Human urotensin‐II is an endothelium‐dependent vasodilator in rat small arteries

Abstract

1 The possible role of the endothelium in modulating responses to human urotensin-II (U-II) was investigated using isolated segments of rat thoracic aorta, small mesenteric artery, left anterior descending coronary artery and basilar artery. 2 Human U-II was a potent vasoconstrictor of endothelium-intact isolated rat thoracic aorta (EC 50 =3.5+1.1 nM, R max =103+10% of control contraction induced by 60 mM KCl and 1 mM noradrenaline). However the contractile response was not signi®cantly altered by removal of the endothelium or inhibition of nitric oxide synthesis with L-NAME (100 mM). Human U-II did not cause relaxation of noradrenaline-precontracted, endothelium-intact rat aortae. 3 Human U-II contracted endothelium-intact rat isolated left anterior descending coronary arteries (EC 50 =1.3+0.8 nM, R max =20.1+4.9% of control contraction induced by 10 mM 5-HT). The contractile response was signi®cantly enhanced by removal of the endothelium (R max =55.4+16.1%). Moreover, human U-II caused concentration-dependent relaxation of 5-HTprecontracted arteries, which was abolished by L-NAME or removal of the endothelium. 4 No contractile eects of human U-II were found in rat small mesenteric arteries. However the peptide caused potent, concentration-and endothelium-dependent relaxations of methoxamineprecontracted vessels. The relaxant responses were potentiated by L-NAME (300 mM) but abolished in the additional presence of 25 mM KCl (which inhibits the actions of endothelium-derived hyperpolarizing factor). 5 The present study is the ®rst to show that human U-II is a potent endothelium-dependent vasodilator in some rat resistance vessels, and acts through release of EDHF as well as nitric oxide. Our ®ndings have also highlighted clear anatomical dierences in the responses of dierent vascular beds to human U-II which are likely to be important in determining the overall cardiovascular activity of this peptide.

Differential vasoconstrictor activity of human urotensin‐II in vascular tissue isolated from the rat, mouse, dog, pig, marmoset and cynomolgus monkey

“…However, regional and species di erences in the extent of endothelium modulation cannot account for the di erential e ects recorded in the present study since all vessels were denuded of endothelium and studied in the presence of indomethacin. Interestingly, however, not only are signi®cant anatomical di erences observed for the vasoconstrictor activity of U-II, a similar phenomenon has recently been reported to exist with respect to the vasodilator capacity of U-II (Bottrill et al, 2000). In the rat, for example, a spectrum of vesseldependent constrictor/dilator activity can be observed ranging from those preparations which (a) are refractory to U-II (where no constrictor or relaxant response is seen e.g.…”

“…NO, PGI 2 . For example, goby U-II elicits transient endothelium-dependent relaxation in the rat aorta (although, in the rat aorta at least, responses are relatively refactory to endothelial denudation and indomethacin/NDGA; Gibson, 1987;Bottrill et al, 2000). However, regional and species di erences in the extent of endothelium modulation cannot account for the di erential e ects recorded in the present study since all vessels were denuded of endothelium and studied in the presence of indomethacin.…”

“…As such, the identi®cation of novel agonist-GPCR interactions within the cardiovascular system o ers great potential for the development of novel therapeutic modalities. The cloning of the vasoactive cyclic undecapeptide human Urotensin-II (U-II), a selective ligand for the novel serpentine seven transmembrane receptor, GPR14 (Ames et al, 1999), is one such pairing that has met with considerable interest recently (Hare et al, 1999;Davenport & Maguire, 2000;Newby & Jalan, 2000;Gray et al, 2000) since (a) human U-II and GPR14 are both expressed within the vasculature and (b) preliminary pharmacological evaluation indicates that human U-II possesses signi®cant vasoactive properties (Ames et al, 1999;Bottrill et al, 2000;MacLean et al, 2000).GPR14 (Mori et al, 1999;Nothacker et al, 1999). However, in addition to the CNS, U-II is clearly present within the mammalian periphery including the vasculature (cardiac myocytes, coronary atheroma; Ames et al, 1999) and several other peripheral tissues including kidney, adrenal gland, pancreas and liver (Coulouarn et al, 1998;Nothacker et al, 1999).…”

“…rat basilar artery), (b) exhibit mixed dilator/constrictor activity to U-II (rat coronary/mesenteric artery) or (c) only respond to U-II with a contractile response (e.g. absence of goby or human U-II-induced dilation in rat aorta; Bottrill et al, 2000). These regional di erences are further complicated by the fact that the underlying mechanisms also di er between vascular beds (NO versus EDHF).…”

Urotensin‐II regulates intracellular calcium in dissociated rat spinal cord neurons

“…The cyclic peptide has been shown to be a potent vascular constricting and proliferative agent Sauzeau et al 2001), but it also has relaxing properties in resistance arteries (Bottrill et al 2000). In addition, U-II is involved in cardiac remodeling (Zhang et al 2002), acting synergistically with oxidized low-density lipoprotein (LDL; Watanabe et al 2001).…”