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Wolf-georg Forssmann - One of the best experts on this subject based on the ideXlab platform.
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Synthesis of phospho-Urodilatin by combination of global phosphorylation with the segment coupling approach
International journal of peptide and protein research, 2009Co-Authors: Hossein Mostafavi, Wolf-georg Forssmann, Sabine Austermann, Knut AdermannAbstract:The chemical synthesis of biologically active phosphorylated Urodilatin (CDD/ANP-95-126) was achieved by using a strategy of coupling protected peptide segments in solution. Three protected peptide segments corresponding to Urodilatin (1-14) with side chain-unprotected Ser10, (15-24) and (25-32) were prepared manually using Fmoc chemistry on an aminopropyl polystyrene resin with the super acid-labile HMPB linker. For the coupling of segments, the carboxy group of the C-terminal segment (25-32) was converted into the tert-butyl ester by treatment with TBTA. The protected peptide segments were coupled in the presence of EDC/HOOBt or TBTU/HOBt to yield fully protected Urodilatin with a free hydroxy function at Ser10. Introduction of the phosphate was performed with Et2NP(OtBu)2 and tetrazole followed by oxidation of the phosphite. Alternatively, a prephosphorylated protected segment (1-14) was used in the segment condensation. Our investigations indicate that both pathways, phosphorylation of protected Urodilatin in solution and use of a prephosphorylated building block, are suitable methods to obtain a large phosphopeptide of high purity without formation of H-phosphonates or other by-products.
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Renal Natriuretic Peptide System and Actions of Urodilatin
Handbook of Biologically Active Peptides, 2006Co-Authors: Markus Meyer, Jochen R. Hirsch, Wolf-georg ForssmannAbstract:ABSTRACT Urodilatin, a natriuretic peptide with four additional amino acids compared to atrial natriuretic peptide (ANP), is generated in distal tubule cells of the renal nephron. Whereas the fundamental role of ANP in the kidney, namely the regulation of natriuresis and diuresis, is questionable, Urodilatin may be responsible for this task when secreted into the lumen of the distal tubule. More stable than ANP, it can act as a paracrine regulator and bind to its specific receptors located in the luminal membrane of cortical collecting duct (CCD) and inner medullary collecting duct (IMCD), thus, displaying its effects on cellular pH, Na + transport, and H 2 O homeostasis. Urodilatin might also play a future role in the treatment of acute decompensated heart failure, acute renal failure, and bronchial asthma.
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Urodilatin, the renal natriuretic peptide: preclinical and clinical review
BMC Pharmacology, 2005Co-Authors: Wolf-georg Forssmann, V. Mitrovic, Markus Meyer, Hartmut LüssAbstract:Pre-Clinical background Natriuretic peptides were identified as regulatory diureticnatriuretic substances responsible for salt and water homeostasis and as hormones lowering blood pressure. Urodilatin is a natriuretic peptide type A which is synthesized in the kidney and generated from the prohormone ANP-1-126. While the circulating ANP-99-126 is synthesized in the heart atrium and processed during exocytosis Urodilatin (ANP-95-126) is differentially processed in the kidney and detected only in urine.
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Effects of the renal natriuretic peptide Urodilatin (ularitide) in patients with decompensated chronic heart failure: a double-blind, placebo-controlled, ascending-dose trial.
American heart journal, 2005Co-Authors: V. Mitrovic, Wolf-georg Forssmann, Hartmut Lüss, Kristin Forssmann, Klaus Nitsche, Erik Maronde, Katrin Fricke, Markus MeyerAbstract:Background Urodilatin (ularitide), a natriuretic peptide, is produced within the kidneys. The aim of this study was to define the role of 24-hour intravenous infusions of Urodilatin in the treatment of decompensated chronic heart failure (DHF). Methods In this randomized, double-blind, ascending-dose safety study, 24 patients with DHF (cardiac index 1.91 ± 0.34 L/min per square meter, pulmonary capillary wedge pressure 26 ± 6 mm Hg, right atrial pressure 11 ± 4 mm Hg) received Urodilatin (7.5, 15, or 30 ng/(kg · min)) or placebo infusions over 24 hours. Results Compared with baseline, Urodilatin decreased pulmonary capillary wedge pressure by 10 mm Hg in the 15 ng/(kg · min) group ( P P P Conclusions Our findings show that Urodilatin may be a new agent for the therapy for DHF.
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The renal Urodilatin system: clinical implications.
Cardiovascular research, 2001Co-Authors: Wolf-georg Forssmann, M. Meyer, Kristin ForssmannAbstract:A renal natriuretic peptide and the 'renal Urodilatin system' were identified after the observation that immunoassayable ANP in urine may not be identical to the circulating cardiac hormone ANP, which is a peptide of 28 amino acids. Urodilatin (INN: Ularitide) is a natriuretic peptide isolated from human urine and belongs to the family of A-type natriuretic peptides. Urodilatin is differentially processed to a peptide of 32 amino acids from the same precursor as ANP. It is synthesized in kidney tubular cells and secreted luminally. After secretion from epithelial cells of the distal and/or connecting tubules, Urodilatin interacts downstream at distal segments of the nephron with luminally located receptors whereby it regulates Na(+) and water reabsorption. Thus, the physiological function of the renal Urodilatin system can be described as a paracrine intrarenal regulator for Na(+) and water homeostasis, considering Urodilatin as a real diuretic-natriuretic regulatory peptide. However, the regulation upon which the Urodilatin secretion depends is still not clear. Since Urodilatin has been discovered, a great number of pharmacological and clinical investigations have been carried out using Urodilatin as a drug for several indications. So far, clinical phase I and II studies for acute renal failure, congestive heart failure, and bronchial asthma have been performed.
Christian Drummer - One of the best experts on this subject based on the ideXlab platform.
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Regulation of natriuretic peptide (Urodilatin) release in a human kidney cell line
Kidney international, 1999Co-Authors: Wolfgang Lenz, Herten M, Rupert Gerzer, Christian DrummerAbstract:Regulation of natriuretic peptide (Urodilatin) release in a human kidney cell line. Background To identify the molecular mechanisms underlying the release of a renal natriuretic peptide (NP) we selected a human kidney cell line (HEK 293) that displays several characteristics of distal tubular cells. Methods Cells were exposed to different extracellular and intracellular stimuli, and the effect on NP release was measured with a specific Urodilatin radioimmunoassay, as well as with an atrial NP (ANP) radioimmunoassay. Results In the absence of stimuli, HEK 293 cells showed a basal release of Urodilatin immunoreactivity and ANP immunoreactivity. Raising the osmolality of the secretion medium with sodium chloride and various other osmolytes rapidly increased cellular NP secretion. Elevation of intracellular cAMP levels by forskolin plus 3-isobutyl-1-methylxanthine and administration of phorbol-12-myristate-13-acetate together with the calcium-ionophore A23187 also resulted in respective increases in the amount of secreted peptide. HEK 293 cells exhibit the endogenous expression of both particulate and soluble guanylyl cyclases. In the presence of 8-Br-cGMP, cell cultures showed the enhanced secretion of an ANP immunoreactive peptide only, indicating that guanylyl cyclase activation provoked the secretion of ANP immunoreactivity but not of Urodilatin immunoreactivity. Conclusions The human embryonic kidney cell line HEK 293 represents a renal cellular model system in which we have identified a rapid and regulated release of NPs in response to the osmotic effect of increased extracellular sodium chloride and various intracellular stimuli.
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The renal natriuretic peptide Urodilatin is present in human kidney.
Nephrology dialysis transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 1998Co-Authors: Herten M, Rupert Gerzer, Wolfgang Lenz, Christian DrummerAbstract:BACKGROUND The natriuretic peptide Urodilatin was first isolated from human urine and may be one of the important mediators of natriuresis, while the atrial natriuretic peptide alpha-ANP, the circulating member of the family, rather seems to play a role in cardiovascular regulation. Although the renal expression of the common propeptide for Urodilatin and alpha-ANP has been detected in rat and pig, it is not yet shown that Urodilatin is synthesized in human kidney. METHODS Immunohistochemically we localized Urodilatin with an Urodilatin-antibody, which does not cross-react with alpha-ANP, the ANP propeptide, brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). Radiolabelled Urodilatin binding was examined autoradiographically. RESULTS We could demonstrate that Urodilatin is present in human distal tubular cells, in which we could also localize propeptide immunoreactivity. The glomeruli, the cells of the proximal tubule, and the collecting duct did not show any Urodilatin immunoreactivity. In human kidney homogenate the Urodilatin content was 4600 + 520 fmol/g protein (n = 6). The renal concentration of BNP and CNP, mainly localized in the distal tubule, was much lower at 40 + 8 and 400+/-50 fmol/g protein (n=6) respectively. Furthermore the autoradiographic examinations showed that radiolabelled Urodilatin binds to natriuretic peptide receptors in the glomeruli, blood vessels, and collecting ducts. CONCLUSIONS Our data suggest that Urodilatin may be the predominant representative of natriuretic peptides in human kidneys. Urodilatin being synthesized in the distal tubular region may be transported as a paracrine factor to the collecting duct, where it exerts its suppressing effect on the sodium reabsorption by stimulating the guanylyl cyclase A.
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Renal Urodilatin secretion is associated with diuresis and natriuresis after spontaneous, supraventricular tachycardia
Zeitschrift fur Kardiologie, 1998Co-Authors: Michael Kentsch, Christian Drummer, Rupert Gerzer, T. Kuhrmann, U. Rodemerk, G. Müller-eschAbstract:Patienten mit paroxysmaler supraventrikularer Tachykardie (SVT) haben oftmals eine Polyurie nach Terminierung der Tachykardie. Jungere Untersuchungen weisen darauf hin, das beim Menschen das renale Peptid Urodilatin (ANP(95–126)) – und nicht Plasma-ANP (ANP(99–126)) – der an Natriurese und Diurese beteiligten Mediator aus der Familie natriuretischer Peptide ist. Im Rahmen einer Untersuchung bei Patienten mit SVT wurde deshalb die Beziehung zwischen Diurese, Natriures, ANP-Plasma-Spiegeln, renaler Ausscheidung von Urodilatin und cGMP, dem second messenger im ANP-System, analysiert. Wahrend und nach klinischer Prasentation mit einer spontan auftretenden SVT wurden zwei Patienten mit AV-Knoten-Tachykardien und ein Patient mit artioventrikularer Reentry-Tachykardie (Frequenz 160 bis 200/min) untersucht. Die renale Urodilatin-Sekretion war mit der Diurese (r = 0,73) und Natriurese (r = 0,93) korreliert; eine ahnliche Beziehung bestand zwischen renaler cGMP-Ausscheidung und Diurese (r = 0,80) sowie Natriurese (r = 0,87; jeweils p < 0,001). Im Gegensatz hierzu ergab sich keine signifikante Korrelation zwischen ANP-Plasmaspiegeln und Diurese (r = 0,28, n.s.) oder Natriurese (r = 0,11, n.s.). Im Rahmen einer explorativen Analyse konnte mittels schrittweiser logistischer Regression die renale Urodilation-Sekretion als wichtigster unabhangiger Faktor fur die Diurese und Natriurese nach SVT identifiziert werden. Diese Daten zur Polyurie nach spontanter SVT stimmen mit jungsten Ergebnissen zur Physiologie der Nierenfunktion uberein, die zeigen, das Urodilatin das an der Regulation der Nierenfunktion beteiligte natriuretische Peptid ist.
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increased renal natriuretic peptide Urodilatin excretion in heart failure patients
European Journal of Medical Research, 1997Co-Authors: Christian Drummer, Martina Heer, M. Kentsch, W. Otter, M Herten, Rupert GerzerAbstract:Accumulating evidence suggests that Urodilatin, a kidney-derived member of the natriuretic peptide family, contributes as a major mediator of sodium excretion to body fluid regulation in healthy men. In contrast to other members of the natriuretic peptide family, pathophysiological data for the renal natriuretic peptide have still been missing. The present study compares renal synthesis of Urodilatin in patients with congestive heart failure (CHF) and healthy volunteers. Because Urodilatin excretion, considerably increases with increasing nutritive sodium intake (p<0.004), the CHF patients (15 NYHA I/II, 8 NYHA III/IV) were kept on a 165 mmol/day sodium diet and 6 healthy volunteers on a identical nutritive sodium intake level were selected as proper controls. Although Urodilatin excretion significantly increased (p<0.027) with increasing severity of CHF and was therefore significantly higher in mild CHF (40.7 +/- 2.5 fmol/min) and severe CHF (54.7 +/- 6.6 fmol/min) than in healthy controls (3.2 +/- 4.2 fmol/min), both groups of CHF patients retained sodium and had significantly lower sodium excretion rates (NYHA I/II 79.0 +/- 6.9 micromol/min, NYHA III/IV 97.9 +/- 12.7 micromol/min) than the healthy controls (139 +/- 3.4 micromol/min). Our data suggest that renal Urodilatin synthesis, may not be involved in the etiology of sodium retention in CHF, but may rather be stimulated to counteract antinatriuresis during CHF.
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Increased renal natriuretic peptide (Urodilatin) excretion in heart failure patients.
European journal of medical research, 1997Co-Authors: Christian Drummer, Martina Heer, Herten M, M. Kentsch, W. Otter, Rupert GerzerAbstract:Accumulating evidence suggests that Urodilatin, a kidney-derived member of the natriuretic peptide family, contributes as a major mediator of sodium excretion to body fluid regulation in healthy men. In contrast to other members of the natriuretic peptide family, pathophysiological data for the renal natriuretic peptide have still been missing. The present study compares renal synthesis of Urodilatin in patients with congestive heart failure (CHF) and healthy volunteers. Because Urodilatin excretion, considerably increases with increasing nutritive sodium intake (p
Rupert Gerzer - One of the best experts on this subject based on the ideXlab platform.
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Regulation of natriuretic peptide (Urodilatin) release in a human kidney cell line
Kidney international, 1999Co-Authors: Wolfgang Lenz, Herten M, Rupert Gerzer, Christian DrummerAbstract:Regulation of natriuretic peptide (Urodilatin) release in a human kidney cell line. Background To identify the molecular mechanisms underlying the release of a renal natriuretic peptide (NP) we selected a human kidney cell line (HEK 293) that displays several characteristics of distal tubular cells. Methods Cells were exposed to different extracellular and intracellular stimuli, and the effect on NP release was measured with a specific Urodilatin radioimmunoassay, as well as with an atrial NP (ANP) radioimmunoassay. Results In the absence of stimuli, HEK 293 cells showed a basal release of Urodilatin immunoreactivity and ANP immunoreactivity. Raising the osmolality of the secretion medium with sodium chloride and various other osmolytes rapidly increased cellular NP secretion. Elevation of intracellular cAMP levels by forskolin plus 3-isobutyl-1-methylxanthine and administration of phorbol-12-myristate-13-acetate together with the calcium-ionophore A23187 also resulted in respective increases in the amount of secreted peptide. HEK 293 cells exhibit the endogenous expression of both particulate and soluble guanylyl cyclases. In the presence of 8-Br-cGMP, cell cultures showed the enhanced secretion of an ANP immunoreactive peptide only, indicating that guanylyl cyclase activation provoked the secretion of ANP immunoreactivity but not of Urodilatin immunoreactivity. Conclusions The human embryonic kidney cell line HEK 293 represents a renal cellular model system in which we have identified a rapid and regulated release of NPs in response to the osmotic effect of increased extracellular sodium chloride and various intracellular stimuli.
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The renal natriuretic peptide Urodilatin is present in human kidney.
Nephrology dialysis transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 1998Co-Authors: Herten M, Rupert Gerzer, Wolfgang Lenz, Christian DrummerAbstract:BACKGROUND The natriuretic peptide Urodilatin was first isolated from human urine and may be one of the important mediators of natriuresis, while the atrial natriuretic peptide alpha-ANP, the circulating member of the family, rather seems to play a role in cardiovascular regulation. Although the renal expression of the common propeptide for Urodilatin and alpha-ANP has been detected in rat and pig, it is not yet shown that Urodilatin is synthesized in human kidney. METHODS Immunohistochemically we localized Urodilatin with an Urodilatin-antibody, which does not cross-react with alpha-ANP, the ANP propeptide, brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). Radiolabelled Urodilatin binding was examined autoradiographically. RESULTS We could demonstrate that Urodilatin is present in human distal tubular cells, in which we could also localize propeptide immunoreactivity. The glomeruli, the cells of the proximal tubule, and the collecting duct did not show any Urodilatin immunoreactivity. In human kidney homogenate the Urodilatin content was 4600 + 520 fmol/g protein (n = 6). The renal concentration of BNP and CNP, mainly localized in the distal tubule, was much lower at 40 + 8 and 400+/-50 fmol/g protein (n=6) respectively. Furthermore the autoradiographic examinations showed that radiolabelled Urodilatin binds to natriuretic peptide receptors in the glomeruli, blood vessels, and collecting ducts. CONCLUSIONS Our data suggest that Urodilatin may be the predominant representative of natriuretic peptides in human kidneys. Urodilatin being synthesized in the distal tubular region may be transported as a paracrine factor to the collecting duct, where it exerts its suppressing effect on the sodium reabsorption by stimulating the guanylyl cyclase A.
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Renal Urodilatin secretion is associated with diuresis and natriuresis after spontaneous, supraventricular tachycardia
Zeitschrift fur Kardiologie, 1998Co-Authors: Michael Kentsch, Christian Drummer, Rupert Gerzer, T. Kuhrmann, U. Rodemerk, G. Müller-eschAbstract:Patienten mit paroxysmaler supraventrikularer Tachykardie (SVT) haben oftmals eine Polyurie nach Terminierung der Tachykardie. Jungere Untersuchungen weisen darauf hin, das beim Menschen das renale Peptid Urodilatin (ANP(95–126)) – und nicht Plasma-ANP (ANP(99–126)) – der an Natriurese und Diurese beteiligten Mediator aus der Familie natriuretischer Peptide ist. Im Rahmen einer Untersuchung bei Patienten mit SVT wurde deshalb die Beziehung zwischen Diurese, Natriures, ANP-Plasma-Spiegeln, renaler Ausscheidung von Urodilatin und cGMP, dem second messenger im ANP-System, analysiert. Wahrend und nach klinischer Prasentation mit einer spontan auftretenden SVT wurden zwei Patienten mit AV-Knoten-Tachykardien und ein Patient mit artioventrikularer Reentry-Tachykardie (Frequenz 160 bis 200/min) untersucht. Die renale Urodilatin-Sekretion war mit der Diurese (r = 0,73) und Natriurese (r = 0,93) korreliert; eine ahnliche Beziehung bestand zwischen renaler cGMP-Ausscheidung und Diurese (r = 0,80) sowie Natriurese (r = 0,87; jeweils p < 0,001). Im Gegensatz hierzu ergab sich keine signifikante Korrelation zwischen ANP-Plasmaspiegeln und Diurese (r = 0,28, n.s.) oder Natriurese (r = 0,11, n.s.). Im Rahmen einer explorativen Analyse konnte mittels schrittweiser logistischer Regression die renale Urodilation-Sekretion als wichtigster unabhangiger Faktor fur die Diurese und Natriurese nach SVT identifiziert werden. Diese Daten zur Polyurie nach spontanter SVT stimmen mit jungsten Ergebnissen zur Physiologie der Nierenfunktion uberein, die zeigen, das Urodilatin das an der Regulation der Nierenfunktion beteiligte natriuretische Peptid ist.
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increased renal natriuretic peptide Urodilatin excretion in heart failure patients
European Journal of Medical Research, 1997Co-Authors: Christian Drummer, Martina Heer, M. Kentsch, W. Otter, M Herten, Rupert GerzerAbstract:Accumulating evidence suggests that Urodilatin, a kidney-derived member of the natriuretic peptide family, contributes as a major mediator of sodium excretion to body fluid regulation in healthy men. In contrast to other members of the natriuretic peptide family, pathophysiological data for the renal natriuretic peptide have still been missing. The present study compares renal synthesis of Urodilatin in patients with congestive heart failure (CHF) and healthy volunteers. Because Urodilatin excretion, considerably increases with increasing nutritive sodium intake (p<0.004), the CHF patients (15 NYHA I/II, 8 NYHA III/IV) were kept on a 165 mmol/day sodium diet and 6 healthy volunteers on a identical nutritive sodium intake level were selected as proper controls. Although Urodilatin excretion significantly increased (p<0.027) with increasing severity of CHF and was therefore significantly higher in mild CHF (40.7 +/- 2.5 fmol/min) and severe CHF (54.7 +/- 6.6 fmol/min) than in healthy controls (3.2 +/- 4.2 fmol/min), both groups of CHF patients retained sodium and had significantly lower sodium excretion rates (NYHA I/II 79.0 +/- 6.9 micromol/min, NYHA III/IV 97.9 +/- 12.7 micromol/min) than the healthy controls (139 +/- 3.4 micromol/min). Our data suggest that renal Urodilatin synthesis, may not be involved in the etiology of sodium retention in CHF, but may rather be stimulated to counteract antinatriuresis during CHF.
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Increased renal natriuretic peptide (Urodilatin) excretion in heart failure patients.
European journal of medical research, 1997Co-Authors: Christian Drummer, Martina Heer, Herten M, M. Kentsch, W. Otter, Rupert GerzerAbstract:Accumulating evidence suggests that Urodilatin, a kidney-derived member of the natriuretic peptide family, contributes as a major mediator of sodium excretion to body fluid regulation in healthy men. In contrast to other members of the natriuretic peptide family, pathophysiological data for the renal natriuretic peptide have still been missing. The present study compares renal synthesis of Urodilatin in patients with congestive heart failure (CHF) and healthy volunteers. Because Urodilatin excretion, considerably increases with increasing nutritive sodium intake (p
Markus Meyer - One of the best experts on this subject based on the ideXlab platform.
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ANP and Urodilatin: who is who in the kidney.
European journal of medical research, 2006Co-Authors: Jochen R. Hirsch, Markus MeyerAbstract:Mounting evidence suggests that Urodilatin, not atrial natriuretic peptide (ANP) is the responsible peptide in regulation of renal Na superset+- and water homeostasis. Following the discovery of ANP this peptide was thought to be responsible for the induction of natriuresis and diuresis in the mammalian kidney. However, the isolation of Urodilatin from human urine and substantial work contributed to a better understanding of the renal physiology of these two natriuretic peptides. Indeed, subsequent elucidation supported that Urodilatin rather than ANP seems to be the natriuretic peptide responsible for the regulation of Na superset+- and water homeostasis in the kidney. Urodilatin - synthesized and secreted from the distal tubules of the kidney - may act as a paracrine mediator when secreted into the lumen. In contrast, while the role of ANP as regulator of the cardiovascular system is established, its physiological regulatory role on transport processes in the nephron is questionable. This review attempts to analyze the roles of both ANP and Urodilatin and to discuss new potential candidates which may also play a role in electrolyte and water handling in the kidney.
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Renal Natriuretic Peptide System and Actions of Urodilatin
Handbook of Biologically Active Peptides, 2006Co-Authors: Markus Meyer, Jochen R. Hirsch, Wolf-georg ForssmannAbstract:ABSTRACT Urodilatin, a natriuretic peptide with four additional amino acids compared to atrial natriuretic peptide (ANP), is generated in distal tubule cells of the renal nephron. Whereas the fundamental role of ANP in the kidney, namely the regulation of natriuresis and diuresis, is questionable, Urodilatin may be responsible for this task when secreted into the lumen of the distal tubule. More stable than ANP, it can act as a paracrine regulator and bind to its specific receptors located in the luminal membrane of cortical collecting duct (CCD) and inner medullary collecting duct (IMCD), thus, displaying its effects on cellular pH, Na + transport, and H 2 O homeostasis. Urodilatin might also play a future role in the treatment of acute decompensated heart failure, acute renal failure, and bronchial asthma.
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Urodilatin, the renal natriuretic peptide: preclinical and clinical review
BMC Pharmacology, 2005Co-Authors: Wolf-georg Forssmann, V. Mitrovic, Markus Meyer, Hartmut LüssAbstract:Pre-Clinical background Natriuretic peptides were identified as regulatory diureticnatriuretic substances responsible for salt and water homeostasis and as hormones lowering blood pressure. Urodilatin is a natriuretic peptide type A which is synthesized in the kidney and generated from the prohormone ANP-1-126. While the circulating ANP-99-126 is synthesized in the heart atrium and processed during exocytosis Urodilatin (ANP-95-126) is differentially processed in the kidney and detected only in urine.
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Effects of the renal natriuretic peptide Urodilatin (ularitide) in patients with decompensated chronic heart failure: a double-blind, placebo-controlled, ascending-dose trial.
American heart journal, 2005Co-Authors: V. Mitrovic, Wolf-georg Forssmann, Hartmut Lüss, Kristin Forssmann, Klaus Nitsche, Erik Maronde, Katrin Fricke, Markus MeyerAbstract:Background Urodilatin (ularitide), a natriuretic peptide, is produced within the kidneys. The aim of this study was to define the role of 24-hour intravenous infusions of Urodilatin in the treatment of decompensated chronic heart failure (DHF). Methods In this randomized, double-blind, ascending-dose safety study, 24 patients with DHF (cardiac index 1.91 ± 0.34 L/min per square meter, pulmonary capillary wedge pressure 26 ± 6 mm Hg, right atrial pressure 11 ± 4 mm Hg) received Urodilatin (7.5, 15, or 30 ng/(kg · min)) or placebo infusions over 24 hours. Results Compared with baseline, Urodilatin decreased pulmonary capillary wedge pressure by 10 mm Hg in the 15 ng/(kg · min) group ( P P P Conclusions Our findings show that Urodilatin may be a new agent for the therapy for DHF.
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Bronchodilation using combined Urodilatin - albuterol administration in asthma: a randomized, double-blind, placebo-controlled trial.
European journal of medical research, 1999Co-Authors: Thomas Flüge, Wolf-georg Forssmann, Mentz P, Kunkel G, Berthold Schneider, K. Forssmann, Markus MeyerAbstract:Urodilatin, the renal form of natriuretic peptide type A, induces bronchodilation, increasing intracellular cyclic guanosine monophosphate (cGMP), whereas the bronchorelaxant effect by b2-agonists is triggered by cyclic adenosine monophosphate (cAMP). The objective of this investigation is to demonstrate the efficacy of Urodilatin in inducing bronchodilation, and to show this activity alone or in combination with albuterol. Therefore, a randomized, double-blind, placebo-controlled, dose-finding study with cross-over design was carried out including 12 stable, mild to severe (step 2 to 4, definition by NIH/NHLBI guideline 1997) asthmatics. 96 treatments were thus performed. The intervention was comprised of an intravenous infusion of Urodilatin (0, 10, 30, or 60 ng/kg/min) combined with inhaled albuterol (0 or 200 microg). As primary objective, the increase in forced expiratory volume in one second (FEV subset1) was measured. - The trial shows that Urodilatin at all applied doses or 200 microg albuterol significantly increases FEV subset1 (p < 0.05). Combination of Urodilatin and albuterol treament significantly improves FEV subset1 (p < 0.05) compared to either monotherapy and results in maximum bronchodilation. - From the results, the following conclusions can be drawn. In stable asthmatics, the combined activation of cGMP- and cAMP-mediated pathways results in a significantly improved, maximal bronchodilation in comparison to either type of monotherapy. This shows that Urodilatin combined with albuterol improves lung function and ameliorates the therapy in asthmatics.
M. Meyer - One of the best experts on this subject based on the ideXlab platform.
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ANP AND Urodilatin: WHO IS WHO IN THE KIDNEY
2013Co-Authors: Jochen R. Hirsch, M. Meyer, -g. W. Forssmann, Cardiopep Pharma Gmbh HannoverAbstract:Mounting evidence suggests that Urodilatin, not atrial natriuretic peptide (ANP) is the responsible peptide in regulation of renal Na +- and water homeostasis. Following the discovery of ANP this peptide was thought to be responsible for the induction of natriuresis and diuresis in the mammalian kidney. However, the isolation of Urodilatin from human urine and substantial work contributed to a better understanding of the renal physiology of these two natriuretic peptides. Indeed, subsequent elucidation supported that Urodilatin rather than ANP seems to be the natriuretic peptide responsible for the regulation of Na +- and water homeostasis in the kidney. Urodilatin – synthesized and secreted from the distal tubules of the kidney-may act as a paracrine mediator when secreted into the lumen. In contrast, while the role of ANP as regulator of the cardiovascular system is established, its physiological regulatory role on transport processes in the nephron is questionable. This review attempts to analyze the roles of both ANP and Urodilatin and to discuss new potential candidates which may also play a role in electrolyte and water handling in the kidney
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The renal Urodilatin system: clinical implications.
Cardiovascular research, 2001Co-Authors: Wolf-georg Forssmann, M. Meyer, Kristin ForssmannAbstract:A renal natriuretic peptide and the 'renal Urodilatin system' were identified after the observation that immunoassayable ANP in urine may not be identical to the circulating cardiac hormone ANP, which is a peptide of 28 amino acids. Urodilatin (INN: Ularitide) is a natriuretic peptide isolated from human urine and belongs to the family of A-type natriuretic peptides. Urodilatin is differentially processed to a peptide of 32 amino acids from the same precursor as ANP. It is synthesized in kidney tubular cells and secreted luminally. After secretion from epithelial cells of the distal and/or connecting tubules, Urodilatin interacts downstream at distal segments of the nephron with luminally located receptors whereby it regulates Na(+) and water reabsorption. Thus, the physiological function of the renal Urodilatin system can be described as a paracrine intrarenal regulator for Na(+) and water homeostasis, considering Urodilatin as a real diuretic-natriuretic regulatory peptide. However, the regulation upon which the Urodilatin secretion depends is still not clear. Since Urodilatin has been discovered, a great number of pharmacological and clinical investigations have been carried out using Urodilatin as a drug for several indications. So far, clinical phase I and II studies for acute renal failure, congestive heart failure, and bronchial asthma have been performed.
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Prophylactic use of low-dose Urodilatin for prevention of renal impairment following liver transplantation: a randomized placebo-controlled study.
Clinical transplantation, 1997Co-Authors: Jan M. Langrehr, M. Meyer, A. Kahl, U. Neumann, M. Knoop, Sven Jonas, Thomas Steinmüller, Wolf O. Bechstein, U. Frei, W.-g. ForssmannAbstract:Many therapeutic measures have been employed to prevent or at least ameliorate postoperative renal impairment following liver transplantation. Recent clinical phase II studies have demonstrated that the new natri-uretic peptide Urodilatin has beneficial effects on renal function following heart and liver transplantation. The present study reports the first prospective randomized placebo-controlled trial of prophylactic Urodilatin administration following liver transplantation. Seventy consecutive recipients of primary liver transplants were included in the study following randomization, and 33 patients continuously received Urodilatin at a dose of 20 ng/kg/min for 7 d. The remaining 37 patients received a placebo infusion for the same time period. The course of serum creatinine and urea did not differ between the two groups nor did the daily urine production. However, the Urodilatin group showed a higher preoperative median serum creatinine and a significant reduction on days 1 and 2, whereas this observation was not made in the placebo group. Furthermore, less furosemide was administered to the patients in the Urodilatin group during the first 2 d. The incidence of post-operative hemodialysis and the number of treatments did not differ between the groups either (Urodilatin group 4, vs. placebo group 6 and 22 for both groups, respectively). Side effects of the Urodilatin therapy were not detected. The prophylactic low-dose Urodilatin administration resulted in a trend towards amelioration of the renal function, but did not result in significant differences between the two experimental groups. Further studies, using higher doses, will be required to define the value of Urodilatin for prevention of renal impairment after liver transplantation.
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The renal paracrine peptide system — possible urologic implications of Urodilatin
World Journal of Urology, 1996Co-Authors: M. Meyer, C. G. Stief, A. J. Becker, M. C. Truss, A. Taher, U. Jonas, W.-g. ForssmannAbstract:Cardiodilatin/atrial natriuretic peptide (CDD/ANP) is a hormone system of great clinical importance. The prohormone CDD/ANP-1-126 is a peptide synthesized in the heart and cleaved during exocytosis into the circulating form CDD/ANP-99-126. Urodilatin (CDD/ANP-95-126) is a homologue natriuretic peptide that differs from CDD/ANP-99-126 by four amino acids. Whereas CDD/ANP-99-126 circulates in blood plasma and is not excreted into the urine, Urodilatin is detected only in urine. Urodilatin exerts its renal effects in a paracrine fashion. After its secretion from cells in the distal tubule, it interacts with luminally located receptors in the collecting duct, resulting in increased diuresis and natriuresis. Results suggest that Urodilatin plays an important role in the physiologic regulation of fluid balance and sodium homeostasis. Pharmacology studies reveal significant differences when Urodilatin and CDD/ANP-99-126 are given intravenously, showing that stronger diuresis and natriuresis are induced by Urodilatin as compared with those induced by CDD/ANP-99-126. Clinical studies indicate the prophylactic and therapeutic effect of Urodilatin in patients suffering from acute renal failure following heart and liver transplantation. A significant reduction in requirements for hemodialysis/hemofiltration can be achieved using Urodilatin. Postobstructive diuresis and natriuresis is probably due to a defective urinary concentrating mechanism and is usually resistant to treatment with antidiuretic hormone. The distal tubule and collecting duct have often been considered to be the site of altered sodium and water excretion following relief of obstruction. Since circulating CDD/ANP-99-126 levels are markedly elevated during obstruction and decrease upon relief of the obstruction, natriuretic peptides may play an important role in this clinical feature. On the basis of recent findings attributing an important role in sodium homeostasis to Urodilatin in contrast to CDD/ANP-99-126, future studies have to clarify whether Urodilatin, not CDD/ANP-99-126, might be responsible for the altered renal sodium excretion observed in postobstructive diuresis.
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Urodilatin is involved in sodium homeostasis and exerts sodium-state-dependent natriuretic and diuretic effects.
The American journal of physiology, 1996Co-Authors: M. Meyer, P Schulz-knappe, R Richter, R Brunkhorst, E Wrenger, A Kist, P Mentz, E G Brabant, K M Koch, G RechkemmerAbstract:Urodilatin is involved in sodium homeostasis exerts sodium-state-dependent natriuretic and diuretic cts. Eight male volunteers participated in a study consisting of three consecutive phases of 7 days each. The volunteers a sodium diet with 52, 172.6, and 347.8 mmol um/day. Sodium excretion increased from 57.4 +/- 3.7 via .8 +/- 4.6 (P < 0.001) to 322.5 +/- 10.2 mmol/24 h (P < 0.001) at the end of each sodium diet. Urinary Urodilatin excretion increased from 24.8 +/- 3.0 via 35.5 +/- 9.0 (P = 0.07) to 49.0 = mol/min (P < 0.01). At the end of each diet, Urodilatin was infused for 2 h at 20 ng.kg body wt-1.min-1. Natriuresis increased after low- (4.1 to 52.9 mmol/h, P < 0.001), normal (6.9 to 44.9 mmol/h, P < 0.05), and high-sodium diet (20.1 to 102.9 mmol/h, P < 0.001). Diuresis increased from 174 to 709 (P < 0.001), 395 to 1,026 (P < 0.05), and 266 to 1,339 ml/h < 0.001). The present results indicate that endogenous Urodilatin plays an important role in sodium homeostasis and that renal response to exogenous Urodilatin is modulated by sodium balance.
