Urotensin II: from osmoregulation in fish to cardiovascular regulation in man
2007; Elsevier BV; Volume: 98; Issue: 5 Linguagem: Inglês
10.1093/bja/aem088
ISSN1471-6771
Autores Tópico(s)Apelin-related biomedical research
ResumoUrotensin II (U-II) is a cyclic peptide first isolated from the urophysis of the teleost fish Gillichthys mirabilis where it is involved in osmoregulation.1Bern HA Lederis K A reference preparation for the study of bioactive substances in the caudal neurosecretory system of teleosts.J Endocrinol. 1969; 45: xi-xiiPubMed Google Scholar The human isoform was identified in 1998,2Coulouarn Y Lihrmann I Jegou S et al.Cloning of the cDNA encoding the urotensin II precursor in frog and human reveals intense expression of the urotensin II gene in motoneurons of the spinal cord.Proc Natl Acad Sci USA. 1998; 95: 15803-15808Crossref PubMed Scopus (377) Google Scholar and 1 yr later its cognate Gq G-protein coupled receptor, UT (de-orphanized GPR14) was identified.3Ames RS Sarau HM Chambers JK et al.Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14.Nature. 1999; 401: 282-286Crossref PubMed Scopus (789) Google Scholar Human U-II is composed of 11 amino acids and is cleaved from a larger precursor. An additional urotensin-related peptide has also been identified. Human UT is encoded on chromosome 17q25.3, is intronless, and is composed of 389 amino acids. There are several single nucleotide polymorphisms of both U-II and UT and their association with the range of cardiovascular disease phenotypes is largely undefined. The peptide and receptor show diverse distribution, including brain, respiratory system, heart, vasculature, and kidney. U-II is currently described as the most potent vasoconstrictor. However, the responses it produces are extremely variable and are of low efficacy.4Davenport AP Maguire JJ Urotensin II: fish neuropeptide catches orphan receptor.Trends Pharmacol Sci. 2000; 21: 80-82Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 5Douglas SA Ohlstein EH Human urotensin-II, the most potent mammalian vasoconstrictor identified to date, as a therapeutic target for the management of cardiovascular disease.Trends Cardiovasc Med. 2000; 10: 229-237Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar, 6Douglas SA Human urotensin-II as a novel cardiovascular target: ‘heart’ of the matter or simply a fishy ‘tail’?.Curr Opin Pharmacol. 2003; 3: 159-167Crossref PubMed Scopus (97) Google Scholar, 7Onan D Hannan RD Thomas WG Urotensin II: the old kid in town.Trends Endocrinol Metab. 2004; 15: 175-182Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 8Douglas SA Dhanak D Johns DG From ‘gills to pills’: urotensin-II as a regulator of mammalian cardiorenal function.Trends Pharmacol Sci. 2004; 25: 76-85Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, 9Watson AM May CN Urotensin II, a novel peptide in central and peripheral cardiovascular control.Peptides. 2004; 25: 1759-1766Crossref PubMed Scopus (38) Google Scholar, 10Nothacker HP Clark S From heart to mind. The urotensin II system and its evolving neurophysiological role.FEBS J. 2005; 272: 5694-5702Crossref PubMed Scopus (22) Google Scholar, 11Ong KL Lam KS Cheung BM Urotensin II: its function in health and its role in disease.Cardiovasc Drugs Ther. 2005; 19: 65-75Crossref PubMed Scopus (93) Google Scholar, 12Zhu YC Zhu YZ Moore PK The role of urotensin II in cardiovascular and renal physiology and diseases.Br J Pharmacol. 2006; 148: 884-901Crossref PubMed Scopus (69) Google Scholar Interaction of U-II with UT leads to activation of phospholipase C and the liberation of inositol (1Bern HA Lederis K A reference preparation for the study of bioactive substances in the caudal neurosecretory system of teleosts.J Endocrinol. 1969; 45: xi-xiiPubMed Google Scholar,4Davenport AP Maguire JJ Urotensin II: fish neuropeptide catches orphan receptor.Trends Pharmacol Sci. 2000; 21: 80-82Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar,5Douglas SA Ohlstein EH Human urotensin-II, the most potent mammalian vasoconstrictor identified to date, as a therapeutic target for the management of cardiovascular disease.Trends Cardiovasc Med. 2000; 10: 229-237Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar) trisphosphate [Ins(1Bern HA Lederis K A reference preparation for the study of bioactive substances in the caudal neurosecretory system of teleosts.J Endocrinol. 1969; 45: xi-xiiPubMed Google Scholar,4Davenport AP Maguire JJ Urotensin II: fish neuropeptide catches orphan receptor.Trends Pharmacol Sci. 2000; 21: 80-82Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar,5Douglas SA Ohlstein EH Human urotensin-II, the most potent mammalian vasoconstrictor identified to date, as a therapeutic target for the management of cardiovascular disease.Trends Cardiovasc Med. 2000; 10: 229-237Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar)P3]. This interacts with the Ins(1Bern HA Lederis K A reference preparation for the study of bioactive substances in the caudal neurosecretory system of teleosts.J Endocrinol. 1969; 45: xi-xiiPubMed Google Scholar,4Davenport AP Maguire JJ Urotensin II: fish neuropeptide catches orphan receptor.Trends Pharmacol Sci. 2000; 21: 80-82Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar,5Douglas SA Ohlstein EH Human urotensin-II, the most potent mammalian vasoconstrictor identified to date, as a therapeutic target for the management of cardiovascular disease.Trends Cardiovasc Med. 2000; 10: 229-237Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar)P3 receptor located on the endoplasmic/sarcoplasmic reticulum to release Ca2 + from intracellular stores leading to a tissue-dependent response. In the cardiovascular system, if the receptor is located on the cardiomyocyte, increased contractility would be anticipated. In the vasculature, constrictor and dilator responses have been recorded if the receptor is located on vascular smooth muscle cell or endothelium, respectively. Activation of the endothelial Ca2 + dependent enzyme nitric oxide synthase increases nitric oxide which diffuses into the vascular smooth muscle to produce a vasodilatation.4Davenport AP Maguire JJ Urotensin II: fish neuropeptide catches orphan receptor.Trends Pharmacol Sci. 2000; 21: 80-82Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 5Douglas SA Ohlstein EH Human urotensin-II, the most potent mammalian vasoconstrictor identified to date, as a therapeutic target for the management of cardiovascular disease.Trends Cardiovasc Med. 2000; 10: 229-237Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar, 6Douglas SA Human urotensin-II as a novel cardiovascular target: ‘heart’ of the matter or simply a fishy ‘tail’?.Curr Opin Pharmacol. 2003; 3: 159-167Crossref PubMed Scopus (97) Google Scholar, 7Onan D Hannan RD Thomas WG Urotensin II: the old kid in town.Trends Endocrinol Metab. 2004; 15: 175-182Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 8Douglas SA Dhanak D Johns DG From ‘gills to pills’: urotensin-II as a regulator of mammalian cardiorenal function.Trends Pharmacol Sci. 2004; 25: 76-85Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, 9Watson AM May CN Urotensin II, a novel peptide in central and peripheral cardiovascular control.Peptides. 2004; 25: 1759-1766Crossref PubMed Scopus (38) Google Scholar, 10Nothacker HP Clark S From heart to mind. The urotensin II system and its evolving neurophysiological role.FEBS J. 2005; 272: 5694-5702Crossref PubMed Scopus (22) Google Scholar, 11Ong KL Lam KS Cheung BM Urotensin II: its function in health and its role in disease.Cardiovasc Drugs Ther. 2005; 19: 65-75Crossref PubMed Scopus (93) Google Scholar, 12Zhu YC Zhu YZ Moore PK The role of urotensin II in cardiovascular and renal physiology and diseases.Br J Pharmacol. 2006; 148: 884-901Crossref PubMed Scopus (69) Google Scholar Unlike the majority of transmitter molecules, the binding of U-II to its receptor is essentially irreversible; this has been reported for both recombinant and native UT.13Douglas SA Naselsky D Ao Z et al.Identification and pharmacological characterization of native, functional human urotensin-II receptors in rhabdomyosarcoma cell lines.Br J Pharmacol. 2004; 142: 921-932Crossref PubMed Scopus (38) Google Scholar 14Song W McDonald J Camarda V et al.Cell and tissue responses of a range of urotensin II analogs at cloned and native urotensin II receptors. Evidence for coupling promiscuity.Naunyn Schmiedebergs Arch Pharmacol. 2006; 373: 148-157Crossref PubMed Scopus (23) Google Scholar This irreversibility of binding is probably related to the presence of the highly conserved cyclic hexapeptide core. Irreversibility of binding has important consequences for regulation of receptor-driven signalling.6Douglas SA Human urotensin-II as a novel cardiovascular target: ‘heart’ of the matter or simply a fishy ‘tail’?.Curr Opin Pharmacol. 2003; 3: 159-167Crossref PubMed Scopus (97) Google Scholar8Douglas SA Dhanak D Johns DG From ‘gills to pills’: urotensin-II as a regulator of mammalian cardiorenal function.Trends Pharmacol Sci. 2004; 25: 76-85Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar Under ‘normal’ conditions, the receptor-peptide system is likely to be functionally silent. This rather bold statement is based on the following observations. (i)There are no major physiological consequences in mice deficient in the U-II receptor (UT-knockouts).(ii)As U-II binding to UT is irreversible, circulating U-II may desensitize the receptor, essentially creating a knockout phenotype. U-II/UT responsiveness would then be predicted to result from increased receptor expression rather than U-II production. The situation in disease is intriguing where both peptide and receptor appear to be variably up-regulated in heart failure, hypertension, diabetes, and renal disease.The effects of U-II are extremely variable between species, between vascular beds in the same species, and within the same vessel. For example, in rats, U-II constricts the thoracic aorta with high potency but low efficacy, yet this peptide is ineffective in abdominal portions of the same vessel. Responsiveness correlates with differences in receptor expression along the vessel. The basis of this is not yet known and is puzzling, especially if the system is silenced under normal physiological conditions. In some vascular beds, dilation is reported and, as expected from the comments above, this is endothelium-dependent. In humans, venoconstrictor responses can also be recorded. In addition to the noted effects on the heart and vasculature, this peptide has actions on the kidney, brain, and airways4Davenport AP Maguire JJ Urotensin II: fish neuropeptide catches orphan receptor.Trends Pharmacol Sci. 2000; 21: 80-82Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 5Douglas SA Ohlstein EH Human urotensin-II, the most potent mammalian vasoconstrictor identified to date, as a therapeutic target for the management of cardiovascular disease.Trends Cardiovasc Med. 2000; 10: 229-237Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar, 6Douglas SA Human urotensin-II as a novel cardiovascular target: ‘heart’ of the matter or simply a fishy ‘tail’?.Curr Opin Pharmacol. 2003; 3: 159-167Crossref PubMed Scopus (97) Google Scholar, 7Onan D Hannan RD Thomas WG Urotensin II: the old kid in town.Trends Endocrinol Metab. 2004; 15: 175-182Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 8Douglas SA Dhanak D Johns DG From ‘gills to pills’: urotensin-II as a regulator of mammalian cardiorenal function.Trends Pharmacol Sci. 2004; 25: 76-85Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, 9Watson AM May CN Urotensin II, a novel peptide in central and peripheral cardiovascular control.Peptides. 2004; 25: 1759-1766Crossref PubMed Scopus (38) Google Scholar, 10Nothacker HP Clark S From heart to mind. The urotensin II system and its evolving neurophysiological role.FEBS J. 2005; 272: 5694-5702Crossref PubMed Scopus (22) Google Scholar, 11Ong KL Lam KS Cheung BM Urotensin II: its function in health and its role in disease.Cardiovasc Drugs Ther. 2005; 19: 65-75Crossref PubMed Scopus (93) Google Scholar, 12Zhu YC Zhu YZ Moore PK The role of urotensin II in cardiovascular and renal physiology and diseases.Br J Pharmacol. 2006; 148: 884-901Crossref PubMed Scopus (69) Google Scholar (Fig. 1). Targeting of peptide-receptor systems in clinical medicine is common, and most anaesthetists will see patients receiving angiotensin-II-converting enzyme inhibitors or angiotensin-II receptor antagonists15Oh YJ Lee JH Nam SB Shim JK Song JH Kwak YL Effects of chronic angiotensin II receptor antagonist and angiotensin-converting enzyme inhibitor treatments on neurohormonal levels and haemodynamics during cardiopulmonary bypass.Br J Anaesth. 2006; 97: 792-798Crossref PubMed Scopus (36) Google Scholar and the majority of surgical patients will receive opioids in one form or another.16Zollner C Stein C Opioids.Hand Exp Pharmacol. 2007; 177: 31-63Crossref PubMed Scopus (146) Google Scholar The clinical potential of U-II is being explored from three angles: (i)measurement of U-II in various biological fluids as a function of disease presentation;(ii)measurement of UT expression as a function of disease presentation; and(iii)administration of U-II and UT antagonists in man.U-II is elevated in heart disease and hypertension, although some studies have not confirmed this, and there is some relationship with the degree of heart failure and level of hypertension. In addition, plasma U-II is elevated in renal disease, diabetes, and hepatic disease.11Ong KL Lam KS Cheung BM Urotensin II: its function in health and its role in disease.Cardiovasc Drugs Ther. 2005; 19: 65-75Crossref PubMed Scopus (93) Google Scholar 12Zhu YC Zhu YZ Moore PK The role of urotensin II in cardiovascular and renal physiology and diseases.Br J Pharmacol. 2006; 148: 884-901Crossref PubMed Scopus (69) Google Scholar 17Aiyar N Guida B Ao Z et al.Differential levels of ‘urotensin-II-like’ activity determined by radio-receptor and radioimmuno-assays.Peptides. 2004; 25: 1339-1347Crossref PubMed Scopus (18) Google Scholar We have previously reported, in pre-eclamptic patients that maternal plasma, umbilical cord plasma, and maternal cerebrospinal fluid U-II levels were not elevated when compared with those from normotensive control pregnancies.18Cowley E Thompson JP Sharpe P Waugh J Ali N Lambert DG Effects of pre-eclampsia on maternal plasma, cerebrospinal fluid, and umbilical cord urotensin II concentrations: a pilot study.Br J Anaesth. 2005; 95: 495-499Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar However, Balat and colleagues19Balat O Aksoy F Kutlar I et al.Increased plasma levels of urotensin-II in preeclampsia–eclampsia: a new mediator in pathogenesis?.Eur J Obstet Gynecol Reprod Biol. 2005; 120: 33-38Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar reported an increase in pre-eclamptic patients compared with controls. The variable data are a common observation in urotensin studies and encompass basic ex vivo animal/human tissue response studies through to these plasma measurements. UT is similarly increased in cardiomyocytes, endothelial cells, and smooth muscle cells from diseased hearts.20Douglas SA Tayara L Ohlstein EH Halawa N Giaid A Congestive heart failure and expression of myocardial urotensin II.Lancet. 2002; 359: 1990-1997Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar In two volunteer studies, U-II has been infused intra-arterially and i.v.21Wilkinson IB Affolter JT de Haas SL et al.High plasma concentrations of human urotensin II do not alter local or systemic hemodynamics in man.Cardiovasc Res. 2002; 53: 341-347Crossref PubMed Scopus (95) Google Scholar 22Affolter JT Newby DE Wilkinson IB Winter MJ Balment RJ Webb DJ No effect on central or peripheral blood pressure of systemic urotensin II infusion in humans.Br J Clin Pharmacol. 2002; 54: 617-621Crossref PubMed Scopus (58) Google Scholar After intra-arterial infusion, plasma concentrations rose, but there was no change in forearm blood flow. As part of a placebo-controlled study, i.v. infusion of U-II concentrations also failed to affect systemic haemodynamics. This might be consistent with the suggestion that, in healthy individuals, the system is functionally silent. This suggestion will, of course, require rigorous experimental validation. The situation in disease states is very different. In two simple but elegant studies,23Lim M Honisett S Sparkes CD Komesaroff P Kompa A Krum H Differential effect of urotensin II on vascular tone in normal subjects and patients with chronic heart failure.Circulation. 2004; 109: 1212-1214Crossref PubMed Scopus (90) Google Scholar24Sondermeijer B Kompa A Komesaroff P Krum H Effect of exogenous urotensin-II on vascular tone in skin microcirculation of patients with essential hypertension.Am J Hypertens. 2005; 18: 1195-1199Crossref PubMed Scopus (52) Google Scholar U-II has been administered to patients with heart failure or hypertension and to normal controls using an iontophoresis technique, with subsequent measurement of microvascular blood flow using Doppler flow probes. In both studies, the control groups displayed increased blood flow consistent with a dilatory response indicating that U-II was probably interacting with an endothelial target. These data are also at variance with the notion of U-II/UT functional silence. More interestingly, in the heart failure and hypertensive groups a decrease in blood flow was observed, indicating vasoconstriction. This information is a clear clinical lead for the use of U-II antagonists to reverse these constrictor effects. The first clinical use of a UT antagonist in man was published late last year by researchers from Actelion.25Sidharta PN Wagner FD Bohnemeier H et al.Pharmaco-dynamics and pharmacokinetics of the urotensin II receptor antagonist palosuran in macroalbuminuric, diabetic patients.Clin Pharmacol Ther. 2006; 80: 246-256Crossref PubMed Scopus (69) Google Scholar This paper detailed the pharmacokinetics and pharmacodynamics of palosuran (a U-II antagonist) in macroalbuminuric diabetic patients. The rationale for the study was that diabetes increases plasma U-II and this may constrict renal vessels and reduce blood flow. On the basis of two phase 1 safety/tolerability studies in healthy volunteers,26Sidharta PN van Giersbergen PLM Schaarschmidt D Dingemanse J Pharmacokinetics and pharmacodynamics of the urotensin-II receptor antagonist palosuran in healthy human subjects.J Clin Pharmacol. 2004; 44: 1192Google Scholar 27Sidharta PN van Giersbergen PLM Schaarschmidt D Dingemanse J Multiple-dose tolerability, safety, pharmacokinetics and pharmacodynamics of the urotensin-II receptor antagonist palosuran in healthy human subjects.Br J Clin Pharmacol. 2005; 60: 677-678Google Scholar an oral dose of 125 mg twice daily was chosen and the treatment continued for 13.5 days. Type 2 diabetic patients with hypertension and of both sexes (n = 18) were subdivided into two groups based on renal function, normal/mild impairment, and moderate/severe impairment. In both groups, palosuran was rapidly absorbed, reaching a peak (Cmax ∼110–140 ng ml−1) at around 1 h. Urinary albumin excretion decreased significantly (26.2%) in the normal/mild impairment group. There was a 22.3% reduction in the moderate/severe impairment group but this failed to reach statistical significance. Overall, in both groups (18 patients) there was a significant 24.3% decrease in urinary albumin excretion and palosuran was well tolerated. The authors suggest further larger studies should be performed with palosuran as monotherapy or as combination therapy in patients with renal failure. These further studies are eagerly awaited. With the availability of U-II receptor antagonists, such as palosuran (and no doubt several more in the clinical pipeline), the future for this peptide-receptor system is encouraging. For the anaesthetist, such drugs may be of use in the care of patients in the intensive care and perioperative settings, for example those with heart and renal failure. From an experimental point of view, the interaction of some of the commonly used anaesthetic agents with this system remains to be explored. Work on U-II in my laboratory has been funded by the British Journal of Anaesthesia/Royal College of Anaesthetists and British Heart Foundation.
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