High plasma concentrations of human urotensin II do not alter local or systemic hemodynamics in man.
OBJECTIVE
Human urotensin II (hUII) is an endocrine hormone that acts as a potent arterial vasoconstrictor in both in vitro and in vivo studies in animals. We examined, for the first time, the local and systemic hemodynamic response to hUII in man in vivo.


METHODS
Four healthy male volunteers took part in pilot studies and 11 in definitive studies. Forearm blood flow (FBF) was measured in response to intra-arterial infusion of authentic, biologically active hUII (incremental rates of 0.001-300 pmol min(-1)) and saline placebo using venous occlusion plethysmography. Blood pressure, heart rate, cardiac output and hUII plasma concentrations were also measured. Forearm studies were repeated in five subjects with inhibition of endothelial mediators using aspirin and a "nitric oxide clamp". Dorsal hand vein diameter was determined by a standard displacement technique in response to local administration of hUII (3-300 pmol min(-1)) with and without nitric oxide synthase inhibition.


RESULTS
There was no significant change in FBF during brachial infusion of saline or hUII (dose range, 0.001 to 300 pmol min(-1)). A nitric oxide clamp did not unmask vasoactive effects of hUII. Human UII infusions (100 and 300 pmol min(-1)) significantly increased plasma hUII concentrations from baseline (12 +/- 3 pmol l(-1)) to 106 +/- 15 and 307 +/- 98 pmol l(-1), respectively. Despite high circulating hUII concentrations, no change was seen in systemic hemodynamics and ECGs were unchanged. Human UII had no effect on hand vein diameter (n=6).


CONCLUSIONS
In contrast to our hypothesised role of hUII, we found no vasoactive responses to hUII in vivo, consistent with recent in vitro studies in human blood vessels, but in contrast to non-human primate studies in vivo. Our data do not support a key role for hUII in the regulation of vascular tone and resting blood pressure in man. However, studies with hUII receptor antagonists are also needed before firm conclusions can be drawn.
Wilkinson
Ian B
IB
Clinical Pharmacology Unit, Department of Medical Sciences, University of Edinburgh, Western General Hospital, Edinburgh EH4 2LH, Scotland, UK.
Affolter
Jonathan T
JT
de Haas
Sanne L
SL
Pellegrini
M Paola
MP
Boyd
Judith
J
Winter
Matthew J
MJ
Balment
Richard J
RJ
Webb
David J
DJ
D000328:Adult; D000704:Analysis of Variance; D001241:Aspirin / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002352:Carrier Proteins / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000037:antagonists & inhibitors; D005542:Forearm / Q000098:blood supply*; D006225:Hand / Q000098:blood supply; D006801:Humans; D007261:Infusions, Intra-Arterial; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010455:Peptides; D010865:Pilot Projects; D010991:Plethysmography; D012039:Regional Blood Flow / Q000187:drug effects; D013931:Thromboxanes / Q000037:antagonists & inhibitors; D014579:Urotensins / Q000097:blood / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014680:Veins; D019323:omega-N-Methylarginine / Q000494:pharmacology
D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D020030:Nitric Oxide Donors; D010455:Peptides; C121720:SNP-1 protein, synthetic; D013931:Thromboxanes; D014579:Urotensins; D014662:Vasoconstrictor Agents; D019323:omega-N-Methylarginine; C029677:urotensin II; D011464:Epoprostenol; D019001:Nitric Oxide Synthase; D001241:Aspirin