Urotensin II alters vascular reactivity in animals subjected to volume overload

Congestive heart failure (CHF) alters vascular reactivity and up regulates in urotensin II (UTII), a potent vasoactive peptide. The aim of this study was to investigate the interaction between CHF and UTII in altering vascular reactivity in a rat model of volume overload heart failure. Animals were divided into 4 groups: control, UTII infused (UTII), volume overload only (VO) or volume overload + UTII (VO + UTII). Volume overload was established by the formation of an aortocaval fistula. Following fistula formation animals were administered UTII at a rate of 300 pmol/kg/h for 4 weeks subcutaneously with mini-osmotic pumps. Thoracic aorta rings, with/without endothelium, were subjected to cumulative dose–responses to phenylephrine, sodium nitroprusside (SNP), acetylcholine (ACH), UTII, and the Rho-kinase inhibitor HA-1077. Aortas from VO animals exhibited increased sensitivity to phenylephrine and UTII with a decreased relaxation response to ACH and HA-1077. Aortas from animals subjected to chronic UTII with volume overload (VO + UTII) retained their sensitivity to phenylephrine and UTII while they improved their relaxation to HA-1077 but not ACH. The constrictive response to UTII was dose-dependent and augmented at concentrations <0.01 μM in VO animals. The changes in vascular reactivity paralleled an elevation of both the UTII and α1A-adrenergic receptor while the Rho and Rho-kinase signalling proteins were diminished. We found that volume overload increased sensitivity to the vasoconstrictor agents that was inversely related to changes in the Rho-kinase expression. The addition of UTII with VO reversed the constrictive vascular response through alterations in the Rho-kinase signalling pathway.

Research highlights▶ Volume overload alters vascular reactivity and up regulates urotensin II. ▶ Changes in thoracic aorta reactivity were sensitive to Rho-kinase inhibition. ▶ Sensitivity changes were opposite of UTII receptor or Rho-kinase protein expression.