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RESEARCH PRODUCT

Relaxation by urocortin of human saphenous veins

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Urocortin, an endogenous peptide structurally related to corticotropin-releasing factor (CRF), has potent cardiovascular effects, suggesting that it may be of significance in cardiovascular regulation. The objective of this study was to analyse the effects of urocortin and its action mechanisms on human blood vessels. To this, 3 mm long segments from human saphenous veins were prepared for isometric tension recording in an organ bath. In the segments at basal resting tone, urocortin did not produce any effect, but in the segments precontracted with endothelin-1 (1 – 10 nM), urocortin (1 pM – 10 nM) produced concentration-dependent relaxation. This relaxation was not modified by the inhibitor of nitric oxide synthase NG-nitro-L-arginine methyl ester (L-NAME, 100 μM), but it was potentiated by the cyclo-oxygenase inhibitor meclofenamate (10 μM) and it was reduced by the inhibitors of high-conductance Ca2+-dependent potassium channels tetraethylammonium (TEA, 10 mM) and charybdotoxin (100 nM). These results indicate that human saphenous veins are very sensitive to urocortin, which produces vascular relaxation by a mechanism independent of nitric oxide and dependent of high-conductance Ca2+-dependent potassium channels, and that it may be opposed by the release of vasoconstrictor prostanoids. Therefore, urocortin may be of significance for regulation of the venous circulation in humans. Keywords: Ion channels, peptides, prostaglandins, vasodilation, veins Introduction Urocortin is a recently isolated 40 amino acid peptide, which has a high degree of structural homology with corticotropin-releasing factor (CRF), and belongs to a group of structurally related peptides which includes, in addition to urocortin and CRF, fish urotensin I and amphibian sauvagine (Parkes & May, 2000). CRF and urocortin may act as neurotransmitters in the central nervous system and may also act on peripheral tissues, particularly in the cardiovascular system. These peptides produce potent effects on the cardiovascular system when administered both intravenously or directly into the central nervous system (Parkes & May, 2000; Parkes et al., 2001). It has been observed that the effects of intravenous urocortin are more potent than those of CRF, probably because the affinity of urocortin is higher than that of CRF for the subtype of CRF – R2β receptors (Vaughan et al., 1995), which are expressed in peripheral tissues (Perrin et al., 1995). Moreover, urocortin mRNA is expressed in smooth muscle cells of blood vessels and in cardiac myocites (Parkes & May, 2000). Because of that, it has been suggested that urocortin may be the endogenous CRF-like peptide that binds to cardiovascular receptors and mediates their cardiocirculatory effects (Parkes et al., 2001). In rats, intravenous urocortin produce potent and long lasting hypotension which might be due to systemic vasodilation, and tachycardia, probably in part baroreflex mediated (Vaughan et al., 1995). Indeed, it has been shown that this peptide produces relaxation of rat basilar arteries (Schilling et al., 1998) and of rat coronary circulation (Terui et al., 2001). In mice, urocotin also produces hypotension, which is abolished in knockout mice with the CRF – R2 receptor subtype inactivated (Bale et al., 2000; Coste et al., 2000). Interestingly, these knockout mice have elevated resting blood pressure, suggesting that activation of CRF – R2 receptors may play a role in regulation of basal vascular tone (Coste et al., 2000). However, there may exist species differences in the vascular effects of urocortin, as in sheep this peptide increases systemic blood pressure, in addition to increasing cardiac contractility (Parkes et al., 1997). All these observations have aroused the interest for the possible role of urocortin in cardiovascular regulation. In addition, urocortin is produced in human hearts, and it increases in failing hearts (Nishikimi et al., 2000), suggesting that this peptide could be involved in human cardiovascular regulation under normal and pathologic conditions. Considering that there is marked species variability in the cardiovascular effects of urocortin, these effects should be also studied in human tissues before the results obtained in animals can be extrapolated to humans. To our knowledge, there is only one study analysing the response to urocortin in human blood vessels, this study shows that this peptide produces dilatation of human perfused placenta (Leitch et al., 1998). Therefore, the objective of our study was to analyse the effects of urocortin on human blood vessels, using segments from human saphenous veins. The role of nitric oxide, prostanoids and potassium channels in the vascular effects of urocortin were also examined.