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Human urotensin-II enhances plasma extravasation in specific vascular districts in Wistar rats Gabrielle Gendron, Bryan Simard, Fernand Gobeil, Jr., Pierre Sirois, Pedro D’Orléans-Juste, and Domenico Regoli
Abstract: Plasma extravasation (PE) was measured in adult Wistar rats by injecting Evans blue dye (EB) (20 mg kg–1) intravenously in the absence or presence of human urotensin II (U-II) (0.1–10 nmol kg–1). A consistent increase of PE was observed in specific organs (e.g., aorta, from 28.1 ± 2.4 to 74.6 ± 3.6 µg EB g–1 dry tissue; P < 0.001) after an administration of 4.0 nmol kg–1 (a preselected optimal dose) of U-II. The effects of U-II (4.0 nmol kg–1) were compared with those of endothelin-1 (ET-1) (1.0 nmol kg–1). In the thoracic aorta and pancreas, U-II was active, while ET-1 was not. The two agents were equivalent in the heart and kidney, whereas, in the duodenum, ET-1 was more active than U-II. Increases of plasma extravasation induced by U-II, but not by ET-1, were reduced after treatment with [Orn8]U-II (0.3 µmol kg–1). This latter antagonist did not show any significant residual agonistic activity in vivo in the rat. Other specific receptor antagonists for ET-1, such as BQ-123 (endothelin type A (ETA) receptor) and BQ-788 (endothelin type B (ETB) receptor), and for the platelet activating factor (PAF), such as BN50730, failed to modify the action of U-II. The present study is the first report describing the modulator roles of U-II on vascular permeability in specific organs. Moreover, the action of U-II appears specific, since it is independent of the ET-1 and PAF signalling pathways. Key words: urotensin-II, receptors antagonists, Evans blue dye, vascular permeability, rats. Résumé : On a mesuré l’extravasation de plasma (EP) chez des rats Wistar adultes en pratiquant une injection intraveineuse de bleu d’Evans (BE) (20 mg kg–1) en l’absence ou en présence d’urotensine II humaine (U-II) (0,1–10 nmol kg–1). Une augmentation constante d’EP a été observée dans des organes précis (p.ex. dans l’aorte, de 28,1 ± 2,4 à 74,6 ± 3,6 µg g–1 tissu sec; P < 0,001) après l’administration de 4,0 nmol kg–1 (une dose optimale présélectionnée) d’U-II. Les effets de l’U-II (4,0 nmol kg–1) ont été comparés avec ceux de l’endothéline-1 (ET-1) (1,0 nmol kg–1). Dans l’aorte thoracique et le pancréas, l’U-II a été active et l’ET-1 inactive. Les deux agents ont eu une activité équivalente dans le cœur et le rein, alors que, dans le duodénum, l’ET-1 a été plus active que l’U-II. Les augmentations d’extravasation de plasma induites par l’U-II, mais pas par l’ET-1, ont été réduites après un traitement par [Orn8]U-II (0,3 µmol kg–1). Cet antagoniste n’a montré aucune activité agoniste résiduelle significative in vivo chez le rat. D’autres antagonistes spécifiques des récepteurs de l’ET-1, tels que BQ-123 (récepteur ETA) et BQ-788 (récepteur ETB), et du facteur d’activation plaquettaire (PAF), tels que BN50730, n’ont pu modifier l’action de l’U-II. La présente étude est la première à décrire les rôles modulateurs de l’U-II sur la perméabilité vasculaire dans des organes précis. De plus, l’action de l’U-II semble spécifique puisqu’elle est indépendante des voies de signalisation de l’ET-1 et du PAF. Mots clés : urotensine-II, antagonistes des récepteurs, colorant bleu d’Evans, perméabilité vasculaire, rats. [Traduit par la Rédaction]
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Introduction The urophysis, an endocrine organ in fish, similar to the mammalian hypothalamo–neurohypophysial axis, contains a number of hormones, among them urotensins I and II. Urotensin-II has been recently found in human and animal tissues (Coulouarn et al. 1998) and shown to be a potent arterial vasoconstrictor in vitro (Gibson 1987; Ames et al. 1999; Camarda et al. 2002a). Human urotensin-II (U-II) is a
cyclic undecapeptide with the following primary structure: Glu1-Thr2-Pro3-Asp4-Cys5-Phe6-Trp7-Lys8-Tyr9-Cys10-Val11, which derives from a larger precursor, preprourotensin II, a peptide of 124 amino acids (Coulouarn et al. 1998). Biological activities of U-II are attributed to the cyclic hexapeptide (Cys5–Cys10), which is highly conserved in all U-II isoforms, from fish to mammals. Human urotensin-II shows high affinity for the UT-II receptor (Ames et al. 1999; Itoh et al. 1988) and acts by inducing a phospholipase-C-dependent
Received 11 August 2003. Published on the NRC Research Press Web site at http://cjpp.nrc.ca on 13 January 2004. G. Gendron, B. Simard, F. Gobeil, Jr., P. Sirois, P. D’Orléans-Juste, and D. Regoli.1 Institute of Pharmacology, Faculty of Medicine, 3001, 12e avenue Nord, Université de Sherbrooke, Sherbrooke, QC J1K 2R1, Canada. 1
Corresponding author (e-mail:
[email protected]).
Can. J. Physiol. Pharmacol. 82: 16–21 (2004)
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doi: 10.1139/Y03-122
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increase of inositol phosphate, which leads to elevation of intracellular calcium and contraction of vascular smooth muscles (e.g., rat aorta) (Saetrum Opgaard et al. 2000; Rossowski et al. 2002). Preprourotensin II mRNA is predominantly expressed in the brain, the spinal cord, and, to a lesser extent, in peripheral tissues such as the kidney, spleen, small intestine, thymus, prostate, pituitary, and adrenal glands (Coulouarn et al.1998). The mRNA for the UT-II receptor has been found in the brain, spinal cord, pancreas and other endocrine organs, skeletal muscle, vascular smooth muscles, endothelia, and cardiomyocytes (Ames et al. 1999; Liu et al. 1999; Clark et al. 2001), where it may contribute to cardiovascular homeostasis in animals (Douglas et al. 2000b) and humans (Douglas et al. 2002). Hemodynamic responses induced by U-II are currently unclear and appear to be highly variable according to the species and (or) organs under investigation. For instance, when injected intravenously in conscious male Sprague– Dawley rats, high doses (0.3–3 nmol kg–1) of human and rat U-II have been shown to exert dilator effects in some vascular arterial districts (mesentery, hind quarter) and to decrease blood pressure (Gardiner et al. 2001). However, no change of systemic blood pressure was observed following i.v. injection of U-II at doses ranging from 0.4–4.0 nmol kg–1 in adult Wistar rats (Gendron et al. 2001). Similarly, in humans, Wilkinson et al. (2002) failed to demonstrate any hemodynamic activity of U-II, while Bohm and Pernow (2002) reported that U-II, given in the brachial artery in humans, acts as a potent vasoconstrictor. In this context, an extensive survey of the cardiovascular effects of U-II in mammals has recently been presented and discussed by Douglas (2003). In the present experiment, we have attempted to evaluate the vascular peripheral effects of U-II indirectly by measuring plasma extravasation (using the conventional Evans blue dye (EB) method) in several organs of Wistar rats, considering the variability of the reported effects of U-II in the cardiovascular system. We also compared the responses of U-II to those of endothelin-1 (ET-1) and used a series of specific antagonists, including [Orn8]U-II, a newly described UT-II receptor antagonist (Camarda et al. 2002b), to delineate the functional sites mediating plasma extravasation by U-II in the rat.
Material and methods Animals Experiments carried out in adult male Wistar rats (300– 350 g body mass) from Charles River were approved by the Ethics Committee of the Medical School in Sherbrooke and were performed in accordance with the principles and guidelines of the Canadian Council on Animal Care. Recording of blood pressure and heart rate In some experiments, the rats were anesthetized with ketamine/xylazine (87/13 mg kg–1 i.m.). Increasing doses of U-II (0.1–100 nmol kg–1) were injected into the jugular vein through a polyethylene catheter. Another cannula was inserted in a carotid artery for direct recording of blood pressure and heart rate with a blood pressure analyser (Micro-
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Med, Louisville, Ky.), as previously reported (Gobeil et al. 1999). Plasma extravasation: experimental protocol Experiments were carried out as described previously (Filep et al. 1992). Briefly, unanesthetised male Wistar rats (300–350 g) were kept in a retention cage. The tail was immersed in hot water (55 °C) to dilate the caudal vein and injected with increasing doses of U-II (0.4, 1.0, 4.0, and 10 nmol kg–1) or ET-1 (0.4 and 1.0 nmol kg–1) together with a bolus of EB dye (20 mg kg–1). Ten minutes later, the animals were killed by cervical dislocation and exsanguination. The thorax was opened, and a cannula was placed into the left ventricle with the tip in the aorta to wash out the EB dye by injecting saline at a flow rate of 10 mL min–1. Thereafter, the aorta, heart, pancreas, duodenum, kidney, lung, and liver were removed and weighed, and half of each organ was put in formamide (4 mL g–1 wet mass tissue) for 24 h, whereas the other half was dried by incubation at 60 °C for 24 h and weighed again. EB dye was extracted from the remaining tissue with formamide (1 mL) and incubated at room temperature for 24 h. EB dye was quantified by measuring the optical density of the formamide extract at 620 nm. Absorbance was compared with a standard curve of 0.05– 25 µg mL–1 EB in formamide. Extravasation is expressed as micrograms of EB per milligram of dry mass tissue. Dose–response curves were performed with U-II (0.1, 0.4, 4.0, and 10 nmol kg–1). ET-1 was applied at 400 pmol kg–1 and 1.0 nmol kg–1 to avoid marked hemodynamic changes occurring with higher doses (Filep et al. 1992). In a first series of experiments, the effects of U-II and ET-1 were measured by applying one of the two agents with EB in the same i.v. injection. In other experiments, antagonists were injected i.v. 5 min before injecting U-II or ET-1 with EB. The antagonists used were as follows: [Orn8]U-II, a new UT-II receptor ligand that shows antagonistic properties (Camarda et al. 2002b); BN50730, a platelet activating factor (PAF) receptor antagonist; BQ-123, a selective endothelin type A (ETA) receptor antagonist; and BQ-778, a selective endothelin type B (ETB) receptor antagonist. The dose of 0.3 µmol kg–1 of [Orn8]U-II was selected as being the most efficient in counteracting U-II in vivo responses and was therefore used in all experiments. Chemical agents EB dye was purchased from Sigma (St. Louis, Mo.); formamide was from Fisher (Montréal, Que.); platelet activating factor (PAF; 1-0-hexadecyl-2-0-acetyl-sn-glycero-3phosphorylcholine) was from Cayman Chemical (Ann Arbor, Michigan); and endothelin-1 (ET-1) and BQ-788 were from American Peptide (Sunnyvale, California). BQ-123 was prepared by W. Neugebauer, Department of Pharmacology, Université de Sherbrooke; U-II and [Orn8]U-II were synthesized by S. Salvadori and R. Guerrini of the Department of Pharmaceutical Sciences of the University of Ferrara, Italy; BN50730 (tetrahydro-4,7,8,10-methyl-1(chloro-2-phenyl)-6 (methoxy-4-phenyl-carbamoyl)-9-pyrido [4′,3′-4,5] thieno [3,2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4), the PAF receptor antagonist, was kindly supplied by the Institute Henri Beaufour, Paris, France. © 2004 NRC Canada
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Fig. 1. Dose–response curves of U-II inducing PE in various organs of adult Wistar rats. Data are expressed as means ± SE of six to nine measurements. *, P < 0.05 versus control; **, P < 0.01 versus control; ***, P < 0.001 versus control.
Statistical analysis The data are expressed as means ± SE of n experiments (number of animals used). Data were analysed statistically with one way ANOVA followed by Tukey’s test for multiple comparisons.
Results Effect of U-II on blood pressure and heart rate In anaesthetized Wistar rats, injections (i.v) of increasing doses (0.1–100 nmol kg–1) of U-II had no effects on blood pressure and heart rate. Average values (from 10 animals) for mean arterial pressure, systolic blood pressure, diastolic blood pressure, and heart rate were 88.9 ± 2.2 mmHg (1 mmHg = 133.322 Pa), 103.6 ± 2.3 mmHg, 74.5 ± 2.7 mmHg, and 280.0 ± 7.4 beats minute–1, respectively. Effects of U-II on plasma extravasation Basal leakage of EB varies from one tissue to another and averages 20–25 µg EB g–1 tissue in the aorta and the pancreas, but reaches 45–60 µg EB g–1 tissue in the heart, kidney cortex, and duodenum. Such fluctuation in basal permeability among organs is not uncommon and has been shown to depend on the degree of vascularization inherent to these organs (Lortie et al. 1994). It should be noted that the albumin-bound EB remaining within the vascular compartment after tissue washout is considered to be negligible (Lortie et al. 1994). Data in Fig. 1 illustrate the changes of plasma extravasation (PE) induced in five organs by increasing doses of U-II. The low dose (0.4 nmol kg–1) was found to be inactive in all tissues. Increases of PE were observed in the aorta and pancreas with 1.0 and 4.0 nmol kg–1: the increase produced by 4.0 nmol kg–1 of U-II was found to be significant in all tissues. Higher doses of U-II (10 nmol kg–1) did not produce any further increase of PE (Fig. 1). Comparison of the effects of U-II and ET-1 The effects of U-II (4.0 nmol kg–1) were compared with those of ET-1 (1.0 nmol kg–1). Results illustrated in Fig. 2 indicate that U-II was able to increase PE in the five tissues,
while ET-1 increased PE only in the heart, kidney cortex, and duodenum. ET-1 is inactive in the aorta and pancreas, while in the heart and kidney cortex, the two agents induce a similar increase of PE. The effect of ET-1 was 35% higher than that of U-II in the duodenum. Characterization of the effect of U-II on plasma extravasation Experiments were undertaken with antagonists to characterize the functional site which mediates the increase of plasma extravasation by U-II. Results shown in Fig. 3 indicate that [Orn8]U-II, given intravenously at a high dose (0.3 µmol kg–1) is devoid of residual agonistic activity in the five tissues investigated. When injected i.v. 5 min before U-II, [Orn8]U-II is able to reduce significantly the increase of PE induced by U-II in the thoracic aorta and the pancreas (Fig. 3) as well as in the heart, abdominal aorta, and duodenum (data not shown). The other antagonists, namely BQ-123 (ETA), BQ-788 (ETB), and BN50730 (PAF receptor), did not modify the changes of PE induced by U-II in all organs (Fig. 3).
Discussion U-II and ET-1 are potent stimulants of rat isolated vessels, especially the aorta (Camarda et al. 2002a). Their contractile effects in vitro are prolonged and stable (Camarda et al. 2002a) and, their hemodynamic effects in vivo show the same characteristics as those of cyclic peptides (e.g., vasopressin), which are partially resistant to degradation by proteases and have a longer duration of action than linear peptides, such as angiotensin II (De Gasparo et al. 2000) and bradykinin (Regoli et Barabé 1980). In rats in vivo, ET-1 is a potent vasoconstrictor and hypertensive agent, while U-II is apparently inactive, but its lack of effect may be the result of opposite effects (vasoconstriction or vasodilatation, in different vascular districts) as proposed by many investigators (MacLean et al. 2000; Katano et al. 2000; Gardiner et al. 2001). In the present study, U-II has been shown to be a potent promoter of plasma extravasation in specific organs of © 2004 NRC Canada
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Fig. 2. Effects of U-II and ET-1 on plasma extravasation in vascular and extravascular tissues of adult Wistar rats. Data are expressed as means ± SE of six to nine measurements. *, P < 0.05 versus control; **, P < 0.01 versus control; ***, P < 0.001 versus control.
Fig. 3. Effects of several receptor antagonists on U-II-induced PE in the thoracic aorta and pancreas of adult Wistar rats. Data are expressed as means ± SE of five to six measurements. ***, P < 0.001 for controls versus U-II-treated animals; ££, P < 0.01 for U-II alone versus U-II plus [Orn8]U-II; £££, P < 0.001 for U-II alone versus U-II plus [Orn8]U-II.
Wistar rats, similarly to ET-1. The results reported in this paper show important differences between the two agents, since U-II is active in the aorta and the pancreas, whereas endothelin acts in the duodenum and the kidney, in accordance with findings by other workers (Sirois et al. 1992; Filep et al. 1993). The action of U-II in the wall of large conductance vessels, especially in the vasa vasorum of the aorta, may be of importance in the context of the overall negative (toxic) roles of this peptide, which has been found (i) to induce systemic vasoconstriction in primates, (ii) to depress myocardial function and evoke cardiac dysfunction probably through a compensatory mechanism in cynomolgus monkeys (Douglas et al. 2000a) and (iii) to evoke local vasoconstriction in humans (Bohm and Pernow 2002). A survey of recent literature indicates that UT-II receptors are expressed (i) in vascular smooth muscle, where it mediates vasoconstriction through increase of intracellular Ca2+ (Saetrum Opgaard et al. 2000; Sauzeau et al. 2001; Ames et al. 1999; Gibson 1987); (ii) in endothelial cells, where it probably promotes the release of NO (also through increase of Ca2+ (Gray et al. 2001; Abdelrahman et Pang 2002)); and
(iii) in peripheral vessels, capillaries, and veinules, where U-II induces increased plasma extravasation (present study). Based on the above-mentioned studies, it appears that the mechanism of action of U-II may be the same in various target cells. In fact, the way by which permeabilization of the endothelium is accomplished is partly due to the formation of intercellular gaps, which allow the passage of macromolecules from blood to the extracellular fluid. Such changes in morphology are possible by the rearrangement of the cytoskeleton, which results from the phosphorylation of the myosin light chains by Ca2+–calmodulin-kinase-activated myosin light chain kinase (Garcia et al. 1997). It is therefore proposed that, upon activation by U-II, UT-II receptors may mediate capillary endothelial and venous smooth muscle contraction (through intracellular Ca2+ accumulation). This leads to the formation of pores in the capillaries and to increases of intracapillary pressure, as suggested by Gabbiani et al. (1970) already in the 70’s and again recently by Farmer et al. (2001). The various functional sites of U-II in the vascular system have been characterized with [Orn8]U-II, a new ligand with © 2004 NRC Canada
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antagonist properties developed in our laboratory (Camarda et al. 2002b). This compound antagonizes U-II (apparent affinity (pA2) = 6.56) in the smooth muscle of the rat aorta devoid of endothelium, but maintains up to 20% of residual agonist activity in vitro (Camarda et al. 2002b). In the present study, however, [Orn8]U-II is devoid of consistent agonist activity (in vivo) and blocks the action of U-II when used at high doses. Moreover, the effects of U-II are not influenced by specific PAF and endothelin ETA and ETB receptor antagonists. These results also suggest that the effect of U-II in the capillary venous district is mediated by a functional site that shows pharmacological characteristics very similar to those found in the aorta (Camarda et al. 2002a). The effect of U-II on capillary vessels appears, therefore, to derive from the activation of a specific receptor and does not require the participation of endogenous endothelins and PAF. Worthy of comment is the strong effect of U-II on plasma extravasation in the wall of large vessels, as demonstrated in the present study. On a chronic basis, such an effect could contribute to alterations of elasticity of the arterial wall and thus reduce aortic compliance (Plante et al. 1999; Asmar et al. 1988). Further studies are needed to demonstrate that such an effect is unique to U-II, and that this agent could be an important pathogenic factor in the remodelling of large vessels in cardiovascular diseases. Results reported in this paper clearly demonstrate for the first time that U-II promotes PE in vivo in selected vascular districts (aorta, pancreas) where ET-1 is inactive. The effect of U-II is markedly reduced or prevented by [Orn8]U-II, a new selective ligand for the UT-II receptor, which does not show consistent residual agonist activity in vivo in the rat. In the present study, [Orn8]U-II was found inactive against ET-1 and thus allows us to affirm that the effect of U-II on PE in rats derives from a specific action mediated by the UT-II receptor. This conclusion is supported also by the inability of ETA, ETB, and PAF receptor antagonists to modify the effect of U-II. Therefore, if U-II appears to play a less important role in the control of vascular tone than other vasoactive factors, this particular peptide may exert more profound effects on microvessels and capillary networks and thus play part in plasma leakage.
Acknowledgements We thank W. Neugebauer for generous supply of the BQ123 and S. Salvadori and R. Guerrini for the gift of U-II and [Orn8]U-II. This project was supported by the Canadian Institutes for Health Research.
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