Differential effect of urotensin II on vascular tone in normal subjects and patients with chronic heart failure.
BACKGROUND
Urotensin II (U-II) is a novel vasoactive peptide that also has direct hypertrophic and profibrotic effects on the myocardium. Upregulation of U-II and its receptor has been observed within the heart of patients with chronic heart failure (CHF). Furthermore, plasma levels of U-II have been found to be elevated in some but not all studies in such patients. However, the functional consequences of activation of the U-II system in patients with CHF, assessed by direct administration of exogenous U-II, have not been previously determined.


RESULTS
We compared the effect of iontophoresed U-II on skin microvascular tone in normal subjects and patients with CHF, assessed with the use of laser Doppler velocimetry. U-II mediated a dose-dependent vasodilator response in normal subjects (baseline, 137.9+/-52; U-II, 10(-12) mol/L, 145+/-134; U-II, 10(-9) mol/L, 712+/-179; U-II, 10(-7) mol/L, 943+/-139 arbitrary flux units [AFUs], P<0.0001). In contrast, a dose-dependent vasoconstrictor response was observed in patients with CHF (baseline, 336.1+/-129; U-II, 10(-12) mol/L, 317+/-131; U-II, 10(-9) mol/L, 129+/-137; U-II, 10(-7) mol/L, 22.4+/-130 AFUs, P<0.05). Differences in flow between normal subjects and patients with CHF were significant overall (P<0.001, 2-way ANOVA) and at the U-II 10(-9) mol/L and U-II 10(-7) mol/L dose level by Student's unpaired t test (P<0.05, P<0.0001, respectively). In contrast, there was no significant difference between baseline blood flux and any dose of U-II in either group (or between groups) when the opposite polarity was applied.


CONCLUSIONS
In addition to direct effects on the myocardium, U-II may contribute to the increased peripheral vascular tone that is characteristic of human CHF. The present observations support the contention that the U-II system may be a potentially important target for pharmacological blockade in the treatment of this condition.
National Health and Medical Research Council of Australia Centre of Clinical Research Excellence in Therapeutics, Monash University, Alfred Hospital, Melbourne, Victoria, Australia.
Melissa
M
Lim
Suzy
S
Honisett
Christopher D
CD
Sparkes
Paul
P
Komesaroff
Andrew
A
Kompa
Henry
H
Krum
D000109:Acetylcholine / Q000494:pharmacology; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects; D005260:Female; D006333:Heart Failure / Q000503:physiopathology*; D006801:Humans; D007478:Iontophoresis; D017078:Laser-Doppler Flowmetry; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009599:Nitroprusside / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000502:physiology; D012867:Skin / Q000098:blood supply; D014579:Urotensins / Q000008:administration & dosage / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*
D043562:Receptors, G-Protein-Coupled; C121697:UTS2R protein, human; D014579:Urotensins; D014665:Vasodilator Agents; D009599:Nitroprusside; C029677:urotensin II; D000109:Acetylcholine