Published Online
on March 8, 2004

A more recent version of this article appeared on March 16, 2004

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Submitted on October 23, 2003
Revised on January 22, 2004
Accepted on January 27, 2004

Differential Effect of Urotensin II on Vascular Tone in Normal Subjects and Patients With Chronic Heart Failure

Melissa Lim BBiomedSc, Suzy Honisett BSc, PhD, Christopher D. Sparkes BBiomedSc, Paul Komesaroff MBBS, PhD, FRACP, Andrew Kompa BSc, PhD, and Henry Krum MBBS, PhD, FRACP^*

From the National Health and Medical Research Council of Australia Centre of Clinical Research Excellence in Therapeutics (M.L., C.D.S., A.K., H.K.) and the Department of Medicine (S.H., P.K.), Monash University, Alfred Hospital, Melbourne, Victoria 3004, Australia.

^* To whom correspondence should be addressed. E-mail: henry.krum{at}med.monash.edu.au.

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.

Methods and 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.

Key words: peptides • heart failure • vasculature • ions • endothelium

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