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.
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 humanCHF. 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.
Authors: S J Gold; J P Thompson; J P Williams; E E F Helm; J Sadler; W Song; L L Ng; D G Lambert Journal: Eur J Clin Pharmacol Date: 2007-01-25 Impact factor: 2.953
Authors: Ari Mosenkis; Radhakrishna R Kallem; Theodore M Danoff; Nambi Aiyar; Jonathan Bazeley; Raymond R Townsend Journal: Nephrol Dial Transplant Date: 2010-07-09 Impact factor: 5.992
Authors: David J Behm; Gerald Stankus; Christopher P A Doe; Robert N Willette; Henry M Sarau; James J Foley; Dulcie B Schmidt; Parvathi Nuthulaganti; James A Fornwald; Robert S Ames; David G Lambert; Girolamo Calo'; Valeria Camarda; Nambi V Aiyar; Stephen A Douglas Journal: Br J Pharmacol Date: 2006-05 Impact factor: 8.739