Natriuretic Peptides: Their Structures, Receptors, Physiologic Functions and Therapeutic Applications

Part of the Handbook of Experimental Pharmacology book series (HEP, volume 191)


Natriuretic peptides are a family of three structurally related hormone/ paracrine factors. Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are secreted from the cardiac atria and ventricles, respectively. ANP signals in an endocrine and paracrine manner to decrease blood pressure and cardiac hypertrophy. BNP acts locally to reduce ventricular fibrosis. C-type natriuretic peptide (CNP) primarily stimulates long bone growth but likely serves unappreciated functions as well. ANP and BNP activate the transmembrane guanylyl cyclase, natriuretic peptide receptor-A (NPR-A). CNP activates a related cyclase, natriuretic peptide receptor-B (NPR-B). Both receptors catalyze the synthesis of cGMP, which mediates most known effects of natriuretic peptides. A third natriuretic peptide receptor, natriuretic peptide receptor-C (NPR-C), clears natriuretic peptides from the circulation through receptor-mediated internalization and degradation. However, a signaling function for the receptor has been suggested as well. Targeted disruptions of the genes encoding all natriuretic peptides and their receptors have been generated in mice, which display unique physiologies. A few mutations in these proteins have been reported in humans. Synthetic analogs of ANP (anaritide and carperitide) and BNP (nesiritide) have been investigated as potential therapies for the treatment of decompensated heart failure and other diseases. Anaritide and nesiritide are approved for use in acute decompensated heart failure, but recent studies have cast doubt on their safety and effectiveness. New clinical trials are examining the effect of nesiritide and novel peptides, like CD-NP, on these critical parameters. In this review, the history, structure, function, and clinical applications of natriuretic peptides and their receptors are discussed.


Natriuretic Peptide Brain Natriuretic Peptide Atrial Natriuretic Peptide Acute Decompensated Heart Failure Natriuretic Peptide Receptor 
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  1. Allgren RL, Marbury TC, Rahman SN, Weisberg LS, Fenves AZ, Lafayette RA, Sweet RM, Genter FC, Kurnik BR, Conger JD, Sayegh MH (1997) Anaritide in acute tubular necrosis. Auriculin Anaritide Acute Renal Failure Study Group. N Engl J Med 336:828–834PubMedGoogle Scholar
  2. Almeida FA, Suzuki M, Maack T (1986) Atrial natriuretic factor increases hematocrit and decreases plasma volume in nephrectomized rats. Life Sci 39:1193–1199PubMedGoogle Scholar
  3. Ammarguellat F, Larouche I, Schiffrin EL (2001) Myocardial fibrosis in DOCA-salt hypertensive rats: effect of endothelin ET(A) receptor antagonism. Circulation 103:319–324PubMedGoogle Scholar
  4. Antos LK, Abbey-Hosch SE, Flora DR, Potter LR (2005) ATP-independent activation of natriuretic peptide receptors. J Biol Chem 280:26928–26932PubMedGoogle Scholar
  5. Antos LK, Potter LR (2007) Adenine nucleotides decrease the apparent Km of endogenous natri-uretic peptide receptors for GTP. Am J Physiol Endocrinol Metab 293:E1756–1763PubMedGoogle Scholar
  6. Barbee RW, Perry BD, Re RN, Murgo JP, Field LJ (1994) Hemodynamics in transgenic mice with overexpression of atrial natriuretic factor. Circ Res 74:747–751PubMedGoogle Scholar
  7. Barrett BJ, Parfrey PS (1994) Prevention of nephrotoxicity induced by radiocontrast agents. N Engl J Med 331:1449–1450PubMedGoogle Scholar
  8. Bartels CF, Bukulmez H, Padayatti P, Rhee DK, van Ravenswaaij-Arts C, Pauli RM, Mundlos S, Chitayat D, Shih LY, Al-Gazali LI, Kant S, Cole T, Morton J, Cormier-Daire V, Faivre L, Lees M, Kirk J, Mortier GR, Leroy J, Zabel B, Kim CA, Crow Y, Braverman NE, van den Akker F, Warman MLA (2004) Mutations in the transmembrane natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux. Am J Hum Genet 75:27–34PubMedGoogle Scholar
  9. Bennett BD, Bennett GL, Vitangcol RV, Jewett JR, Burnier J, Henzel W, Lowe DG (1991) Extracellular domain-IgG fusion proteins for three human natriuretic peptide receptors. Hormone pharmacology and application to solid phase screening of synthetic peptide antisera. J Biol Chem 266:23060–23067PubMedGoogle Scholar
  10. Bilder GE, Schofield TL, Blaine EH (1986) Release of atrial natriuretic factor. Effects of repetitive stretch and temperature. Am J Physiol 251:F817–F821PubMedGoogle Scholar
  11. Bocciardi R, Giorda R, Buttgereit J, Gimelli S, Divizia MT, Beri S, Garofalo S, Tavella S, Lerone M, Zuffardi O, Bader M, Ravazzolo R, Gimelli G (2007) Overexpression of the C-type natriuretic peptide (CNP) is associated with overgrowth and bone anomalies in an individual with balanced t(2;7) translocation. Hum Mutat 28:724–731PubMedGoogle Scholar
  12. Brown J, Chen Q, Hong G (1997) An autocrine system for C-type natriuretic peptide within rat carotid neointima during arterial repair. Am J Physiol 272:H2919–H2931PubMedGoogle Scholar
  13. Bryan PM, Smirnov D, Smolenski A, Feil S, Feil R, Hofmann F, Lohmann S, Potter LR (2006) A Sensitive Method for Determining the Phosphorylation Status of Natriuretic Peptide Receptors: cGK-Ialpha Does Not Regulate NPR-A. Biochemistry 45:1295–1303PubMedGoogle Scholar
  14. Burczynska B, Duda T, Sharma RK (2007) ATP signaling site in the ARM domain of atrial natriuretic factor receptor guanylate cyclase. Mol Cell Biochem 301:93–107PubMedGoogle Scholar
  15. Burnett JC Jr, Kao PC, Hu DC, Heser DW, Heublein D, Granger JP, Opgenorth TJ, Reeder GS (1986) Atrial natriuretic peptide elevation in congestive heart failure in the human. Science 231:1145–1147PubMedGoogle Scholar
  16. Chan JC, Knudson O, Wu F, Morser J, Dole WP, Wu Q (2005) Hypertension in mice lacking the proatrial natriuretic peptide convertase corin. Proc Natl Acad Sci U S A 102:785–790PubMedGoogle Scholar
  17. Chang MS, Lowe DG, Lewis M, Hellmiss R, Chen E, Goeddel DV (1989) Differential activation by atrial and brain natriuretic peptides of two different receptor guanylate cyclases. Nature 341:68–72PubMedGoogle Scholar
  18. Charles CJ, Prickett TC, Espiner EA, Rademaker MT, Richards AM, Yandle TG (2006) Regional sampling and the effects of experimental heart failure in sheep: differential responses in A, B and C-type natriuretic peptides. Peptides 27:62–68PubMedGoogle Scholar
  19. Chen HH, Schirger JA, Cataliotti A, Burnett JC Jr (2006) Intact acute cardiorenal and humoral responsiveness following chronic subcutaneous administration of the cardiac peptide BNP in experimental heart failure. Eur J Heart Fail 8:681–686PubMedGoogle Scholar
  20. Chikuda H, Kugimiya F, Hoshi K, Ikeda T, Ogasawara T, Shimoaka T, Kawano H, Kamekura S, Tsuchida A, Yokoi N, Nakamura K, Komeda K, Chung UI, Kawaguchi H (2004) Cyclic GMP-dependent protein kinase II is a molecular switch from proliferation to hypertrophic differentiation of chondrocytes. Genes Dev 18:2418–2429PubMedGoogle Scholar
  21. Chinkers M, Wilson EM (1992) Ligand-independent oligomerization of natriuretic peptide receptors. Identification of heteromeric receptors and a dominant negative mutant. J Biol Chem 267:18589–18597PubMedGoogle Scholar
  22. Chrisman TD, Schulz S, Potter LR, Garbers DL (1993) Seminal plasma factors that cause large elevations in cellular cyclic GMP are C-type natriuretic peptides. J Biol Chem 268:3698–3703PubMedGoogle Scholar
  23. Chun TH, Itoh H, Ogawa Y, Tamura N, Takaya K, Igaki T, Yamashita J, Doi K, Inoue M, Masatsugu K, Korenaga R, Ando J, Nakao K (1997) Shear stress augments expression of C-type natriuretic peptide and adrenomedullin. Hypertension 29:1296–1302PubMedGoogle Scholar
  24. Chusho H, Tamura N, Ogawa Y, Yasoda A, Suda M, Miyazawa T, Nakamura K, Nakao K, Kurihara T, Komatsu Y, Itoh H, Tanaka K, Saito Y, Katsuki M (2001) Dwarfism and early death in mice lacking C-type natriuretic peptide. Proc Natl Acad Sci U S A 98:4016–4021PubMedGoogle Scholar
  25. Clavell AL, Stingo AJ, Wei CM, Heublein DM, Burnett JC, Jr. (1993) C-type natriuretic peptide: a selective cardiovascular peptide. Am J Physiol 264:R290–295PubMedGoogle Scholar
  26. Cleland JG, Coletta AP, Clark AL (2007) Clinical trials update from the American College of Cardiology 2007: ALPHA, EVEREST, FUSION II, VALIDD, PARR-2, REMODEL, SPICE, COURAGE, COACH, REMADHE, pro-BNP for the evaluation of dyspnoea and THIS-diet. Eur J Heart Fail 9:740–745PubMedGoogle Scholar
  27. Cody RJ, Atlas SA, Laragh JH, Kubo SH, Covit AB, Ryman KS, Shaknovich A, Pondolfino K, Clark M, Camargo MJ, Scarborough RM, Lewicki JA (1986) Atrial natriuretic factor in normal subjects and heart failure patients. Plasma levels and renal, hormonal, and hemodynamic responses to peptide infusion. J Clin Invest 78:1362–1374PubMedGoogle Scholar
  28. Currie MG, Geller DM, Cole BR, Siegel NR, Fok KF, Adams SP, Eubanks SR, Galluppi GR, Needleman P (1984) Purification and sequence analysis of bioactive atrial peptides (atri- opeptins). Science 223:67–69PubMedGoogle Scholar
  29. de Bold AJ, Borenstein HB, Veress AT, Sonnenberg H (1981) A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats. Life Sci 28:89–94PubMedGoogle Scholar
  30. de Lissovoy G, Stier DM, Ciesla G, Munger M, Burger AJ (2003) Economic implications of nesiritide versus dobutamine in the treatment of patients with acutely decompensated congestive heart failure. Am J Cardiol 92:631–633PubMedGoogle Scholar
  31. Del Ry S, Passino C, Maltinti M, Emdin M, Giannessi D (2005) C-type natriuretic peptide plasma levels increase in patients with chronic heart failure as a function of clinical severity. Eur J Heart Fail 7:1145–1148PubMedGoogle Scholar
  32. Dickey DM, Flora DR, Bryan PM, Xu X, Chen Y, Potter LR (2007) Differential regulation of membrane guanylyl cyclases in congestive heart failure: natriuretic peptide receptor (NPR)-B, Not NPR-A, is the predominant natriuretic peptide receptor in the failing heart. Endocrinology 148:3518–3522PubMedGoogle Scholar
  33. Edwards BS, Zimmerman RS, Schwab TR, Heublein DM, Burnett JC, Jr. (1988) Atrial stretch, not pressure, is the principal determinant controlling the acute release of atrial natriuretic factor. Circ Res 62:191–195PubMedGoogle Scholar
  34. Fan D, Bryan PM, Antos LK, Potthast RJ, Potter LR (2005) Down-Regulation Does Not Mediate Natriuretic Peptide-Dependent Desensitization of Natriuretic Peptide Receptor (NPR)-A or NPR-B: Guanylyl Cyclase-Linked Natriuretic Peptide Receptors Do Not Internalize. Mol Pharmacol 67:174–183PubMedGoogle Scholar
  35. Fifer MA, Molina CR, Quiroz AC, Giles TD, Herrmann HC, De Scheerder IR, Clement DL, Kubo S, Cody RJ, Cohn JN, et al (1990) Hemodynamic and renal effects of atrial natriuretic peptide in congestive heart failure. Am J Cardiol 65:211–216PubMedGoogle Scholar
  36. Fluckiger JP, Waeber B, Matsueda G, Delaloye B, Nussberger J, Brunner HR (1986) Effect of atriopeptin III on hematocrit and volemia of nephrectomized rats. Am J Physiol 251: H880–H883PubMedGoogle Scholar
  37. Flynn TG, de Bold ML, de Bold AJ (1983) The amino acid sequence of an atrial peptide with potent diuretic and natriuretic properties. Biochem Biophys Res Commun 117:859–865PubMedGoogle Scholar
  38. Forssmann WG, Richter R, Meyer M (1998) The endocrine heart and natriuretic peptides: histochemistry, cell biology, and functional aspects of the renal urodilatin system. Histochem Cell Biol 110:335–357PubMedGoogle Scholar
  39. Fried T, Aronoff GR, Benabe JE, Brunner HR, DiBona GF, Fleischhauer T, Lam M, Lawton WJ, Luft FC, Martinez-Maldonado M, et al (1990) Renal and hemodynamic effects of atrial natriuretic peptide in patients with cirrhosis. Am J Med Sci 299:2–9PubMedGoogle Scholar
  40. Fuller F, Porter JG, Arfsten AE, Miller J, Schilling JW, Scarborough RM, Lewicki JA, Schenk DB (1988) Atrial natriuretic peptide clearance receptor. Complete sequence and functional expression of cDNA clones. J Biol Chem 263:9395–9401PubMedGoogle Scholar
  41. Gardner DG (2003) Natriuretic peptides: markers or modulators of cardiac hypertrophy? Trends Endocrinol Metab 14:411–416PubMedGoogle Scholar
  42. Goy MF, Oliver PM, Purdy KE, Knowles JW, Fox JE, Mohler PJ, Qian X, Smithies O, Maeda N (2001) Evidence for a novel natriuretic peptide receptor that prefers brain natriuretic peptide over atrial natriuretic peptide. Biochem J 358:379–387PubMedGoogle Scholar
  43. Grepin C, Dagnino L, Robitaille L, Haberstroh L, Antakly T, Nemer M (1994) A hormone-encoding gene identifies a pathway for cardiac but not skeletal muscle gene transcription. Mol Cell Biol 14:3115–3129PubMedGoogle Scholar
  44. Henry JP, Gauer OH, Reeves JL (1956) Evidence of the atrial location of receptors influencing urine flow. Circ Res 4:85–90PubMedGoogle Scholar
  45. Herman JP, Dolgas CM, Rucker D, Langub MC, Jr. (1996) Localization of natriuretic peptide-activated guanylate cyclase mRNAs in the rat brain. J Comp Neurol 369:165–187PubMedGoogle Scholar
  46. Holtwick R, Gotthardt M, Skryabin B, Steinmetz M, Potthast R, Zetsche B, Hammer RE, Herz J, Kuhn M (2002) Smooth muscle-selective deletion of guanylyl cyclase-A prevents the acute but not chronic effects of ANP on blood pressure. Proc Natl Acad Sci U S A 99:7142–7147PubMedGoogle Scholar
  47. Holtwick R, Van Eickels M, Skryabin BV, Baba HA, Bubikat A, Begrow F, Schneider MD, Garbers DL, Kuhn M (2003) Pressure-independent cardiac hypertrophy in mice with cardiomyocyte- restricted inactivation of the atrial natriuretic peptide receptor guanylyl cyclase-A. J Clin Invest 111:1399–1407PubMedGoogle Scholar
  48. Hunt PJ, Richards AM, Espiner EA, Nicholls MG, Yandle TG (1994) Bioactivity and metabolism of C-type natriuretic peptide in normal man. J Clin Endocrinol Metab 78:1428–1435PubMedGoogle Scholar
  49. Iwata T, Uchida-Mizuno K, Katafuchi T, Ito T, Hagiwara H, Hirose S (1991) Bifunctional atrial natriuretic peptide receptor (type A) exists as a disulfide-linked tetramer in plasma membranes of bovine adrenal cortex. J Biochem (Tokyo) 110:35–39Google Scholar
  50. Jamieson JD, Palade GE (1964) Specific Granules in Atrial Muscle Cells. J Cell Biol 23:151–172PubMedGoogle Scholar
  51. Jaubert J, Jaubert F, Martin N, Washburn LL, Lee BK, Eicher EM, Guenet JL (1999) Three new allelic mouse mutations that cause skeletal overgrowth involve the natriuretic peptide receptor C gene (Npr3). Proc Natl Acad Sci U S A 96:10278–10283PubMedGoogle Scholar
  52. Jiao Y, Yan J, Jiao F, Yang H, Donahue LR, Li X, Roe BA, Stuart J, Gu W (2007) A single nucleotide mutation in Nppc is associated with a long bone abnormality in lbab mice. BMC Genet 8:16PubMedGoogle Scholar
  53. John SW, Krege JH, Oliver PM, Hagaman JR, Hodgin JB, Pang SC, Flynn TG, Smithies O (1995) Genetic decreases in atrial natriuretic peptide and salt-sensitive hypertension [published erratum appears in Science 1995 Mar 24;267(5205):1753]. Science 267:679–681PubMedGoogle Scholar
  54. John SW, Veress AT, Honrath U, Chong CK, Peng L, Smithies O, Sonnenberg H (1996) Blood pressure and fluid-electrolyte balance in mice with reduced or absent ANP. Am J Physiol 271:R109–114PubMedGoogle Scholar
  55. Joubert S, Jossart C, McNicoll N, De Lean A (2005) Atrial natriuretic peptide-dependent photolabeling of a regulatory ATP-binding site on the natriuretic peptide receptor-A. FEBS J 272:5572–5583PubMedGoogle Scholar
  56. Kalra PR, Clague JR, Bolger AP, Anker SD, Poole-Wilson PA, Struthers AD, Coats AJ (2003) Myocardial production of C-type natriuretic peptide in chronic heart failure. Circulation 107: 571–573PubMedGoogle Scholar
  57. Kangawa K, Tawaragi Y, Oikawa S, Mizuno A, Sakuragawa Y, Nakazato H, Fukuda A, Minamino N, Matsuo H (1984) Identification of rat gamma atrial natriuretic polypeptide and characterization of the cDNA encoding its precursor. Nature 312:152–155PubMedGoogle Scholar
  58. Kenny AJ, Bourne A, Ingram J (1993) Hydrolysis of human and pig brain natriuretic peptides, urodilatin, C-type natriuretic peptide and some C-receptor ligands by endopeptidase-24.11. Biochem J 291(Pt 1):83–88PubMedGoogle Scholar
  59. Kisch B (1956) Electron microscopy of the atrium of the heart. I. Guineo pig. Exp Med Surg 14:99–112Google Scholar
  60. Kishimoto I, Dubois SK, Garbers DL (1996) The heart communicates with the kidney exclusively through the guanylyl cyclase-A receptor: acute handling of sodium and water in response to volume expansion. Proc Natl Acad Sci U S A 93:6215–6219PubMedGoogle Scholar
  61. Kishimoto I, Rossi K, Garbers DL (2001) A genetic model provides evidence that the receptor for atrial natriuretic peptide (guanylyl cyclase-A) inhibits cardiac ventricular myocyte hypertrophy. Proc Natl Acad Sci U S A 98:2703–2706PubMedGoogle Scholar
  62. Knowles JW, Esposito G, Mao L, Hagaman JR, Fox JE, Smithies O, Rockman HA, Maeda N (2001) Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A-deficient mice. J Clin Invest 107:975–984PubMedGoogle Scholar
  63. Koh GY, Nussenzveig DR, Okolicany J, Price DA, Maack T (1992) Dynamics of atrial natriuretic factor-guanylate cyclase receptors and receptor-ligand complexes in cultured glomerular mesangial and renomedullary interstitial cells. J Biol Chem 267:11987–11994PubMedGoogle Scholar
  64. Koller KJ, Lowe DG, Bennett GL, Minamino N, Kangawa K, Matsuo H, Goeddel DV (1991) Selective activation of the B natriuretic peptide receptor by C-type natriuretic peptide (CNP). Science 252:120–123PubMedGoogle Scholar
  65. Kuhn M, Holtwick R, Baba HA, Perriard JC, Schmitz W, Ehler E (2002) Progressive cardiac hypertrophy and dysfunction in atrial natriuretic peptide receptor (GC-A) deficient mice. Heart 87:368–374PubMedGoogle Scholar
  66. Kurnik BR, Allgren RL, Genter FC, Solomon RJ, Bates ER, Weisberg LS (1998) Prospective study of atrial natriuretic peptide for the prevention of radiocontrast-induced nephropathy. Am J Kidney Dis 31:674–680PubMedGoogle Scholar
  67. Labrecque J, Deschenes J, McNicoll N, De Lean A (2001) Agonistic induction of a covalent dimer in a mutant of natriuretic peptide receptor-A documents a juxtamembrane interaction that accompanies receptor activation. J Biol Chem 276:8064–8072PubMedGoogle Scholar
  68. Lang RE, Tholken H, Ganten D, Luft FC, Ruskoaho H, Unger T (1985) Atrial natriuretic factor—a circulating hormone stimulated by volume loading. Nature 314:264–266PubMedGoogle Scholar
  69. Langenickel TH, Buttgereit J, Pagel-Langenickel I, Lindner M, Monti J, Beuerlein K, Al-Saadi N, Plehm R, Popova E, Tank J, Dietz R, Willenbrock R, Bader M (2006) Cardiac hypertrophy in transgenic rats expressing a dominant-negative mutant of the natriuretic peptide receptor B. Proc Natl Acad Sci U S A 103:4735–4740PubMedGoogle Scholar
  70. Langub MC Jr, Dolgas CM, Watson RE Jr, Herman JP (1995) The C-type natriuretic peptide receptor is the predominant natriuretic peptide receptor mRNA expressed in rat hypothalamus. J Neuroendocrinol 7:305–309PubMedGoogle Scholar
  71. Leitman DC, Andresen JW, Kuno T, Kamisaki Y, Chang JK, Murad F (1986) Identification of multiple binding sites for atrial natriuretic factor by affinity cross-linking in cultured endothelial cells. J Biol Chem 261:11650–11655PubMedGoogle Scholar
  72. Lewis J, Salem MM, Chertow GM, Weisberg LS, McGrew F, Marbury TC, Allgren RL (2000) Atrial natriuretic factor in oliguric acute renal failure. Anaritide Acute Renal Failure Study Group. Am J Kidney Dis 36:767–774PubMedGoogle Scholar
  73. Lisy O, Huntley BK, McCormick DJ, Kurlansky PA, Burnett JC Jr (2008) Design, synthesis, and actions of a novel chimeric natriuretic peptide: CD-NP. J Am Coll Cardiol 52:60–68PubMedGoogle Scholar
  74. Lopez MJ, Garbers DL, Kuhn M (1997) The guanylyl cyclase-deficient mouse defines differential pathways of natriuretic peptide signaling. J Biol Chem 272:23064–23068PubMedGoogle Scholar
  75. Lopez MJ, Wong SK, Kishimoto I, Dubois S, Mach V, Friesen J, Garbers DL, Beuve A (1995) Salt-resistant hypertension in mice lacking the guanylyl cyclase-A receptor for atrial natriuretic peptide. Nature 378:65–68PubMedGoogle Scholar
  76. Lowe DG, Chang MS, Hellmiss R, Chen E, Singh S, Garbers DL, Goeddel DV (1989) Human atrial natriuretic peptide receptor defines a new paradigm for second messenger signal transduction. EMBO J 8:1377–1384PubMedGoogle Scholar
  77. Lowe DG, Klisak I, Sparkes RS, Mohandas T, Goeddel DV (1990) Chromosomal distribution of three members of the human natriuretic peptide receptor/guanylyl cyclase gene family. Genomics 8:304–312PubMedGoogle Scholar
  78. Lu B, Gerard NP, Kolakowski LF, Jr., Bozza M, Zurakowski D, Finco O, Carroll MC, Gerard C (1995) Neutral endopeptidase modulation of septic shock. J Exp Med 181:2271–2275PubMedGoogle Scholar
  79. Maack T, Suzuki M, Almeida FA, Nussenzveig D, Scarborough RM, McEnroe GA, Lewicki JA (1987) Physiological role of silent receptors of atrial natriuretic factor. Science 238:675–678PubMedGoogle Scholar
  80. Matsukawa N, Grzesik WJ, Takahashi N, Pandey KN, Pang S, Yamauchi M, Smithies O (1999) The natriuretic peptide clearance receptor locally modulates the physiological effects of the natriuretic peptide system. Proc Natl Acad Sci U S A 96:7403–7408PubMedGoogle Scholar
  81. McGregor A, Richards M, Espiner E, Yandle T, Ikram H (1990) Brain natriuretic peptide administered to man: actions and metabolism. J Clin Endocrinol Metab 70:1103–1107PubMedGoogle Scholar
  82. Michaels AD, Chatterjee K, De Marco T (2005) Effects of intravenous nesiritide on pulmonary vascular hemodynamics in pulmonary hypertension. J Card Fail 11:425–431PubMedGoogle Scholar
  83. Mills RM, LeJemtel TH, Horton DP, Liang C, Lang R, Silver MA, Lui C, Chatterjee K (1999) Sustained hemodynamic effects of an infusion of nesiritide (human b-type natriuretic peptide) in heart failure: a randomized, double-blind, placebo-controlled clinical trial. Natrecor Study Group. J Am Coll Cardiol 34:155–162PubMedGoogle Scholar
  84. Misono KS, Grammer RT, Fukumi H, Inagami T (1984) Rat atrial natriuretic factor: isolation, structure and biological activities of four major peptides. Biochem Biophys Res Commun 123:444–451PubMedGoogle Scholar
  85. Miyagi M, Misono KS (2000) Disulfide bond structure of the atrial natriuretic peptide receptor extracellular domain: conserved disulfide bonds among guanylate cyclase-coupled receptors. Biochim Biophys Acta 1478:30–38PubMedGoogle Scholar
  86. Miyagi M, Zhang X, Misono KS (2000) Glycosylation sites in the atrial natriuretic peptide receptor Oligosaccharide structures are not required for hormone binding. Eur J Biochem 267: 5758–5768PubMedGoogle Scholar
  87. Mizuno T, Iwashina M, Itakura M, Hagiwara H, Hirose S (1993) A variant form of the type C atrial natriuretic peptide receptor generated by alternative RNA splicing. J Biol Chem 268: 5162–5167PubMedGoogle Scholar
  88. Moffatt P, Thomas G, Sellin K, Bessette MC, Lafreniere F, Akhouayri O, St-Arnaud R, Lanctot C (2007) Osteocrin is a specific ligand of the natriuretic Peptide clearance receptor that modulates bone growth. J Biol Chem 282:36454–36462PubMedGoogle Scholar
  89. Moncla A, Missirian C, Cacciagli P, Balzamo E, Legeai-Mallet L, Jouve JL, Chabrol B, Le Merrer M, Plessis G, Villard L, Philip N (2007) A cluster of translocation breakpoints in 2q37 is associated with overexpression of NPPC in patients with a similar overgrowth pheno-type. Hum Mutat 28:1183–1188PubMedGoogle Scholar
  90. Mukoyama M, Nakao K, Hosoda K, Suga S, Saito Y, Ogawa Y, Shirakami G, Jougasaki M, Obata K, Yasue H, et al (1991) Brain natriuretic peptide as a novel cardiac hormone in humans. Evidence for an exquisite dual natriuretic peptide system, atrial natriuretic peptide and brain natriuretic peptide. J Clin Invest 87:1402–1412PubMedGoogle Scholar
  91. Mukoyama M, Nakao K, Saito Y, Ogawa Y, Hosoda K, Suga S, Shirakami G, Jougasaki M, Imura H (1990) Increased human brain natriuretic peptide in congestive heart failure. N Engl J Med 323:757–758PubMedGoogle Scholar
  92. Nagase M, Katafuchi T, Hirose S, Fujita T (1997) Tissue distribution and localization of natriuretic peptide receptor subtypes in stroke-prone spontaneously hypertensive rats. J Hypertens 15:1235–1243PubMedGoogle Scholar
  93. Nakao K, Sugawara A, Morii N, Sakamoto M, Yamada T, Itoh H, Shiono S, Saito Y, Nishimura K, Ban T, et al (1986) The pharmacokinetics of alpha-human atrial natriuretic polypeptide in healthy subjects. Eur J Clin Pharmacol 31:101–103PubMedGoogle Scholar
  94. Nakayama T, Soma M, Takahashi Y, Rehemudula D, Kanmatsuse K, Furuya K (2000) Functional deletion mutation of the 5″-flanking region of type A human natriuretic peptide receptor gene and its association with essential hypertension and left ventricular hypertrophy in the Japanese. Circ Res 86:841–845PubMedGoogle Scholar
  95. Nussenzveig DR, Lewicki JA, Maack T (1990) Cellular mechanisms of the clearance function of type C receptors of atrial natriuretic factor. J Biol Chem 265:20952–20958PubMedGoogle Scholar
  96. Ogawa Y, Itoh H, Tamura N, Suga S, Yoshimasa T, Uehira M, Matsuda S, Shiono S, Nishimoto H, Nakao K (1994a) Molecular cloning of the complementary DNA and gene that encode mouse brain natriuretic peptide and generation of transgenic mice that overexpress the brain natriuretic peptide gene. J Clin Invest 93:1911–1921Google Scholar
  97. Ogawa Y, Itoh H, Yoshitake Y, Inoue M, Yoshimasa T, Serikawa T, Nakao K (1994b) Molecular cloning and chromosomal assignment of the mouse C-type natriuretic peptide (CNP) gene (Nppc): comparison with the human CNP gene (NPPC). Genomics 24:383–387Google Scholar
  98. Oikawa S, Imai M, Ueno A, Tanaka S, Noguchi T, Nakazato H, Kangawa K, Fukuda A, Matsuo H (1984) Cloning and sequence analysis of cDNA encoding a precursor for human atrial natriuretic polypeptide. Nature 309:724–726PubMedGoogle Scholar
  99. Oliver PM, Fox JE, Kim R, Rockman HA, Kim HS, Reddick RL, Pandey KN, Milgram SL, Smithies O, Maeda N (1997) Hypertension, cardiac hypertrophy, and sudden death in mice lacking natriuretic peptide receptor A. Proc Natl Acad Sci U S A 94:14730–14735PubMedGoogle Scholar
  100. Oliver PM, John SW, Purdy KE, Kim R, Maeda N, Goy MF, Smithies O (1998) Natriuretic peptide receptor 1 expression influences blood pressures of mice in a dose-dependent manner. Proc Natl Acad Sci U S A 95:2547–2551PubMedGoogle Scholar
  101. Olney RC, Bukulmez H, Bartels CF, Prickett TC, Espiner EA, Potter LR, Warman ML (2006) Heterozygous mutations in natriuretic peptide receptor-B (NPR2) are associated with short stature. J Clin Endocrinol Metab 91:1229–1232PubMedGoogle Scholar
  102. Pandey KN (2002) Intracellular trafficking and metabolic turnover of ligand-bound guanylyl cy-clase/atrial natriuretic peptide receptor-A into subcellular compartments. Mol Cell Biochem 230:61–72PubMedGoogle Scholar
  103. Pankow K, Wang Y, Gembardt F, Krause E, Sun X, Krause G, Schultheiss HP, Siems WE, Walther T (2007) Successive action of meprin A and neprilysin catabolizes B-type natriuretic peptide. Circ Res 101:875–882PubMedGoogle Scholar
  104. Patel JB, Valencik ML, Pritchett AM, Burnett JC Jr, McDonald JA, Redfield MM (2005) Cardiac-specific attenuation of natriuretic peptide A receptor activity accentuates adverse cardiac remodeling and mortality in response to pressure overload. Am J Physiol Heart Circ Physiol 289:H777–H784PubMedGoogle Scholar
  105. Pfeifer A, Aszodi A, Seidler U, Ruth P, Hofmann F, Fassler R (1996) Intestinal secretory defects and dwarfism in mice lacking cGMP- dependent protein kinase II. Science 274:2082–2086PubMedGoogle Scholar
  106. Porter JG, Arfsten A, Fuller F, Miller JA, Gregory LC, Lewicki JA (1990) Isolation and functional expression of the human atrial natriuretic peptide clearance receptor cDNA. Biochem Biophys Res Commun 171:796–803PubMedGoogle Scholar
  107. Potter LR (1998) Phosphorylation-dependent regulation of the guanylyl cyclase-linked natriuretic peptide receptor B: dephosphorylation is a mechanism of desensitization. Biochemistry 37:2422–2429PubMedGoogle Scholar
  108. Potter LR, Garbers DL (1992) Dephosphorylation of the guanylyl cyclase-A receptor causes desensitization. J Biol Chem 267:14531–14534PubMedGoogle Scholar
  109. Potter LR, Garbers DL (1994) Protein kinase C-dependent desensitization of the atrial natriuretic peptide receptor is mediated by dephosphorylation. J Biol Chem 269:14636–14642PubMedGoogle Scholar
  110. Potter LR, Hunter T (1998a) Identification and characterization of the major phosphorylation sites of the B-type natriuretic peptide receptor. J Biol Chem 273:15533–15539Google Scholar
  111. Potter LR, Hunter T (1998b) Phosphorylation of the kinase homology domain is essential for activation of the A-type natriuretic peptide receptor. Mol Cell Biol 18:2164–2172Google Scholar
  112. Potter LR, Hunter T (2000) Activation of PKC Stimulates the Dephosphorylation of Natriuretic Peptide Receptor-B at a Single Serine Residue: a Possible Mechanism of Heterologous Desen- sitization. J Biol Chem 275:31099–31106PubMedGoogle Scholar
  113. Potthast R, Abbey-Hosch SE, Antos LK, Marchant JS, Kuhn M, Potter LR (2004) Calcium-dependent Dephosphorylation Mediates the Hyperosmotic and Lysophosphatidic Acid-dependent Inhibition of Natriuretic Peptide Receptor-B/Guanylyl Cyclase-B. J Biol Chem 279:48513–48519PubMedGoogle Scholar
  114. Rahman SN, Kim GE, Mathew AS, Goldberg CA, Allgren R, Schrier RW, Conger JD (1994) Effects of atrial natriuretic peptide in clinical acute renal failure. Kidney Int 45:1731–1738PubMedGoogle Scholar
  115. Rahmutula D, Nakayama T, Soma M, Kosuge K, Aoi N, Izumi Y, Kanmatsuse K, Ozawa Y (2002) Structure and polymorphisms of the human natriuretic peptide receptor C gene. Endocrine 17:85–90PubMedGoogle Scholar
  116. Richards AM, Tonolo G, Montorsi P, Finlayson J, Fraser R, Inglis G, Towrie A, Morton JJ (1988) Low dose infusions of 26- and 28-amino acid human atrial natriuretic peptides in normal man. J Clin Endocrinol Metab 66:465–472PubMedCrossRefGoogle Scholar
  117. Rose RA, Giles WR (2008) Natriuretic peptide C receptor signalling in the heart and vasculature. J Physiol 586:353–366PubMedGoogle Scholar
  118. Ruskoaho H (2003) Cardiac hormones as diagnostic tools in heart failure. Endocr Rev 24:341–356PubMedGoogle Scholar
  119. Sabrane K, Kruse MN, Fabritz L, Zetsche B, Mitko D, Skryabin BV, Zwiener M, Baba HA, Yanagisawa M, Kuhn M (2005) Vascular endothelium is critically involved in the hypotensive and hypovolemic actions of atrial natriuretic peptide. J Clin Invest 115:1666–1674PubMedGoogle Scholar
  120. Sackner-Bernstein JD, Kowalski M, Fox M, Aaronson K (2005a) Short-term risk of death after treatment with nesiritide for decompensated heart failure: a pooled analysis of randomized controlled trials. Jama 293:1900–1905Google Scholar
  121. Sackner-Bernstein JD, Skopicki HA, Aaronson KD (2005b) Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation 111:1487–1491Google Scholar
  122. Saito Y, Nakao K, Nishimura K, Sugawara A, Okumura K, Obata K, Sonoda R, Ban T, Yasue H, Imura H (1987) Clinical application of atrial natriuretic polypeptide in patients with congestive heart failure: beneficial effects on left ventricular function. Circulation 76:115–124PubMedGoogle Scholar
  123. Schulz S, Singh S, Bellet RA, Singh G, Tubb DJ, Chin H, Garbers DL (1989) The primary structure of a plasma membrane guanylate cyclase demonstrates diversity within this new receptor family. Cell 58:1155–1162PubMedGoogle Scholar
  124. Steinhelper ME, Cochrane KL, Field LJ (1990) Hypotension in transgenic mice expressing atrial natriuretic factor fusion genes. Hypertension 16:301–307PubMedGoogle Scholar
  125. Stephenson SL, Kenny AJ (1987) The hydrolysis of alpha-human atrial natriuretic peptide by pig kidney microvillar membranes is initiated by endopeptidase-24.11. Biochem J 243:183–187PubMedGoogle Scholar
  126. Stults JT, O'Connell KL, Garcia C, Wong S, Engel AM, Garbers DL, Lowe DG (1994) The disulfide linkages and glycosylation sites of the human natriuretic peptide receptor-C homodimer. Biochemistry 33:11372–11381PubMedGoogle Scholar
  127. Sudoh T, Kangawa K, Minamino N, Matsuo H (1988) A new natriuretic peptide in porcine brain. Nature 332:78–81PubMedGoogle Scholar
  128. Sudoh T, Minamino N, Kangawa K, Matsuo H (1990) C-type natriuretic peptide (CNP): a new member of natriuretic peptide family identified in porcine brain. Biochem Biophys Res Com-mun 168:863–870Google Scholar
  129. Suga S, Itoh H, Komatsu Y, Ogawa Y, Hama N, Yoshimasa T, Nakao K (1993) Cytokine-induced C-type natriuretic peptide (CNP) secretion from vascular endothelial cells–evidence for CNP as a novel autocrine/paracrine regulator from endothelial cells. Endocrinology 133:3038–3041PubMedGoogle Scholar
  130. Suga S, Nakao K, Hosoda K, Mukoyama M, Ogawa Y, Shirakami G, Arai H, Saito Y, Kambayashi Y, Inouye K, Imura H (1992a) Receptor selectivity of natriuretic peptide family, atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide. Endocrinology 130:229–239Google Scholar
  131. Suga S, Nakao K, Itoh H, Komatsu Y, Ogawa Y, Hama N, Imura H (1992b) Endothelial production of C-type natriuretic peptide and its marked augmentation by transforming growth factor-beta. Possible existence of “vascular natriuretic peptide system“. J Clin Invest 90:1145–1149Google Scholar
  132. Suga S, Nakao K, Kishimoto I, Hosoda K, Mukoyama M, Arai H, Shirakami G, Ogawa Y, Komatsu Y, Nakagawa O, et al (1992c) Phenotype-related alteration in expression of natri-uretic peptide receptors in aortic smooth muscle cells. Circ Res 71:34–39Google Scholar
  133. Sward K, Valsson F, Sellgren J, Ricksten SE (2005) Differential effects of human atrial natriuretic peptide and furosemide on glomerular filtration rate and renal oxygen consumption in humans. Intensive Care Med 31:79–85PubMedGoogle Scholar
  134. Takahashi Y, Nakayama T, Soma M, Izumi Y, Kanmatsuse K (1998) Organization of the human natriuretic peptide receptor A gene. Biochem Biophys Res Commun 246:736–739PubMedGoogle Scholar
  135. Tamura N, Chrisman TD, Garbers DL (2001) The regulation and physiological roles of the guanylyl cyclase receptors. Endocr J 48:611–634PubMedGoogle Scholar
  136. Tamura N, Doolittle LK, Hammer RE, Shelton JM, Richardson JA, Garbers DL (2004) Critical roles of the guanylyl cyclase B receptor in endochondral ossification and development of female reproductive organs. Proc Natl Acad Sci U S A 101:17300–17305PubMedGoogle Scholar
  137. Tamura N, Ogawa Y, Chusho H, Nakamura K, Nakao K, Suda M, Kasahara M, Hashimoto R, Katsuura G, Mukoyama M, Itoh H, Saito Y, Tanaka I, Otani H, Katsuki M (2000) Cardiac fibrosis in mice lacking brain natriuretic peptide. Proc Natl Acad Sci U S A 97:4239–4244PubMedGoogle Scholar
  138. Tawaragi Y, Fuchimura K, Tanaka S, Minamino N, Kangawa K, Matsuo H (1991) Gene and precursor structures of human C-type natriuretic peptide. Biochem Biophys Res Commun 175: 645–651PubMedGoogle Scholar
  139. Thuerauf DJ, Hanford DS, Glembotski CC (1994) Regulation of rat brain natriuretic peptide transcription. A potential role for GATA-related transcription factors in myocardial cell gene expression. J Biol Chem 269:17772–17775PubMedGoogle Scholar
  140. Tsuji T, Kunieda T (2005) A loss-of-function mutation in natriuretic peptide receptor 2 (Npr2) gene is responsible for disproportionate dwarfism in cn/cn mouse. J Biol Chem 280:14288–14292PubMedGoogle Scholar
  141. Vanneste Y, Michel A, Dimaline R, Najdovski T, Deschodt-Lanckman M (1988) Hydrolysis of alpha-human atrial natriuretic peptide in vitro by human kidney membranes and purified endopeptidase-24.11. Evidence for a novel cleavage site. Biochem J 254:531–537PubMedGoogle Scholar
  142. Vieira MA, Gao M, Nikonova LN, Maack T (2001) Molecular and cellular physiology of the dissociation of atrial natriuretic peptide from guanylyl cyclase a receptors. J Biol Chem 276: 36438–36445PubMedGoogle Scholar
  143. Wang DJ, Dowling TC, Meadows D, Ayala T, Marshall J, Minshall S, Greenberg N, Thattassery E, Fisher ML, Rao K, Gottlieb SS (2004) Nesiritide does not improve renal function in patients with chronic heart failure and worsening serum creatinine. Circulation 110:1620–1625PubMedGoogle Scholar
  144. Wang Y, de Waard MC, Sterner-Kock A, Stepan H, Schultheiss HP, Duncker DJ, Walther T (2007) Cardiomyocyte-restricted over-expression of C-type natriuretic peptide prevents cardiac hypertrophy induced by myocardial infarction in mice. Eur J Heart Fail 9:548–557PubMedGoogle Scholar
  145. Wilcox JN, Augustine A, Goeddel DV, Lowe DG (1991) Differential regional expression of three natriuretic peptide receptor genes within primate tissues. Mol Cell Biol 11:3454–3462PubMedGoogle Scholar
  146. Witteles RM, Kao D, Christopherson D, Matsuda K, Vagelos RH, Schreiber D, Fowler MB (2007) Impact of nesiritide on renal function in patients with acute decompensated heart failure and pre-existing renal dysfunction a randomized, double-blind, placebo-controlled clinical trial. J Am Coll Cardiol 50:1835–1840PubMedGoogle Scholar
  147. Wu C, Wu F, Pan J, Morser J, Wu Q (2003) Furin-mediated processing of Pro-C-type natriuretic peptide. J Biol Chem 278:25847–25852PubMedGoogle Scholar
  148. Yan W, Wu F, Morser J, Wu Q (2000) Corin, a transmembrane cardiac serine protease, acts as a pro-atrial natriuretic peptide-converting enzyme. Proc Natl Acad Sci U S A 97:8525–8529PubMedGoogle Scholar
  149. Yandle TG, Brennan SO, Espiner EA, Nicholls MG, Richards AM (1989) Endopeptidase-24.11 in human plasma degrades atrial natriuretic factor (ANF) to ANF(99–105/106–126). Peptides 10:891–894PubMedGoogle Scholar
  150. Yandle TG, Richards AM, Nicholls MG, Cuneo R, Espiner EA, Livesey JH (1986) Metabolic clearance rate and plasma half life of alpha-human atrial natriuretic peptide in man. Life Sci 38:1827–1833PubMedGoogle Scholar
  151. Yasoda A, Komatsu Y, Chusho H, Miyazawa T, Ozasa A, Miura M, Kurihara T, Rogi T, Tanaka S, Suda M, Tamura N, Ogawa Y, Nakao K (2004) Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway. Nat Med 10:80–86PubMedGoogle Scholar
  152. Yeung VT, Ho SK, Nicholls MG, Cockram CS (1996) Binding of CNP-22 and CNP-53 to cultured mouse astrocytes and effects on cyclic GMP. Peptides 17:101–106PubMedGoogle Scholar
  153. Yoder AR, Kruse AC, Earhart CA, Ohlendorf DH, Potter LR (2008) Reduced ability of C-type natriuretic peptide (CNP) to activate natriuretic peptide receptor B (NPR-B) causes dwarfism in lbab -/- mice. Peptides 9:1575–1581Google Scholar
  154. Yoshimura M, Yasue H, Morita E, Sakaino N, Jougasaki M, Kurose M, Mukoyama M, Saito Y, Nakao K, Imura H (1991) Hemodynamic, renal, and hormonal responses to brain natriuretic peptide infusion in patients with congestive heart failure. Circulation 84:1581–1588PubMedGoogle Scholar

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© Springer 2009

Authors and Affiliations

  1. 1.Department of Biochemistry, Molecular Biology and BiophysicsUniversity of Minnesota — Twin CitiesMinneapolisUSA

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