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News Physiol Sci 15: 264-268, 2000;
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News in Physiological Sciences, Vol. 15, No. 5, 264-268, October 2000
© 2000 Int. Union Physiol. Sci./Am. Physiol. Soc.

Urocortin: A Novel Player in Cardiac Control

David G. Parkes and Clive N. May

D. G. Parkes is at Amylin Pharmaceuticals, 9373 Towne Centre Dr., San Diego, California 92121, and C. N. May is at the Howard Florey Institute of Physiology and Medicine, University of Melbourne, Parkville, Victoria, 3052 Australia.

   Abstract
 
Urocortin is a potent regulator of cardiac function, with actions that are prolonged in experimental animals. These changes are mediated via binding to corticotropin-releasing factor receptors found in peripheral tissues. The effects of urocortin on behavior, appetite, inflammation, and the cardiovascular system suggest that this peptide may be an endogenous factor mediating actions previously attributed to corticotropin-releasing factor.


   Introduction
Top
 Introduction
Isolation and characterization...
 Cardiovascular actions
 Other actions of Ucn
 Future directions
 References
 
Since corticotropin-releasing factor (CRF) was isolated and characterized by Vale and co-workers (13) at the Salk Institute, peripheral cardiovascular actions of CRF have been observed across species ranging from rodents to humans. However, scientists have been perplexed by the relevance of these cardiovascular actions, since very low levels of CRF normally circulate in peripheral blood and relatively low levels of CRF gene expression are observed in the heart. It is well accepted that CRF is the primary hormone involved in the mammalian response to stress (2, 14) and produces central actions to increase blood pressure and stimulate pituitary adrenocorticotropic hormone (ACTH) and adrenal steroid release in all species studied. CRF belongs to a family of structurally related peptides that includes fish urotensin 1 and amphibian sauvagine, which also possess bioactivity similar to CRF in several mammalian systems. In 1993, the discovery of a high-affinity receptor for CRF (1) added to the acceptance of CRF as a physiologically relevant hormone present in the central nervous system and pituitary blood supply. However, lack of any significant expression of this CRF type 1 receptor (CRF-R1) in peripheral tissues relevant to control of the cardiovascular system did not support the hypothesis that circulating CRF may be directly controlling the heart or vasculature. In 1994, a second CRF receptor was cloned and characterized, and tissue expression of this type 2 receptor (CRF-R2) was reported soon thereafter. A splice variant of this type 2 receptor, CRF receptor type 2ß (CRF-R2ß), is present in both brain and peripheral tissues, including the heart, testis, and gastrointestinal tract. Recently, a third splice variant of the CRF-R2 was isolated, CRF-R2{gamma}, and this receptor is expressed in human brain regions, including the hippocampus and septum (Fig. 1Go).



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  		FIGURE 1. Receptor (CRF-R) and binding protein (CRF-BP) targets for urocortin and corticotropin-releasing factor (CRF).

 

   Isolation and characterization of urocortin
Top
 Introduction
 Isolation and characterization...
Cardiovascular actions
 Other actions of Ucn
 Future directions
 References
 
In 1995, Vaughan and colleagues (15) described the discovery of a CRF-related peptide expressed in rat brain known as urocortin (Ucn), named after its peptide homology to both the teleost hormone urotensin and to mammalian CRF and because it possesses biological activity exhibited by both of these peptides. Rat Ucn is a 40 amino acid peptide with 45% homology to rat/human CRF, 63% homology to teleost urotensin 1, and 35% homology to frog sauvagine (Fig. 2Go) (15). The urotensin-like immunoreactivity possessed by Ucn enabled its initial identification within a discrete region of the rat midbrain known as the Edinger-Westphal nucleus, a region that lacks expression of CRF mRNA. Ucn cDNA was isolated from an mRNA library derived from rat midbrain, which was screened with a urotensin probe. The full-length cDNA encodes a protein deduced to be 122 amino acids in length. The carboxy terminus contains Ucn, a putatively cleaved 40 amino acid peptide with a carboxy terminal amidation. Recently, the sequence of ovine Ucn was published and is identical to that for the rat peptide.



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  		FIGURE 2. Comparison of amino acid sequences for human urocortin (hUcn), rat/ovine urocortin (r/oUcn), ovine CRF (oCRF), rat/human CRF (r/hCRF), carp urotensin (cUro) and frog sauvagine. Amino acid residues exhibiting identity to hUcn are shown in bold. * represents carboxy terminal amidation (3, 15). Reprinted with permission from Parkes and May. Cardiac and vascular actions of urocortin. In: Hormones and the Heart in Health and Disease, edited by Share L. Totowa, NJ: Humana, 1999, chapt. 3, p. 41.

 
Vaughan and colleagues also reported Ucn to have marked cardiovascular actions in rats to lower blood pressure and increase heart rate, with a greater potency and duration of action than CRF itself. In the rat heart, Ucn mRNA is expressed in vascular smooth muscle cells of cardiac blood vessels as well as in cardiac myocytes. Whether this is the primary source of Ucn that induces cardiovascular changes is not known. At present, plasma levels of Ucn have been reported in only one study, in which Ucn was not detectable in plasma from pregnant women. Further studies are required to determine whether Ucn acts as a circulating hormone or whether it only has paracrine effects.

Notwithstanding this, the discovery of Ucn helped fill in the picture concerning potentially circulating CRF-like peptides acting as physiological regulators of regional hemodynamics, and subsequent studies in species such as sheep (9) have confirmed potent actions of Ucn on the heart and vasculature. Of significance, although CRF-R2{alpha} mRNA expression lies exclusively within the central nervous system, high levels of CRF-R2ß mRNA exist within the cardiac atria and ventricles (myocardium, epicardium, arterioles) (10). Ucn is known to strongly bind and activate CRF-R2ß receptors (15), suggesting that there may now be an identified endogenous CRF-like peptide that binds to systemic receptors (Fig. 1Go) and subsequently mediates cardiovascular effects in the periphery. We describe here some potential mechanisms of these hemodynamic effects.


   Cardiovascular actions
Top
 Introduction
 Isolation and characterization...
 Cardiovascular actions
Other actions of Ucn
 Future directions
 References
 
CRF, sauvagine, and urotensin are known to produce potent effects on the cardiovascular system, effects that are dependent on whether the peptide is administered peripherally or directly into the central nervous system. Intravenous CRF is consistently seen to produce vasodilatation in rats, leading to a fall in blood pressure and reflex increase in heart rate, although this action is not observed in species such as sheep and only observed at relatively high concentrations in humans and monkeys. The rat and dog are the most responsive species to this vasodilator action, and these are the two species from which much of the early hemodynamic data on CRF has been obtained. In rats, intravenous CRF produces a peripheral vasodilator action predominantly mediated by a reduction in mesenteric arterial resistance (6, 8). In contrast, in all species studied, including sheep, intracerebroventricular administration of CRF increases blood pressure, cardiac output, and heart rate. This effect is mediated by viscerotropic activation of sympathetic nervous outflow to raise peripheral resistance and heart rate in rats, dogs, and rabbits.

In rats, evidence that CRF or a related peptide may produce direct cardiac actions to increase contractility now exists from several in vitro studies. Grunt and co-workers (4) have shown that CRF perfused through isolated working rat hearts can increase both coronary blood flow and maximal aortic pressure, suggesting direct effects of CRF on cardiac activity. Neither the ß-adrenergic receptor antagonist propranolol nor the nitric oxide synthesis inhibitor NG-nitro-L-arginine blocked these effects. Other studies have reported that CRF can directly increase the contractile force of isolated guinea pig ventricular myocardium, independent of norepinephrine release or Na+-K+-ATPase activity. More recently, Heldwein and colleagues (5) have demonstrated that CRF and related peptides can directly stimulate cAMP accumulation in isolated neonatal rat cardiomyocytes.

Intravenous injection of CRF in conscious sheep promotes little change in mean arterial pressure, heart rate, or cardiac output. Most notably, there is no change in cardiac contractility (9). However, a robust increase in plasma ACTH and cortisol levels is observed. This lack of any significant peripheral hemodynamic action of CRF in sheep may be due to species differences in binding of CRF to peripheral CRF-R2. It is possible that ovine CRF is highly specific for type 1 receptors within the brain and pituitary and lacks any significant binding and activation of ovine cardiac type 2 receptors.

Ucn itself has been shown to possess potent and long-lasting hypotensive actions in conscious rats, as reported by Vale's group in 1995 (15). Ucn produced a dose-dependent hypotension, and CRF showed ~30% of the hypotensive potency of Ucn. The duration of hypotensive action of Ucn in rats was almost 2 h, with that of CRF being <1 h. Increases in heart rate, probably partly baroreflex mediated, were associated with these blood pressure changes. The mechanism of this hypotension following Ucn injection might presumably be via a peripheral vasodilator action, possibly due to a specific action on mesenteric vascular beds, as described for CRF, sauvagine, and urotensin. We have recently observed in anesthetized rats that intravenous Ucn can reduce arterial pressure, aortic flow, stroke volume, and aortic resistance, together with an increase in heart rate and aortic conductance, suggesting that Ucn does indeed act to produce peripheral vasodilatation in rats. Interestingly, we also observed a 50% increase in maximum aortic flow and a 90% increase in aortic flow rate, two indicators of cardiac contractility; hence Ucn does appear to have positive cardiac inotropic actions in anesthetized rats. Spina and co-workers have reported that Ucn injected into the lateral cerebral ventricles in rats increases blood pressure slightly (11); however, there was no change in myocardial contractility. This further supports the concept that the cardiac inotropic action of Ucn may be mediated by a peripheral action, probably directly on the heart. A recent study in isolated rat hearts has indeed observed direct actions of Ucn to induce a positive inotropic action (12), in addition to a reduction in coronary artery perfusion pressure (resistance). The inotropic action was dependent on an intact cyclooxygenase/prostaglandin synthesis pathway and was unaffected by inhibitors of nitric oxide production.

Our study in conscious sheep investigated in detail the cardiovascular actions of rat/ovine Ucn (9), and Fig. 3Go compares these effects to those observed in rats. Ucn produced a slowly developing increase in mean arterial pressure that was associated with a rise in heart rate and in cardiac output.



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  		FIGURE 3. Comparison of the cardiovascular actions of urocortin in rats and sheep.

 
The most striking cardiovascular change seen with intravenous Ucn in sheep was a rapid and extremely potent increase in cardiac contractility, as reflected by the large increases in both maximum aortic flow and aortic dF/dt. Two hours after injection of Ucn, coronary blood flow exhibited a significant increase from control, and this was associated with a rise in coronary conductance. The changes in arterial pressure, heart rate, cardiac output, coronary contractility, blood flow, and conductance were all dose dependent. The onset of the cardiac inotropic effect of Ucn, before any change in blood pressure or central venous pressure, suggests that the action of Ucn to increase cardiac contractility in sheep is not a reflex response to changes in cardiac preload or afterload.

The increase in coronary arterial blood flow and conductance in sheep demonstrates that Ucn has a coronary vasodilator action. Whether this is a direct action of Ucn to produce vascular relaxation as suggested by the in vitro study reported for Ucn (12) or a consequence of greater oxygen demand by the heart due to an increase in cardiac work remains to be determined.

Interestingly, we found that in sheep the Ucn-induced cardiac actions were of extensive duration. The cardiac inotropic and coronary vasodilator actions of Ucn were still maximal 4 h after a bolus injection of Ucn, with the peak response reached ~2 h after injection, plateauing after this time at maximal change. In a group of sheep monitored continuously for 3 days after Ucn injection, we observed that cardiac contractility remained significantly elevated for up to 24 h after injection, whereas other hemodynamic variables had returned to control values within 14 h. There are no reports of such a long duration of inotropic action for any peptide, and the data suggest that once Ucn has bound to receptors mediating cardiovascular changes it can maintain binding and signaling for extremely long periods or persistently stimulate release of endogenous inotropic factors. When comparing the inotropic activity of Ucn with another peptide known to increase cardiac contractility, we have shown that the vasodilator adrenomedullin produces a 15% increase in aortic dF/dt in sheep. Ucn given at equimolar doses increased aortic dF/dt by almost 120%, indicating that Ucn is an extremely potent cardiac inotrope in conscious sheep.

It was also observed that the CRF antagonist {alpha}-helical CRF-(9–41) could abolish the cardiovascular changes produced by Ucn in sheep. Because we observed complete inhibition of the cardiovascular changes produced by Ucn with a dose ratio of {alpha}-helical CRF-(9–41) to Ucn of 10:1, this suggested that these changes are more likely to be mediated via CRF-R2, since this antagonist is reported to be more selective for CRF-R2 and much higher dose ratios of antagonist to agonist are needed to significantly block CRF-R1.

We have recently assessed the ability of Ucn to produce cardiac actions in the absence of an intact autonomic nervous system. These experiments were designed to determine whether Ucn may be acting directly on the heart or via a secondary mechanism, possibly via actions on circumventricular organs in the brain or on the peripheral nervous system, to activate sympathetic outflow to the heart and vasculature. This study demonstrated that ganglion blockade did not prevent the cardiac effects of Ucn. The Ucn-induced increases in cardiac output and heart rate, and the striking increase in cardiac contractility, were similar in intact and ganglion-blocked sheep. This indicates that these actions of Ucn were not mediated by the autonomic nervous system, and it is likely that they are mediated by a direct action of Ucn on the heart, possibly via binding to CRF-R2ß receptors.


   Other actions of Ucn
Top
 Introduction
 Isolation and characterization...
 Cardiovascular actions
 Other actions of Ucn
Future directions
 References
 
Synthetic Ucn can stimulate release of ACTH to a greater extent than CRF from isolated rat pituitary cells as well as in vivo in conscious rats (15) and sheep (9). This is consistent with the peptide's ability to bind and activate CRF-R1 expressed by corticotropes within the anterior pituitary (15). Interestingly, it appears that although exogenous Ucn is a potent stimulator of ACTH release, endogenous Ucn may not play a major role in basal control or stimulated release of ACTH following stressful stimuli. In addition, Ucn is implicated in the central control of the release of another pituitary hormone, vasopressin. The presence of Ucn mRNA has been demonstrated in the supraoptic nucleus of the rat brain, and Ucn immunoreactivity increased in this area with water deprivation. Central administration of Ucn significantly attenuated the release of vasopressin in response to hyperosmolality, indicating that Ucn may play an inhibitory role in the osmotic control of vasopressin release.

Ucn also has actions that may play an important role in cardiac protection. Natriuretic peptides are released from the heart in response to atrial and ventricular stretch, and their levels are increased in heart failure, during which it is proposed that they have a protective action. Ucn stimulated secretion of atrial and brain natriuretic peptides in cultured neonatal rat myocytes by an action on CRF-R2. Furthermore, Ucn has been shown to have protective actions in a rat cardiac myocyte cell line. Expression of Ucn mRNA was increased after thermal injury, and Ucn was shown to protect cardiac myocytes from cell death induced by hypoxia (7), indicating that Ucn may act as an endogenous cardioprotective agent. In response to an injury, such as a myocardial infarction, Ucn could act to cause the release of natriuretic peptides and other locally released mediators, which would have a protective role both systemically and at a local level. However, whether these mechanisms play an important role in vivo remains to be established.

It is well accepted that CRF can have marked effects on behavior to suppress appetite, stimulate arousal, and increase performance in various memory and learning exercises, and at higher doses it can increase emotionality, leading to fear, anxiety, and depression-like effects in a variety of species. Spina and co-workers (11) have demonstrated that Ucn, when given intracerbroventricularly to rats, can strongly suppress food and water intake in both food-deprived and freely feeding states. This appetite-suppressing action of Ucn was significantly more potent than that for CRF. Interestingly, in this study, Ucn did not produce any anxiogenic-like behavior when rats were tested in an emotionality test (elevated plus maze), a test in rats known to be sensitive to CRF. Significant behavioral actions were observed with intravenous Ucn administration in sheep, particularly at higher doses (9). Ucn markedly suppressed appetite for food and water in sheep for at least 12 h after the normal time of feeding; however, the animals did not appear anxious or stressed. Significant levels of CRF-R2 expression are seen within the gastrointestinal tract, and high levels of Ucn mRNA are also seen at several important junctions along the gastrointestinal tract. Consistent with this, Ucn may act directly on the gut to inhibit gastric motility, in combination with central actions to suppress feeding behavior and autonomic control of gastric emptying. These actions of Ucn contribute to the peptide's overall action to regulate caloric intake (Fig. 4Go).



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  		FIGURE 4. Urocortin's actions on the central nervous system and peripheral targets. The source of urocortin acting outside the central nervous system may be within the respective target tissue. BP, blood pressure; ACTH, adrenocorticotropic hormone; CNS, central nervous system.

 
Several of the other localized actions of CRF on inflammation, metabolism, respiration, and the immune system may be mimicked by Ucn when examined in forthcoming studies, especially in regions or tissues in which there are high levels of CRF-R2 expression. Of significance, Ucn exhibits high affinity for the CRF binding protein (CRF-BP), which may modulate actions of Ucn within the brain and periphery.


   Future directions
Top
 Introduction
 Isolation and characterization...
 Cardiovascular actions
 Other actions of Ucn
 Future directions
References
 
Ucn is now emerging as a potential hormone involved in cardiovascular control and may be the "missing link" with regard to some peripheral actions of CRF. Increasing evidence, based on CRF/Ucn receptor expression, Ucn peptide expression, and Ucn physiology, indicates that this peptide may be present in significant concentrations and at relevant sites to control a number of local physiological systems. In addition, Ucn has specific actions within the central nervous system to regulate behavior, blood pressure, and hormonal release from the pituitary. The marked and persistent cardiovascular, hormonal, and behavioral actions of Ucn following intravenous administration are intriguing. In particular, the cardiac inotropic action of Ucn is unique with regard to its potency and duration of action when compared with other cardioactive peptides, and this appears to be the primary cardiovascular action of this peptide in sheep. Whether this potent inotropic action of Ucn may prove useful in developing analogs/therapeutics for treatment of myocardial infarction or congestive heart failure depends on confirmatory studies examining the cardiovascular actions of this peptide in primates and humans. Of high relevance, understanding the control of Ucn secretion into the circulation and within peripheral tissues will provide answers to the physiological and pathological significance of systemic Ucn.

Overall, it is now evident that Ucn plays a significant role in the control of cardiac function and peripheral hemodynamics and may be one of the primary factors involved in the cardiovascular response to a stressful stimulus. To what extent these marked cardiovascular changes of Ucn impact on other actions, such as slowing of gastric emptying, suppression of inflammation, and release of ACTH/cortisol, remains to be elucidated.


   References
Top
 Introduction
 Isolation and characterization...
 Cardiovascular actions
 Other actions of Ucn
 Future directions
 References
 

  1. Chen R, Lewis K, Perrin M, and Vale W. Expression cloning of a human corticotropin-releasing-factor receptor. Proc Natl Acad Sci USA 90: 8967–8971, 1993.[Abstract/Free Full Text]
  2. DeSouza E and Grigoriadis D. Corticotropin releasing factor: physiology, pharmacology, and role in central nervous system and immune disorders. In: Psychopharmacology: The 4th Generation of Progress. New York: Raven, 1995, p. 505–517.
  3. Donaldson C, Sutton S, Perrin M, Corrigan A, Lewis K, Rivier J, Vaughan J, and Vale W. Cloning and characterization of human urocortin. Endocrinology 137: 2167–2170, 1996.[Abstract]
  4. Grunt M, Glaser J, Schmidhuber H, Pauschinger P, and Born J. Effects of corticotropin-releasing factor on isolated rat heart activity. Am J Physiol Heart Circ Physiol 264: H1124–H1129, 1993.[Abstract/Free Full Text]
  5. Heldwein K, Redick D, Rittenberg M, Claycomb W, and Stenzel-Poore M. Corticotropin-releasing hormone receptor expression and functional coupling in neonatal cardiac myocytes and AT-1 cells. Endocrinology 137: 3631–3639, 1996.[Abstract]
  6. MacCannell K, Lederis K, Hamilton P, and Rivier J. Amunine (ovine CRF), urotensin 1 and sauvagine, three structurally related peptides, produce selective dilation of the mesenteric circulation. Pharmacology 25: 116–120, 1982.[Medline]
  7. Okosi A, Brar BK, Chan M, D'souza L, Smith E, Stephanou A, Latchman DS, Chowdrey HS, and Knight RA. Expression and protective effects of urocortin in cardiac myocytes. Neuropeptides 32: 167–171, 1998.[ISI][Medline]
  8. Overton J and Fisher L. Differentiated hemodynamic responses to central versus peripheral administration of corticotropin-releasing factor in conscious rats. J Autonom Nerv Syst 35: 43–52, 1991.[ISI][Medline]
  9. Parkes D, Vaughan J, Rivier J, Vale W, and May C. Cardiac inotropic actions of urocortin in conscious sheep. Am J Physiol Heart Circ Physiol 272: H2115–H2122, 1997.[Abstract/Free Full Text]
  10. Perrin M, Donaldson C, Chen R, Blount A, Berggren T, Bilezikjian L, Sawchenko P, and Vale W. Identification of a second corticotropin-releasing factor receptor gene and characterization of a cDNA expressed in heart. Proc Natl Acad Sci USA 92: 2969–2973, 1995.[Abstract/Free Full Text]
  11. Spina M, Merlo-Pich E, Chan R, Basso A, Rivier J, Vale W, and Koob G. Appetite-suppressing effects of urocortin, a CRF-related neuropeptide. Science 273: 1561–1564, 1996.[Abstract]
  12. Terui K, Higashiyama A, Horiba N, Motomura S, and Suda T. Coronary vasodilation and positive inotropism by urocortin in the isolated rat heart (Abstract). 81st Annual Meeting of the Endocrine Society, San Diego, CA, 1999, p. 269.
  13. Vale W, Spiess J, Rivier C, and Rivier J. Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and ß-endorphin. Science 213: 1394–1397, 1981.[Free Full Text]
  14. Vale W, Vaughan J, and Perrin M. Corticotropin-releasing factor (CRF) family of ligands and their receptors. Endocrinologist 7: 3S–9S, 1997.
  15. Vaughan J, Donaldson C, Bittencourt J, Perrin M, Lewis K, Sutton S, Chan R, Turnbull A, Lovejoy D, Rivier C, Rivier J, Sawchenko P, and Vale W. Urocortin, a mammalian neuropeptide related to fish urotensin 1 and corticotropin-releasing factor. Nature 378: 287–292, 1995.[Medline]



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