Differential vasoconstrictor activity of human urotensin-II in vascular tissue isolated from the rat, mouse, dog, pig, marmoset and cynomolgus monkey.
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 profile of this cyclic undecapeptide in different 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: -log[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 -log[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 (-log[EC(50)] <6.50). These findings were further contrasted by the observation that U-II was a 'coronary-selective' spasmogen in the dog (-log[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 (-log[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, significant differences in reproducibility and vasoconstrictor efficacy 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, efficacious vasoconstrictor of a variety of mammalian vascular tissues. Although significant species/anatomical variations exist, the data support the hypothesis that U-II influences the physiological regulation of mammalian cardiovascular function.
Douglas
S A
SA
Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406-0939, USA. steve_douglas-1@sbphrd.com
Sulpizio
A C
AC
Piercy
V
V
Sarau
H M
HM
Ames
R S
RS
Aiyar
N V
NV
Ohlstein
E H
EH
Willette
R N
RN
D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000502:physiology; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D001158:Arteries / Q000187:drug effects / Q000502:physiology; D001808:Blood Vessels / Q000187:drug effects* / Q000502:physiology; D002144:Callithrix; D002339:Carotid Arteries / Q000187:drug effects / Q000502:physiology; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005263:Femoral Artery / Q000187:drug effects / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D011667:Pulmonary Veins / Q000187:drug effects / Q000502:physiology; D051381:Rats; D013552:Swine; D014132:Trachea / Q000187:drug effects / Q000502:physiology; D014579:Urotensins / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014680:Veins / Q000187:drug effects / Q000502:physiology
D014579:Urotensins; D014662:Vasoconstrictor Agents; C029677:urotensin II