Peptides 25 (2004) 1759–1766
Review
Urotensin II, a novel peptide in central and peripheral cardiovascular control Anna M.D. Watson, Clive N. May∗ Howard Florey Institute, University of Melbourne, Parkville, Vic. 3010, Australia Received 5 February 2004; accepted 15 April 2004 Available online 12 September 2004
Abstract Urotensin II (UII) is a peptide that was originally isolated and characterized in fish. Interest in its effects in mammals increased with the identification of its receptor, G-protein coupled receptor 14, and its localization in humans. UII and its receptor have a wide distribution, including brain and spinal cord as well as heart, kidney and liver, implying that UII has important physiological actions. Recent studies suggest that UII may play an important role in the central nervous system. In conscious sheep, intracerebroventricular administration of UII induced large, prolonged increases in plasma epinephrine, adrenocorticotropic hormone, cardiac output and arterial pressure. Potent chronotropic and inotropic actions accompanied this, as well as peripheral vasodilatation. Administered intravenously, UII is an extremely potent vasoconstrictor in anesthetized monkeys, but reduces pressure in conscious and anesthetized rats, and causes a transient increase in conscious sheep, however vasomotor responses vary depending on species and vessel type. UII is elevated in conditions such as essential hypertension and heart failure suggesting a role in pathology. The results of studies with UII to date, together with its possible role in disease, emphasize the importance of examining the central and peripheral roles of UII in more detail. © 2004 Elsevier Inc. All rights reserved. Keywords: Urotensin II; Intracerebroventricular; Intravenous; Sheep; Epinephrine; Adrenocorticotropic hormone; Review; Inotropic; Chronotropic; Regional blood flow; Cardiac output; Hyperglycemia
Contents 1.
Identification of urotensin II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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2.
Structure of urotensin II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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3.
Urotensin II receptor, GPR14 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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4.
Distribution of urotensin II and GPR14 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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5.
Central actions of urotensin II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Cardiovascular actions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Humoral responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Metabolic changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Behavioral responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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∗
Corresponding author. Tel.: +61 3 83447302; fax: +61 3 93481707. E-mail address:
[email protected] (C.N. May).
0196-9781/$ – see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.peptides.2004.04.016
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6.
Cardiovascular responses to peripheral administration of urotensin II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Vascular actions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Cardiac actions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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7.
Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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8.
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Identification of urotensin II
3. Urotensin II receptor, GPR14
The peptide urotensin II (UII) was first identified in the fish urophysis, a small neurosecretory organ located in the caudal area of the spinal cord. The hypotensive effects of extracts from the goby (Gillichthys mirabilis) urophysis were postulated to be due to urotensin I and effects on smooth muscle (contraction of isolated trout rectum) were attributed to UII [3,13]. The 41 amino acid urotensin I was later found to be a member of the corticotropin-releasing factor (CRF) family [14], and although having some homology to somatostatin, UII did not fit neatly into any pre-existing peptide family group. In various species of fish, UII has been implicated in metabolic, reproductive, osmoregulatory, and cardiovascular regulation [4,6,13,14]. Its role in the regulation of mammalian physiology was discovered well after many of these characteristics had been shown in fish.
The explosion of interest in UII occurred after its receptor was shown to be present in mammals and was identified as the orphaned G-protein coupled receptor 14 (GPR14) [2,34,40,42], also known as sensory epithelium neuropeptide-like receptor (SENR) [49]. Different species forms of GPR14 show high homology, the rat receptor being 75% homologous to the human [2] and 89% homologous to the cow [49]. GPR14 has some homology to other receptors including the somatostatin receptor (sstr4 27%) and opioid receptors (-opioid 25%; ␦- and -opioid 26%), the homology to opioid receptors being greater within the transmembrane domains [37].
2. Structure of urotensin II The structure of UII was first determined from peptide purified from the goby urophysis [43]. It was almost 20 years before the sequence of UII was identified in mammals, the human sequence being determined via the pre-pro UII sequence [16]. Subsequently, UII was found in other mammals including mouse, rat and pig [15,40]. The UII isopeptides are small 11–15-amino acid peptides with the N tail of the peptide varying in amino acid content and length, while the C ring structure is conserved in all species isoforms characterized to date [16,24]. There is evidence that the conserved C cyclic ring portion of the UII isopeptides is essential for biological activity as the C cyclic octapeptide core from goby UII demonstrates full biological activity in rat aorta [29] suggesting that this cyclic region is the biologically active portion of the peptide [24]. It has also been found that human and rat UII isopeptides have almost identical actions on blood pressure and regional blood flows in conscious rats when given intravenously (IV) [25]. Furthermore, competition binding analysis demonstrated equipotent, high-affinity binding of numerous mammalian, amphibian, and piscine UII isopeptides to cloned mouse and monkey UII receptors [24].
4. Distribution of urotensin II and GPR14 UII and its receptor have a wide distribution being found in a variety of different tissues (Table 1). For example, in humans both have been found in the heart [38], kidney [38,47,52], liver (GPR14 in low amounts) [16,52] and in the brain and spinal cord of various species (Table 1). There are some apparent species differences in distribution, for example, GPR14 was found in the pancreas of the mouse and cynomolgus monkey, but not the cow [24,49]. The wide distribution and the close species homologies of UII and its receptor suggest that UII has important functions in both the brain and periphery. The distribution of UII is unusual in that it is found in motor neurons of the spinal cord and motor nuclei in the brain [16,22]. Pre-pro UII also co-localizes with androgen receptors in motor nuclei [44]. Few other neuropeptides are located in motor neurons of the spinal cord [15] and it has been postulated that UII may be involved in sensory–motor integration [12], and/or act as an autocrine modulator of motor neuron firing [7,12,15]. In support of this hypothesis is the finding that human UII has been found to increase miniature endplate potential frequency and amplitude (and hence neurosecretion) at the frog (Rana pipiens) neuromuscular junction [7]. Immunohistochemistry for the UII peptide appears in the neuronal cell soma of the brain and spinal cord [2,10,22], whereas recent evidence shows that GPR14 is located on glial cells within the brainstem, hypothalamus, hippocampus,
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Table 1 Distribution of pre-pro UII, UII and GPR14 in the central nervous system Pre-pro UII
UII
GPR14 (or SENR)
Brain: Abducens nucleus [15]h(R), [44]h(R), [16]h(F) Cerebellum [24]p(C), [15]p(M,R) Cortex [24]p(C) Facial nucleus [15]h(R), [16]h(F), [44]h(R) Glossopharyngeal nucleus [16]h(F) Hypoglossal nucleus [15]h(R), [44]h(R), [16]h(F) Medulla [42]n(H), [15]p,h(R), [16]d(H) Nucleus ambiguous [15]h(R), [44]h(R) Nucleus reticularis inferior [16]h- low (F) Pituitary [16]d (H), [16]p-low(F) Trochlear nucleus [16]h(F) Trigeminal motor nucleus [15]h(R), [44]h(R) Spinal cord: [15]p (M,R), [24]p,s(C), [16]d(H) Motor neurons [16]h(H) Ventral horn [15]h(R), [44]i,h(R), [16]h(F)
Brain: Abducens nucleus [22] i (R) Cerebellum [11] i-fibres(F) Cortex [53]p(H) Facial nucleus [22] i (R) Hypoglossal nucleus[10]i(F),[22]i(R) Hypothalamus [42]m(B), [53]p(H) Medulla [2]n(H), [53]p(H) Nucleus ambiguous [22] i (R) Pituitary [53]p(H) Tectum [11] i-fibres(F) Tegmentum [11] i-fibres (F) Thalamus [11] i-fibres (F) Trigeminal motor nucleus [22] i (R) Vagal dorsal motor nucleus [22]i(R) Spinal cord: [2]n,i (H), [52]p(H), [40]c(P) Caudal motoneurons [11] i (F) Ventral horn [22] i (R), [10] i (F)
Brain: [24]p(M) Abducens nucleus [36]b(R) Accumbens nucleus [26]p(R) Amygdala [26]p(R) Anteroventral thalamus [12]b-low (R) Bed nucleus (stria terminalis) [12]b-low(R) Cerebellum [26]p(R), [49]r(B) Cerebral cortex [36]h(H), [26]p(R), [53]p(H) Choroid plexus [49]r(B) Endopiriform nuclei [12]b-low(R) Hippocampus [33] i (R), [26]p(R) [33] i (R) Hypothalamus [33] i (R), [53]p(H) Interpeduncular nucleus [12]b(R) Lateral dorsal tegmental area [12]h,b(R) Lateral septal nucleus [12]b(R) Medial habenular nucleus [12]b(R) Medial pre-optic nucleus [12]b-low(R) Medulla [26]p(R), [33] i (R), [53]p(H) Parasubiculum [12]b-low(R) Pedunculopontine tegmental area[12]h,b(R) Pituitary [53]p(H) Pons [26]p(R) Pontine nuclei [12]d-low(R) Striatum [26]p-low(R) Substantia nigra [2]p-low (H) Superior occipital gyrus [2]p-low (H) Thalamus [26]p(R), [2]p-low (H), [33] i (R) Ventral lateral geniculate nuclei[12]b-low(R) Ventral tegmental area [12]b-low(R) Spinal cord: [26]p-low (R), [24]p(C),[52]p(H), [34]h(M), [2]p,s(C) Ventral (anterior) horn [34]h(M) Eye: Retina [49]r(B)
Referenced as follows: Reference number (in square brackets), method of analysis (lowercase letter) and species (uppercase letter in brackets). Method of analysis: (b) 125 I-UII binding; (c) cloning of receptor from tissue; (h) in situ hybridisation; (i) immunohistochemistry; (m) cell extract used in calcium mobilisation assay; (n) Northern blot; (p) RT-PCR; (r) RNase protection assay; (s) Southern blot; (d) dot blot. Animal: (B) cow (bovine); (C) cynomolgus monkey; (F) frog; (H) human; (M) mouse; (P) pig; (R) rat.
thalamus [33], as well as motor neurons in the spinal cord [34]. This would suggest a unique modulatory role for UII centrally, possibly influencing neuronal metabolism.
5. Central actions of urotensin II Although there is a large body of data indicating that UII, GPR14, and pre-pro UII are present in the brain and spinal cord of fish [13], tetrapods and humans (Table 1), there are very few studies that have examined the central actions of UII. 5.1. Cardiovascular actions In Rainbow trout (Oncorhynchus mykiss), intracerebroventricular (ICV) administration of UII (50 pmol) caused a slight but significant tachycardia, while a higher dose (500 pmol) significantly increased dorsal aortic blood pressure but did not significantly change heart rate [31].
In normotensive and hypertensive conscious rats, ICV administration of UII (10 nmol) significantly increased mean arterial pressure (MAP) and heart rate [32,33], and greater responses have been found in hypertensive rats [33]. Similarly, in anesthetized rats microinjection of UII into specific areas of the brain, the paraventricular nucleus of the hypothalamus (PVN) and the arcuate nucleus, significantly increased MAP and heart rate [35]. The changes that occurred after ICV UII could be prevented by ganglion blockade, suggesting that they were mediated by the autonomic nervous system [32]. In studies in conscious sheep, we have examined in detail the cardiovascular and endocrine effects of ICV infusion of UII [54]. In sheep it is possible to monitor many cardiovascular variables simultaneously, as well as collecting multiple blood samples. In our study, systemic and regional hemodynamics were monitored before, during, and for 5.5 h after a 1 h ICV infusion of UII or artificial cerebrospinal fluid (aCSF) and blood samples were collected to establish the humoral and metabolic changes. In conscious sheep, ICV infusion of UII (0.2 nmol/kg over 1 h) caused large increases in
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Fig. 1. Cardiovascular changes following a 1 h infusion (0–1 h, dashed lines) of UII (0.2 nmol/kg, open circles) or artificial cerebrospinal fluid (aCSF, closed circles) in conscious sheep. Points at time 0 represent a 1 h control period, and all other points represent half hour means. Mean arterial pressure and heart rate, n = 6, all other variables, n = 5. If there was a significant difference (P ≤ 0.05) between UII and aCSF with a two-way repeated measures ANOVA, a post hoc Bonferroni t test was used to find significant differences at individual time points: (␣) P < 0.001, () P < 0.01, () P≤ 0.05. Reproduced with permission [54].
heart rate and cardiac contractility, which lasted for at least the 5 h that measurements were made. These effects resulted in prolonged increases in cardiac output and MAP (Fig. 1) [54]. These changes were accompanied by a substantial increase in total peripheral conductance, indicating peripheral vasodilatation. The increase in total peripheral conductance resulted from a generalized vasodilatation; blood flows increased in the coronary, mesenteric, renal and iliac vascular beds (Fig. 1) as did the conductances to these vascular beds [54]. The lack of any peripheral vasoconstriction indicates that the increase in MAP resulted from the increased cardiac output. The peripheral vasodilatation seen in the sheep was probably partly baroreflex-induced in response to the increase in arterial pressure. Humoral mechanisms (as discussed below) may also contribute to vasodilatation in specific vascular beds. Interestingly, when human UII is administered ICV it is significantly more potent in sheep than in rats, the highest dose in sheep being 150-fold less (on a per kilogram basis) than that used in rats [32].
5.2. Humoral responses In sheep, concurrent with the cardiovascular changes there were large increases in plasma epinephrine; by 2 h after the commencement of the ICV infusion, plasma epinephrine had increased by 753 ± 166 pg/mL (mean ± SEM) compared to vehicle (Fig. 2). An increase in plasma epinephrine following ICV UII (10 nmol) has also been found to occur in normotensive and hypertensive rats [33]. The increase in circulating levels of epinephrine is probably the cause of the increase in cardiac rate and contractility in sheep, via its action on cardiac -adrenoceptors (Fig. 3). Epinephrine causes skeletal muscle vasodilatation [23] and the increase in this catecholamine in response to ICV UII may account for the iliac vasodilatation that occurred. The mechanism by which ICV administration of UII causes release of epinephrine remains to be determined. Interestingly, this appears to be a selective activation of the adrenal sympathetic nerves, since we found that while plasma epinephrine was significantly elevated following ICV UII,
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there was no significant increase in noradrenaline [54], a finding that has been confirmed in rats following ICV UII [33]. Secretion of epinephrine from the adrenal medulla is known to result from activation of the adrenal sympathetic nerves [23]. A selective stimulation of the adrenal sympathetic nerves occurs in a number of physiological situations, including stress [9], but whether UII is a neurotransmitter or neuromodulator in pathways mediating responses to such stimuli remains to be confirmed. The localization of UII and GPR14 in the medulla oblongata (Table 1) provides the anatomical substrate for a modulatory action of UII on sympathetic outflow, although activation of specific areas related to sympathetic outflow by UII has yet to be shown. Further studies recording sympathetic nerve activity to different vascular beds are required to confirm whether the sympatho-activation caused by ICV UII is selective to the adrenal nerves. ICV infusion of UII in sheep also increased plasma levels of adrenocorticotropic hormone (ACTH) by 14.3 ± 3.5 pmol/L, compared to vehicle (Fig. 2). The increase in ACTH stimulates cortisol release, which we have shown can result in prolonged renal vasodilatation and increased renal blood flow [17]. The UII-induced increase in plasma cortisol may therefore have contributed to the renal vasodilatation in response to ICV UII. It is established that ACTH release is primarily a response to activation of PVN neurons that contain CRF, which in turn stimulate the release of ACTH from the pituitary [46]. The increase in MAP and heart rate following microinjec-
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tion of UII into the PVN [35] lends credence to the idea that UII may be able to stimulate CRF cells in the PVN. In preliminary studies we have found, however, that 100 min after ICV administration of UII (10 g) in conscious rats, PVN sections showed few neurons with immunostaining for both the activation marker c-fos and CRF. Thus, it remains unclear whether the PVN is the main pathway by which UII stimulates ACTH release. Another possible mechanism by which UII could cause ACTH release is via stimulation of vasopressin release, as vasopressin has been shown to augment ACTH release from the pituitary, but it remains to be determined whether UII causes vasopressin release. 5.3. Metabolic changes Following ICV infusion of UII in conscious sheep, plasma glucose increased by 7.0 ± 1.4 mmol/L, compared to vehicle (Fig. 2). The hyperglycemia following ICV UII is probably at least partly due to epinephrine causing increased glycogen breakdown and gluconeogenesis in the liver and skeletal muscle. Cortisol is also capable of causing hyperglycemia, although in sheep this increase in glucose (up to 7 mmol/L) is less than that after ICV UII [39]. It is interesting to note that the hyperglycemia was sustained for at least 4 h after the end of the ICV infusion of UII. This suggests that either elevated plasma epinephrine levels are overriding or impeding glycogenesis, and/or that insulin release or the responses to insulin are in some way impaired. 5.4. Behavioral responses In conscious rats ICV UII has been shown to elicit behavioral changes, including increased rearing, grooming and motor activity [26]. In our study in sheep, we found that during ICV infusion of UII, and for up to an hour after the infusion, sheep scratched their heads vigorously on the sides of their cage, especially around their eye orbit. Concurrent with this, animals tended to squat frequently, as if to urinate. The scratching observed is reminiscent of symptoms seen in patients who can suffer from facial pruritus after being given opiates [50], although the mechanisms causing these symptoms as opposed to those following ICV UII have yet to be determined.
6. Cardiovascular responses to peripheral administration of urotensin II 6.1. Vascular actions
Fig. 2. Changes in plasma epinephrine, glucose (n = 5) and ACTH (n = 6) in conscious sheep following a 1 h infusion (0–1 h, dashed lines) of UII (0.2 nmol/kg, open circles) or artificial cerebrospinal fluid (aCSF, closed circles). Statistics as for Fig. 1. Reproduced with permission [54].
The cardiovascular actions of UII have been examined in a number of in vitro and in vivo systems, sometimes with contrasting responses depending on the species and vessel studied. In mammals, UII was first reported to have a vasoconstrictor action in isolated rat thoracic aorta denuded of endothelium [27], an action that was later shown to be more
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Fig. 3. The cardiovascular and humoral changes following ICV infusion of UII in conscious sheep. Hypothesized changes are marked as dashed lines. Abbreviations: SNA, sympathetic nerve activity. All other abbreviations as in text.
potent than that of endothelin [2]. UII was also shown to cause vasoconstriction in endothelium denuded vessels from various species including cynomolgus monkey thoracic aorta [2], dog coronary artery [19] and human radial artery [36]. The vasoconstrictor action of UII has not, however, been found to be universal. Inconsistent responses have been found between species, between different regions of vasculature within a species, and between the same vascular region from different individuals of the same species. For example, human UII did not constrict mouse, guinea-pig or dog thoracic aorta [8,18,19], rat abdominal aorta, or rat femoral and renal arteries [2]. In marmosets, UII constricted four out of five thoracic aorta preparations and similar inconsistencies have been seen in various vessels from other species [8,19]. Further evidence of diverse vascular actions in response to UII is the finding that it caused vasodilatation in human small pulmonary arteries and abdominal adipose tissue arteries [48]. The cardiovascular responses to UII in vivo are equally variable. In anesthetized rats UII administered IV decreased arterial pressure [28]. In anesthetized cynomolgus monkeys an IV bolus of UII had drastic effects, causing intense vasoconstriction and cardiac arrest [2]. In contrast, in conscious rats IV UII reduced arterial pressure [25,32], the hypotension was associated with mesenteric and hindquarter vasodilatation [25]. Our group has shown that in conscious sheep IV bolus injection of UII (2, 20 and 40 nmol/kg) caused a transient (up to 30 min) increase in MAP followed by a small but
prolonged reduction in MAP [54]. Similarly in humans, IV infusion of UII at a dose which increased plasma levels 100fold failed to result in any cardiovascular changes [1]. Studies of forearm blood flow in healthy human volunteers gave contrasting results with intra-arterial infusion either showing no effect [55] or vasoconstriction [5]. Part of the variation within individuals maybe due to the fact that UII is known to have a high binding affinity, but a low density of receptors in some vessels [30]. It is possible that individual variations in response to UII could be due to slight differential regulation in the trafficking of the UII receptor or levels of its downstream effectors, which could lead to substantial changes in the efficacy of UII. To date, these diverse responses to systemic administration of UII mean that there is no consensus on its role in peripheral cardiovascular control. The finding that circulating levels are altered in certain disease states (see below, UII in Section 7) indicates that it is important to understand the actions and role of UII in cardiovascular control in more detail. The increasing availability of UII antagonists will hopefully make it possible to clarify these issues. 6.2. Cardiac actions IV administration of UII has been shown to cause a decrease in blood pressure and tachycardia in anesthetized and conscious rats [25,28,32]. In conscious sheep, IV UII caused
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a sustained increase in heart rate, the onset of which occurred concurrently with the initial increase in arterial pressure, suggesting that it was not baroreceptor mediated. Receptors for UII are abundantly expressed in the human heart [20], so it is possible that UII could have caused this tachycardia by a direct action on the heart. In anesthetized rats, however, adrenoreceptor blockade prevented the tachycardia after IV UII, suggesting that this response resulted from baroreceptor mediated increases of cardiac sympathetic nerve activity [28], or possibly via epinephrine release. In our studies in conscious sheep, the changes following IV UII differed markedly from those following ICV UII. The only similarity was that heart rate increased with both treatments, but the tachycardia following IV UII was not accompanied by the positive inotropic response that occurred after ICV UII. The different responses to the two routes of administration occurred despite IV UII being delivered as a bolus dose of up to 200 times that given as an ICV infusion. This indicates that the effects seen after ICV UII resulted from direct actions of UII on the CNS, not from non-specific leakage of UII across the blood-brain barrier. 7. Pathology To date there are very few studies that have examined the possible role of UII in disease but there is early evidence that its levels in plasma and CSF are altered in cardiovascular disease. Patients with essential hypertension have levels of UII in cerebrospinal fluid which correlate with arterial pressure, although the levels were not significantly different from normotensive patients [51]. Further evidence supporting a role for UII in essential hypertension is the finding that these patients have a higher urinary excretion of UII [38]. In heart failure, plasma levels of UII are elevated [41,45], although this has not been confirmed by other studies [21]. Other evidence supporting a role for UII in heart failure is the finding that levels of UII message in the heart are elevated in these patients [20]. Whether these changes are primary or secondary to these pathological conditions still remains to be determined. 8. Conclusions While our understanding of UII is rapidly evolving from the first studies conducted in fish, its physiological and pathological roles still remain to be established. It is clear, however, that when administered centrally UII has potent cardiovascular, endocrine and metabolic actions in mammals. The findings that UII stimulates the sympatho-adrenal medullary and pituitary-adrenal-cortex axes, resulting in large and sustained increases in epinephrine and ACTH, suggests that UII may be involved in modulating central endocrine and cardiovascular responses, for example, to stress. The peripheral actions of UII are less clear but the widespread localization of UII and GPR14 indicate that it may have paracrine as well as en-
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docrine actions. The increasing availability of UII antagonists will enhance our ability to determine the physiological and pathophysiological roles of UII in cardiovascular control. Acknowledgments This work was supported by the National Health and Medical Research Council of Australia, Project Grant No. 23212. Figs. 1 and 2 were reproduced with permission from [54]. References [1] Affolter 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;54:617–21. [2] Ames RS, Sarau HM, Chambers JK, Willette RN, Aiyar NV, Romanic AM, et al. Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14. Nature 1999;401:282–6. [3] Bern HA, Lederis K. A reference preparation for the study of active substances in the caudal neurosecretory system of teleosts. J Endocrinol 1969;45, xi–xii. [4] Bern HA, Pearson D, Larson BA, Nishioka RS. Neurohormones from fish tails: the caudal neurosecretory system. I. Urophysiology and the caudal neurosecretory system of fishes. Recent Prog Horm Res 1985;41:533–52. [5] B¨ohm F, Pernow J. Urotensin II evokes potent vasoconstriction in humans in vivo. Br J Pharmacol 2002;135:25–7. [6] Bond H, Winter MJ, Warne JM, McCrohan CR, Balment RJ. Plasma concentrations of arginine vasotocin and urotensin II are reduced following transfer of the euryhaline flounder (Platichthys flesus) from seawater to fresh water. Gen Comp Endocrinol 2002;125:113–20. [7] Brailoiu E, Brailoiu GC, Miyamoto MD, Dun NJ. The vasoactive peptide urotensin II stimulates spontaneous release from frog motor nerve terminals. Br J Pharmacol 2003;138:1580–8. [8] Camarda V, Rizzi A, Calo G, Gendron G, Perron SI, Kostenis E, et al. Effects of human urotensin II in isolated vessels of various species; comparison with other vasoactive agents. Naunyn Schmiedebergs Arch Pharmacol 2002;365:141–9. [9] Carrasco GA, Van de Kar LD. Neuroendocrine pharmacology of stress. Eur J Pharmacol 2003;463:235–72. [10] Chartrel N, Conlon JM, Collin F, Braun B, Waugh D, Vallarino M, et al. Urotensin II in the central nervous system of the frog Rana ridibunda: immunohistochemical localization and biochemical characterization. J Comp Neurol 1996;364:324–39. [11] Chartrel N, Conlon JM, Collin F, Braun B, Waugh D, Vallarino M, et al. Urotensin II in the central nervous system of the frog Rana ridibunda. Biochemical characterization and immunohistochemical localization. Ann NY Acad Sci 1998;839:506–7. [12] Clark SD, Nothacker HP, Wang Z, Saito Y, Leslie FM, Civelli O. The urotensin II receptor is expressed in the cholinergic mesopontine tegmentum of the rat. Brain Res 2001;923:120–7. [13] Conlon JM. Singular contributions of fish neuroendocrinology to mammalian regulatory peptide research. Regul Pept 2000;93:3–12. [14] Conlon JM, Yano K, Waugh D, Hazon N. Distribution and molecular forms of urotensin II and its role in cardiovascular regulation in vertebrates. J Exp Zool 1996;275:226–38. [15] Coulouarn Y, Jegou S, Tostivint H, Vaudry H, Lihrmann I. Cloning, sequence analysis and tissue distribution of the mouse and rat urotensin II precursors. FEBS Lett 1999;457:28–32. [16] Coulouarn Y, Lihrmann I, Jegou S, Anouar Y, Tostivint H, Beauvillain JC, et al. Cloning of the cDNA encoding the urotensin II precursor in frog and human reveals intense expression of the urotensin
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