1 binding in rat kidney following in vivo labeling.Am J Physiol. 1994; 267: F845-F852PubMed Google Scholar, 28.Dean R. Murone C. Lew R.A. Zhuo J. Casley D. Muller-Esterl W. Alcorn D. Mendelsohn F.A.O. Localization of bradykinin B2 binding sites in rat kidney following chronic ACE inhibitor treatment.Kidney Int. 1997; 52: 1261-1270Abstract Full Text PDF PubMed Scopus (17) Google Scholar, 29.Fredrick M.J. Abel F.C. Rightsel W.A. Muirhead E.E. Odya C.E. B2 bradykinin receptor-like binding in rat renomedullary interstitial cells.Life Sci. 1985; 37: 331-338Crossref PubMed Scopus (23) Google Scholar. The concurrent distribution of multiple peptide receptors in RMICs provides a cellular basis for these vasoactive peptides to act alone, or to interact, in the regulation of renal medullary hemodynamics, tubular transport processes, and probably long-term blood pressure homeostasis. Moreover, the effects of Ang II, ET, and BK on cell proliferation and ECM synthesis in RMICs Figure 3 may also imply important roles for these peptides in pathological processes of chronic progressive renal diseases. Supported by grants from the National Health and Medical Research Council of Australia (NHMRC), National Heart Foundation, and Australian Kidney Foundation. We thank Dr. David Williams, Dr. Eveline Eitle, Ms. Jane McCausland and Arianne Antoine, and Mr. David Casley for collaboration or technical assistance. Dr. J. Zhuo and Professor F. A. O. Mendelsohn are supported by a Block Grant by the NHMRC to Howard Florey Institute of Experimental Physiology and Medicine." @default.
• W2068533848 created "2016-06-24" @default.
• W2068533848 creator A5018156590 @default.
• W2068533848 creator A5019781381 @default.
• W2068533848 creator A5025516230 @default.
• W2068533848 creator A5037167529 @default.
• W2068533848 creator A5052248384 @default.
• W2068533848 creator A5062661350 @default.
• W2068533848 creator A5087558793 @default.
• W2068533848 date "1998-09-01" @default.
• W2068533848 modified "2023-09-24" @default.
• W2068533848 title "Localization and interactions of vasoactive peptide receptors in renomedullary interstitial cells of the kidney" @default.
• W2068533848 cites W1969275919 @default.
• W2068533848 cites W1979043418 @default.
• W2068533848 cites W1981045101 @default.
• W2068533848 cites W2001338537 @default.
• W2068533848 cites W2006494855 @default.
• W2068533848 cites W2016080489 @default.
• W2068533848 cites W2025540579 @default.
• W2068533848 cites W2029101330 @default.
• W2068533848 cites W2037669837 @default.
• W2068533848 cites W2044485644 @default.
• W2068533848 cites W2055951155 @default.
• W2068533848 cites W2068708974 @default.
• W2068533848 cites W2112128323 @default.
• W2068533848 cites W2131033837 @default.
• W2068533848 cites W2138443098 @default.
• W2068533848 cites W2155760372 @default.
• W2068533848 cites W2162804111 @default.
• W2068533848 cites W2167364889 @default.
• W2068533848 doi "https://doi.org/10.1046/j.1523-1755.1998.06705.x" @default.
• W2068533848 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/9736248" @default.
• W2068533848 hasPublicationYear "1998" @default.
• W2068533848 type Work @default.
• W2068533848 sameAs 2068533848 @default.
• W2068533848 citedByCount "38" @default.
• W2068533848 countsByYear W20685338482012 @default.
• W2068533848 countsByYear W20685338482013 @default.
• W2068533848 countsByYear W20685338482015 @default.
• W2068533848 countsByYear W20685338482016 @default.
• W2068533848 countsByYear W20685338482017 @default.
• W2068533848 countsByYear W20685338482018 @default.
• W2068533848 countsByYear W20685338482020 @default.
• W2068533848 crossrefType "journal-article" @default.
• W2068533848 hasAuthorship W2068533848A5018156590 @default.
• W2068533848 hasAuthorship W2068533848A5019781381 @default.
• W2068533848 hasAuthorship W2068533848A5025516230 @default.
• W2068533848 hasAuthorship W2068533848A5037167529 @default.
• W2068533848 hasAuthorship W2068533848A5052248384 @default.
• W2068533848 hasAuthorship W2068533848A5062661350 @default.
• W2068533848 hasAuthorship W2068533848A5087558793 @default.
• W2068533848 hasBestOaLocation W20685338481 @default.
• W2068533848 hasConcept C118303440 @default.
• W2068533848 hasConcept C126322002 @default.
• W2068533848 hasConcept C133828647 @default.
• W2068533848 hasConcept C134018914 @default.
• W2068533848 hasConcept C170493617 @default.
• W2068533848 hasConcept C185592680 @default.
• W2068533848 hasConcept C2779281246 @default.
• W2068533848 hasConcept C2780091579 @default.
• W2068533848 hasConcept C55493867 @default.
• W2068533848 hasConcept C71924100 @default.
• W2068533848 hasConcept C8330315 @default.
• W2068533848 hasConcept C86803240 @default.
• W2068533848 hasConcept C95444343 @default.
• W2068533848 hasConceptScore W2068533848C118303440 @default.
• W2068533848 hasConceptScore W2068533848C126322002 @default.
• W2068533848 hasConceptScore W2068533848C133828647 @default.
• W2068533848 hasConceptScore W2068533848C134018914 @default.
• W2068533848 hasConceptScore W2068533848C170493617 @default.
• W2068533848 hasConceptScore W2068533848C185592680 @default.
• W2068533848 hasConceptScore W2068533848C2779281246 @default.
• W2068533848 hasConceptScore W2068533848C2780091579 @default.
• W2068533848 hasConceptScore W2068533848C55493867 @default.
• W2068533848 hasConceptScore W2068533848C71924100 @default.
• W2068533848 hasConceptScore W2068533848C8330315 @default.
• W2068533848 hasConceptScore W2068533848C86803240 @default.
• W2068533848 hasConceptScore W2068533848C95444343 @default.
• W2068533848 hasLocation W20685338481 @default.
• W2068533848 hasLocation W20685338482 @default.
• W2068533848 hasOpenAccess W2068533848 @default.
• W2068533848 hasPrimaryLocation W20685338481 @default.
• W2068533848 hasRelatedWork W1966638871 @default.
• W2068533848 hasRelatedWork W1995680439 @default.
• W2068533848 hasRelatedWork W2003450342 @default.
• W2068533848 hasRelatedWork W2016408069 @default.
• W2068533848 hasRelatedWork W2016899150 @default.
• W2068533848 hasRelatedWork W2027568289 @default.
• W2068533848 hasRelatedWork W2030613578 @default.
• W2068533848 hasRelatedWork W2084109973 @default.
• W2068533848 hasRelatedWork W2132497793 @default.
• W2068533848 hasRelatedWork W2748952813 @default.
• W2068533848 hasVolume "54" @default.
• W2068533848 isParatext "false" @default.
• W2068533848 isRetracted "false" @default.
• W2068533848 magId "2068533848" @default.
• W2068533848 workType "article" @default.