Skip to main content
Top
Published in: Heart Failure Reviews 4/2009

Open Access 01-12-2009

Relaxin, a pleiotropic vasodilator for the treatment of heart failure

Authors: Sam L. Teichman, Elaine Unemori, Thomas Dschietzig, Kirk Conrad, Adriaan A. Voors, John R. Teerlink, G. Michael Felker, Marco Metra, Gad Cotter

Published in: Heart Failure Reviews | Issue 4/2009

Login to get access

Abstract

Relaxin is a naturally occurring peptide hormone that plays a central role in the hemodynamic and renovascular adaptive changes that occur during pregnancy. Triggering similar changes could potentially be beneficial in the treatment of patients with heart failure. The effects of relaxin include the production of nitric oxide, inhibition of endothelin, inhibition of angiotensin II, production of VEGF, and production of matrix metalloproteinases. These effects lead to systemic and renal vasodilation, increased arterial compliance, and other vascular changes. The recognition of this has led to the study of relaxin for the treatment of heart failure. An initial pilot study has shown favorable hemodynamic effects in patients with heart failure, including reduction in ventricular filling pressures and increased cardiac output. The ongoing RELAX-AHF clinical program is designed to evaluate the effects of relaxin on the symptoms and outcomes in a large group of patients admitted to hospital for acute heart failure. This review will summarize both the biology of relaxin and the data supporting its potential efficacy in human heart failure.
Literature
1.
go back to reference Adams KF, Fonarow GC et al (2005) Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100, 000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J 149:209–216. doi:10.1016/j.ahj.2004.08.005 CrossRefPubMed Adams KF, Fonarow GC et al (2005) Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100, 000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J 149:209–216. doi:10.​1016/​j.​ahj.​2004.​08.​005 CrossRefPubMed
2.
go back to reference Bani D, Failli P et al (1998) Relaxin activates the L-arginine-nitric oxide pathway in vascular smooth muscle cells in culture. Hypertension 31(6):1240–1247PubMed Bani D, Failli P et al (1998) Relaxin activates the L-arginine-nitric oxide pathway in vascular smooth muscle cells in culture. Hypertension 31(6):1240–1247PubMed
3.
go back to reference Bani-Sacchi T, Bigazzi M et al (1995) Relaxin-induced increased coronary flow through stimulation of nitric oxide production. Br J Pharmacol 116(1):1589–1594PubMed Bani-Sacchi T, Bigazzi M et al (1995) Relaxin-induced increased coronary flow through stimulation of nitric oxide production. Br J Pharmacol 116(1):1589–1594PubMed
4.
go back to reference Baylis C (1999) Relaxin may be the “elusive” renal vasodilatory agent of normal pregnancy. Am J Kidney Dis 34(6): 1142–1144; discussion 1144–1145 Baylis C (1999) Relaxin may be the “elusive” renal vasodilatory agent of normal pregnancy. Am J Kidney Dis 34(6): 1142–1144; discussion 1144–1145
5.
go back to reference Butler J, Forman DE et al (2004) Relationship between heart failure treatment and development of worsening renal function among hospitalized patients. Am Heart J 147(2):331–338CrossRefPubMed Butler J, Forman DE et al (2004) Relationship between heart failure treatment and development of worsening renal function among hospitalized patients. Am Heart J 147(2):331–338CrossRefPubMed
7.
go back to reference Conrad KP, Gandley RE et al (1999) Endothelin mediates renal vasodilation and hyperfiltration during pregnancy in chronically instrumented conscious rats. Am J Physiol 276(5 Pt 2):F767–F776PubMed Conrad KP, Gandley RE et al (1999) Endothelin mediates renal vasodilation and hyperfiltration during pregnancy in chronically instrumented conscious rats. Am J Physiol 276(5 Pt 2):F767–F776PubMed
12.
go back to reference Danielson LA, Conrad KP (1995) Acute blockade of nitric oxide synthase inhibits renal vasodilation and hyperfiltration during pregnancy in chronically instrumented conscious rats. J Clin Invest 96(1):482–490. doi:10.1172/JCI118059 CrossRefPubMed Danielson LA, Conrad KP (1995) Acute blockade of nitric oxide synthase inhibits renal vasodilation and hyperfiltration during pregnancy in chronically instrumented conscious rats. J Clin Invest 96(1):482–490. doi:10.​1172/​JCI118059 CrossRefPubMed
13.
go back to reference Danielson LA, Conrad KP (2003) Time course and dose response of relaxin-mediated renal vasodilation, hyperfiltration, and changes in plasma osmolality in conscious rats. J Appl Physiol 95:1509–1514PubMed Danielson LA, Conrad KP (2003) Time course and dose response of relaxin-mediated renal vasodilation, hyperfiltration, and changes in plasma osmolality in conscious rats. J Appl Physiol 95:1509–1514PubMed
15.
go back to reference Danielson LA, Kercher LJ et al (2000) Impact of gender and endothelin on renal vasodilation and hyperfiltration induced by relaxin in conscious rats. Am J Physiol Regul Integr Comp Physiol 279(4):R1298–R1304PubMed Danielson LA, Kercher LJ et al (2000) Impact of gender and endothelin on renal vasodilation and hyperfiltration induced by relaxin in conscious rats. Am J Physiol Regul Integr Comp Physiol 279(4):R1298–R1304PubMed
16.
go back to reference Davison JM, Noble MCB (1981) Serial changes in 24-hour creatinine clearance during normal menstrual cycles and the first trimester of pregnancy. Br J Obstet Gynecol 88:10–17 Davison JM, Noble MCB (1981) Serial changes in 24-hour creatinine clearance during normal menstrual cycles and the first trimester of pregnancy. Br J Obstet Gynecol 88:10–17
17.
go back to reference Debrah DO, Conrad KP et al (2005) Effects of relaxin on systemic arterial hemodynamics and mechanical properties in conscious rats: sex dependency and dose response. J Appl Physiol 98:1013–1020CrossRefPubMed Debrah DO, Conrad KP et al (2005) Effects of relaxin on systemic arterial hemodynamics and mechanical properties in conscious rats: sex dependency and dose response. J Appl Physiol 98:1013–1020CrossRefPubMed
19.
go back to reference Dries D, Exner D, Domanski M, Greenberg B, Stevenson L (2000) The prognostic implications of renal insufficiency in asymptomatic and symptomatic patients with left ventricular systolic dusfunction. J Am Coll Cardiol 35:681–689. doi:10.1016/S0735-1097(99)00608-7 CrossRefPubMed Dries D, Exner D, Domanski M, Greenberg B, Stevenson L (2000) The prognostic implications of renal insufficiency in asymptomatic and symptomatic patients with left ventricular systolic dusfunction. J Am Coll Cardiol 35:681–689. doi:10.​1016/​S0735-1097(99)00608-7 CrossRefPubMed
20.
go back to reference Dschietzig T, Unemori E et al (2009) A pilot safety, tolerability and pharmacodynamic trial of intravenous recombinant human relaxin in compensated heart failure. J Card Fail (in press) Dschietzig T, Unemori E et al (2009) A pilot safety, tolerability and pharmacodynamic trial of intravenous recombinant human relaxin in compensated heart failure. J Card Fail (in press)
21.
go back to reference Dschietzig T, Richter C et al (2001) Flow-induced pressure differentially regulates endothelin-1, urotensin II, adrenomedullin, and relaxin in pulmonary vascular endothelium. Biochem Biophys Res Commun 289(1):245–251. doi:10.1006/bbrc.2001.5946 CrossRefPubMed Dschietzig T, Richter C et al (2001) Flow-induced pressure differentially regulates endothelin-1, urotensin II, adrenomedullin, and relaxin in pulmonary vascular endothelium. Biochem Biophys Res Commun 289(1):245–251. doi:10.​1006/​bbrc.​2001.​5946 CrossRefPubMed
23.
go back to reference Dschietzig T, Bartsch C et al (2003) Relaxin, a pregnancy hormone, is a functional endothelin-1 antagonist: attenuation of endothelin-1-mediated vasoconstriction by stimulation of endothelin type-B receptor expression via ERK-1/2 and nuclear factor-kappaB. Circ Res 92(1):32–40. doi:10.1161/01.RES.0000051884.27117.7E CrossRefPubMed Dschietzig T, Bartsch C et al (2003) Relaxin, a pregnancy hormone, is a functional endothelin-1 antagonist: attenuation of endothelin-1-mediated vasoconstriction by stimulation of endothelin type-B receptor expression via ERK-1/2 and nuclear factor-kappaB. Circ Res 92(1):32–40. doi:10.​1161/​01.​RES.​0000051884.​27117.​7E CrossRefPubMed
25.
go back to reference Erikson MS, Unemori E (2001) Relaxin clinical trials in systemic sclerosis. Relaxin 2000. G. Tregear, R Ivell, R Bathgate, JD Wade. Kluwer Academic Publishers, Dordrecht, pp 373–381 Erikson MS, Unemori E (2001) Relaxin clinical trials in systemic sclerosis. Relaxin 2000. G. Tregear, R Ivell, R Bathgate, JD Wade. Kluwer Academic Publishers, Dordrecht, pp 373–381
26.
28.
go back to reference Fisher C, Berry C et al (2003) N-terminal pro B type natriuretic peptide, but not the new putative cardiac hormone relaxin, predicts prognosis in patients with chronic heart failure. Heart (British Cardiac Society) 89(8):879–881. doi:10.1136/heart.89.8.879 Fisher C, Berry C et al (2003) N-terminal pro B type natriuretic peptide, but not the new putative cardiac hormone relaxin, predicts prognosis in patients with chronic heart failure. Heart (British Cardiac Society) 89(8):879–881. doi:10.​1136/​heart.​89.​8.​879
30.
go back to reference Francis G (2006) Acute decompensated heart failure: the cardiorenal syndrome. Cleve Clin J Med 73(suppl 2):S8–S13CrossRefPubMed Francis G (2006) Acute decompensated heart failure: the cardiorenal syndrome. Cleve Clin J Med 73(suppl 2):S8–S13CrossRefPubMed
32.
go back to reference Gheorghiade M, Abraham WT et al (2006) Systolic blood pressure at admission, clinical characteristics, and outcomes in patients hospitalized with acute heart failure. J Am Med Assoc 296(18):2217–2226. doi:10.1001/jama.296.18.2217 CrossRef Gheorghiade M, Abraham WT et al (2006) Systolic blood pressure at admission, clinical characteristics, and outcomes in patients hospitalized with acute heart failure. J Am Med Assoc 296(18):2217–2226. doi:10.​1001/​jama.​296.​18.​2217 CrossRef
33.
go back to reference Halls ML, Bond CP et al (2005) Multiple binding sites revealed by interaction of relaxin family peptides with native and chimeric relaxin family peptide receptors 1 and 2 (LGR7 and LGR8). J Pharmacol Exp Ther 313(2):677–687. doi:10.1124/jpet.104.080655 CrossRefPubMed Halls ML, Bond CP et al (2005) Multiple binding sites revealed by interaction of relaxin family peptides with native and chimeric relaxin family peptide receptors 1 and 2 (LGR7 and LGR8). J Pharmacol Exp Ther 313(2):677–687. doi:10.​1124/​jpet.​104.​080655 CrossRefPubMed
34.
go back to reference Halls ML, Bathgate RA et al (2006) Relaxin family peptide receptors RXFP1 and RXFP2 modulate cAMP Signaling by distinct mechanisms. Mol Pharmacol 70:214–226PubMed Halls ML, Bathgate RA et al (2006) Relaxin family peptide receptors RXFP1 and RXFP2 modulate cAMP Signaling by distinct mechanisms. Mol Pharmacol 70:214–226PubMed
37.
go back to reference Hisaw FL, Hisaw FL Jr, Dawson AB (1967) Effects of relaxin on the endothelium of endometrial blood vessels in monkeys (Macaca mulatta). Endocrinology 81:375–385CrossRefPubMed Hisaw FL, Hisaw FL Jr, Dawson AB (1967) Effects of relaxin on the endothelium of endometrial blood vessels in monkeys (Macaca mulatta). Endocrinology 81:375–385CrossRefPubMed
41.
43.
go back to reference Liang KV, Williams AW, Greene EL, Redfield MM (2008) Acute decompensated heart failure and the cardiorenal syndrome. Crit Care Med 36:S75–S88CrossRefPubMed Liang KV, Williams AW, Greene EL, Redfield MM (2008) Acute decompensated heart failure and the cardiorenal syndrome. Crit Care Med 36:S75–S88CrossRefPubMed
44.
go back to reference Massicotte G, Parent A et al (1989) Blunted responses to vasoconstrictors in mesenteric vasculature but not in portal vein of spontaneously hypertensive rats treated with relaxin. Proc Soc Exp Biol Med 190(3): 254–259 Massicotte G, Parent A et al (1989) Blunted responses to vasoconstrictors in mesenteric vasculature but not in portal vein of spontaneously hypertensive rats treated with relaxin. Proc Soc Exp Biol Med 190(3): 254–259
46.
go back to reference Nguyen BT, Yang L et al (2003) Phosphoinositide 3-Kinase activity is required for biphasic stimulation of cyclic AMP by relaxin. Mol Endocrinol (Baltimore, Md) 17:1075–1084. doi:10.1210/me.2002-0284 CrossRef Nguyen BT, Yang L et al (2003) Phosphoinositide 3-Kinase activity is required for biphasic stimulation of cyclic AMP by relaxin. Mol Endocrinol (Baltimore, Md) 17:1075–1084. doi:10.​1210/​me.​2002-0284 CrossRef
47.
go back to reference Novak J, Ramirez RJ et al (2002) Myogenic reactivity is reduced in small renal arteries isolated from relaxin-treated rats. Am J Physiol Regul Integr Comp Physiol 283(2):R349–R355PubMed Novak J, Ramirez RJ et al (2002) Myogenic reactivity is reduced in small renal arteries isolated from relaxin-treated rats. Am J Physiol Regul Integr Comp Physiol 283(2):R349–R355PubMed
49.
51.
go back to reference Samuel CS, Unemori EN et al (2004) Relaxin modulates cardiac fibroblast proliferation, differentiation, and collagen production and reverses cardiac fibrosis in vivo. Endocrinology 145(9):4125–4133. doi:10.1210/en.2004-0209 CrossRefPubMed Samuel CS, Unemori EN et al (2004) Relaxin modulates cardiac fibroblast proliferation, differentiation, and collagen production and reverses cardiac fibrosis in vivo. Endocrinology 145(9):4125–4133. doi:10.​1210/​en.​2004-0209 CrossRefPubMed
53.
go back to reference Schrier RW, Dürr JA (1987) Pregnancy: an overfill or underfill state. Am J Kidney Dis 9(4):284–289PubMed Schrier RW, Dürr JA (1987) Pregnancy: an overfill or underfill state. Am J Kidney Dis 9(4):284–289PubMed
55.
go back to reference Svendsen AM, Zalesko A et al (2008) Negative cooperativity in H2 relaxin binding to a dimeric relaxin family peptide receptor 1. Mol cell Endocrinol 296(1–2):10–17 Svendsen AM, Zalesko A et al (2008) Negative cooperativity in H2 relaxin binding to a dimeric relaxin family peptide receptor 1. Mol cell Endocrinol 296(1–2):10–17
57.
go back to reference Unemori EN, Amento EP (1990) Relaxin modulates synthesis and secretion of procollagenase and collagen by human dermal fibroblasts. J Biol Chem 265(18):10681–10685PubMed Unemori EN, Amento EP (1990) Relaxin modulates synthesis and secretion of procollagenase and collagen by human dermal fibroblasts. J Biol Chem 265(18):10681–10685PubMed
58.
go back to reference Unemori EN, Erikson ME et al (1999) Relaxin stimulates expression of vascular endothelial growth factor in normal human endometrial cells in vitro and is associated with menometrorrhagia in women. Hum Reprod (Oxford, England) 14(3):800–806. doi:10.1093/humrep/14.3.800 CrossRef Unemori EN, Erikson ME et al (1999) Relaxin stimulates expression of vascular endothelial growth factor in normal human endometrial cells in vitro and is associated with menometrorrhagia in women. Hum Reprod (Oxford, England) 14(3):800–806. doi:10.​1093/​humrep/​14.​3.​800 CrossRef
Metadata
Title
Relaxin, a pleiotropic vasodilator for the treatment of heart failure
Authors
Sam L. Teichman
Elaine Unemori
Thomas Dschietzig
Kirk Conrad
Adriaan A. Voors
John R. Teerlink
G. Michael Felker
Marco Metra
Gad Cotter
Publication date
01-12-2009
Publisher
Springer US
Published in
Heart Failure Reviews / Issue 4/2009
Print ISSN: 1382-4147
Electronic ISSN: 1573-7322
DOI
https://doi.org/10.1007/s10741-008-9129-3

Other articles of this Issue 4/2009

Heart Failure Reviews 4/2009 Go to the issue