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

Abstract

1 Urotensin-II (U-II) and its G-protein-coupled receptor, GPR14, are expressed within mammalian cardiac and peripheral vascular tissue and, as such, may regulate mammalian cardiovascular function. The present study details the vasoconstrictor pro®le of this cyclic undecapeptide in di erent vascular tissues isolated from a diverse range of mammalian species (rats, mice, dogs, pigs, marmosets and cynomolgus monkeys). 2 The vasoconstrictor activity of human U-II was dependent upon the anatomical origin of the vessel studied and the species from which it was isolated. In the rat, constrictor responses were most pronounced in thoracic aortae and carotid arteries: 7log[EC 50 ]s 9.09+0.19 and 8.84+0.21, R max s 143+21 and 67+26% 60 mM KCl, respectively (compared, for example, to 7log[EC 50 ] 7.90+0.11 and R max 142+12% 60 mM KCl for endothelin-1 [ET-1] in thoracic aortae). Responses were, however, absent in mice aortae (7log [EC 50 ] 56.50). These ®ndings were further contrasted by the observation that U-II was a`coronary-selective' spasmogen in the dog (7log [EC 50 ] 9.46+0.11, R max 109+23% 60 mM KCl in LCX coronary artery), yet exhibited a broad spectrum of vasoconstrictor activity in arterial tissue from Old World monkeys (7log [EC 50 ]s range from 8.96+0.15 to 9.92+0.13, R max s from 43+16 to 527+135% 60 mM KCl). Interestingly, signi®cant di erences in reproducibility and vasoconstrictor e cacy were seen in tissue from pigs and New World primates (vessels which responded to noradrenaline, phenylephrine, KCl or ET-1 consistently). 3 Thus, human U-II is a potent, e cacious vasoconstrictor of a variety of mammalian vascular tissues. Although signi®cant species/anatomical variations exist, the data support the hypothesis that U-II in¯uences the physiological regulation of mammalian cardiovascular function. British Journal of Pharmacology (2000) 131, 1262 ± 1274 Keywords: Urotensin-II; GPR14; SENR; endothelin-1; somatostatin; vascular reactivity; spasmogen; coronary artery; endothelium; vasoconstriction Abbreviations: FLIPR,¯uorescent imaging plate reader; GPCR, guanosine triphosphate-binding protein [G-protein]-coupled receptor; LAD coronary artery, left anterior descending coronary artery; LCX, left circum¯ex coronary artery; SENR, sensory epithelial neuropeptide-like receptor; U-II, Urotensin-II IntroductionThe integrated control of cardiovascular homeostasis is achieved through a combination of direct neuronal control and systemic activation of the neurohumoral axis. The principal mammalian vasoactive factors of this axis (angiotensin-II, endothelin [ET]-1, noradrenaline) exert their haemodynamic e ects exclusively via interactions with speci®c seven transmembrane heterotrimeric G-protein-coupled receptors (GPCRs). Drugs which antagonize such interactions constitute one of the most successful classes of therapeutic agents identi®ed to date (Stadel et al., 1997; Wilson et al., 1998). Nowhere is this more evident than within the vasculature where numerous agents have been developed successfully for the clinical ...

Urotensin II is a New Chemotactic Factor for UT Receptor-Expressing Monocytes

“…Expression of U-II and UT receptor has been reported in kidney, CNS, and in the cardiovascular system (10 -14). Pharmacological studies have shown that U-II exerts potent vasoactive activity in different mammal species, including humans and rats (13,(15)(16)(17)(18)(19). The contractile activity of U-II is mediated by the activation the small GTPase RhoA and its effector, Rho kinase (20).…”

Expression of urotensin II and its receptor in human lung adenocarcinoma A549 cells and the effect of urotensin II on lung adenocarcinoma growth in vitro and in vivo

“…It has been shown that UII is an endogenous ligand for the orphan G protein-coupled receptor GRP14 (5), which is now termed as urotensin II receptor (UT-R) (6). UII has been demonstrated to exert a profound vascular effect including vasoconstrictor activity (5,7,8) and vasodilator activity (9,10) dependent on the anatomic sites and the species studied. In addition, UII has a positive inotropic effect (11) and stimulates the proliferation of vascular smooth muscle cells (12)(13)(14).…”

Depressor and regionally‐selective vasodilator effects of human and rat urotensin II in conscious rats

“…Ames et al (1999) described potent vasoconstrictor activity of human U-II in arterial, but not venous, preparations from a wide range of vascular territories in cynomolgus monkeys, whereas the vasoconstrictor activity, in preparations from rats, was restricted to the thoracic aorta. Marked species dierences, and regional variations in the vasoconstrictor eects of human U-II, have since been shown by others (Bottrill et al, 2000;Douglas et al, 2000;Maclean et al, 2000;Maguire et al, 2000). Vascular contractions induced by human U-II are described as being slow in onset, sustained and resistant to washout, and the potency of human U-II to cause constriction is generally found to be either greater than, or equal to, that of endothelin.…”

“…Douglas et al (2000) alluded to unpublished observations showing the lack of systemic pressor responses to human U-II in anaesthetized or pithed rats, but clearly, as stated by Bottrill et al (2000), the marked regional variations in the vascular responses to U-II make it dicult to interpret data restricted to measurements of blood pressure. Therefore, the aim of the present study was to establish the regional haemodynamic eects of human U-II in conscious, freely-moving rats.…”