Effect of RANTES on Vascular Contractile and Relaxant Responses in Rat Carotid Arteries

Although regulated-upon-activation normal T-cell expressed and secreted (RANTES), a chemokine originally identified as a T-cell-specific gene product, has been shown to influence various cellular processes, its effects on vascular reactivity remain unclear. Therefore, we investigated the direct effects of prolonged RANTES exposure on responses to various vasoactive agents in isolated rat carotid arteries. Contractile responses to serotonin, isotonic high K⁺, noradrenaline, the thromboxane A₂ analog U46619, and endothelin-1 were similar between the control and RANTES-treated groups (100 ng/mL for approximately 24 h). However, RANTES treatment impaired acetylcholine-induced relaxation, whereas relaxations induced by the nitric oxide donor sodium nitroprusside, the ATP-sensitive potassium channel activator cromakalim, and the large-conductance calcium-activated potassium channel activator NS19504 were unaffected. Acute incubation with the nitric oxide synthase inhibitor N^G-nitro-l-arginine abolished acetylcholine-induced relaxation and eliminated the differences between the control and RANTES-treated groups. Furthermore, the cyclooxygenase inhibitor indomethacin also abolished the differences in acetylcholine-induced relaxation between the 2 groups. Co-treatment with the antioxidant N-acetyl-l-cysteine enhanced acetylcholine-induced relaxation in the presence of RANTES, while co-treatment with the C-C motif chemokine receptor 5 antagonist maraviroc slightly improved the relaxation response. These findings suggest that RANTES impairs acetylcholine-induced relaxation, likely due to the reduction of nitric oxide bioavailability and the unmasking of vasoconstrictor prostanoids through increased reactive oxygen species.