Deletion of the UT receptor gene results in the selective loss of urotensin-II contractile activity in aortae isolated from UT receptor knockout mice.
1 Urotensin-II (U-II) is among the most potent mammalian vasoconstrictors identified and may play a role in the aetiology of essential hypertension. Currently, only one mouse U-II receptor (UT) gene has been cloned. It is postulated that this protein is solely responsible for mediating U-II-induced vasoconstriction. 2 This hypothesis has been investigated in the present study, which assessed basal haemodynamics and vascular reactivity to hU-II in wild-type (UT((+/+))) and UT receptor knockout (UT((-/-))) mice. 3 Basal left ventricular end-diastolic and end-systolic volumes/pressures, stroke volumes, mean arterial blood pressures, heart rates, cardiac outputs and ejection fractions in UT((+/+)) mice and in UT((-/-)) mice were similar. 4 Relative to UT((+/+)) mouse isolated thoracic aorta, where hU-II was a potent spasmogen (pEC(50)=8.26+/-0.08) that evoked relatively little vasoconstriction (17+/-2% 60 mM KCl), vessels isolated from UT((-/-)) mice did not respond to hU-II. However, in contrast, the superior mesenteric artery isolated from both the genotypes did not contract in the presence of hU-II. Reactivity to unrelated vasoconstrictors (phenylephrine, endothelin-1, KCl) and endothelium-dependent/independent vasodilator agents (carbachol, sodium nitroprusside) was similar in the aorta and superior mesenteric arteries isolated from both the genotypes. 5 The present study is the first to directly link hU-II-induced vasoconstriction with the UT receptor. Deletion of the UT receptor gene results in loss of hU-II contractile action with no 'nonspecific' alterations in vascular reactivity. However, as might be predicted based on the limited contractile efficacy recorded in vitro, the contribution that hU-II and its receptor make to basal systemic haemodynamics appears to be negligible in this species.
Behm
David J
DJ
Department of Vascular Biology, Cardiovascular and Urogenital Diseases Center of Excellence for Drug Discovery, GlaxoSmithKline, King of Prussia, PA 19406-0939, USA. David_J_Behm@gsk.com
Harrison
Stephen M
SM
Ao
Zhaohui
Z
Maniscalco
Kristeen
K
Pickering
Susan J
SJ
Grau
Evelyn V
EV
Woods
Tina N
TN
Coatney
Robert W
RW
Doe
Christopher P A
CP
Willette
Robert N
RN
Johns
Douglas G
DG
Douglas
Stephen A
SA
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D001835:Body Weight; D018390:Gene Targeting; D005838:Genotype; D006439:Hemodynamics; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D017538:Mesenteric Artery, Superior / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D014579:Urotensins / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D043562:Receptors, G-Protein-Coupled; D014579:Urotensins; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C029677:urotensin II