Serotonin receptor-mediated vasorelaxation occurs primarily through 5-HT₄ activation in bovine lateral saphenous vein

To better understand mechanisms of serotonin- (5-HT) mediated vasorelaxation, isolated lateral saphenous veins from cattle were assessed for vasoactivity using myography in response to increasing concentrations of 5-HT or selective 5-HT receptor agonists. Vessels were pre-contracted with 1 × 10⁻⁴ M phenylephrine and exposed to increasing concentrations of 5-HT or 5-HT receptor agonists that were selective for 5-HT_1B, 5-HT_2B, 5-HT₄, and 5-HT₇. Vasoactive response data were normalized as a percentage of the maximum contractile response induced by the phenylephrine pre-contraction. At 1 × 10⁻⁷ M 5-HT, a relaxation was observed with an 88.7% decrease (p < 0.01) from the phenylephrine maximum. At 1 × 10⁻⁴ M 5-HT, a contraction was observed with a 165% increase (p < 0.01) from the phenylephrine maximum. Increasing concentrations of agonists selective for 5-HT_2B, 5-HT₄, or 5-HT₇ resulted in a 27%, 92%, or 44% (p < 0.01) decrease from the phenylephrine maximum, respectively. Of these 5-HT receptor agonists, the selective 5-HT₄ receptor agonist resulted in the greatest potency (−log EC₅₀) value (6.30) compared with 5-HT_2B and 5-HT₇ receptor agonists (4.21 and 4.66, respectively). To confirm the involvement of 5-HT₄ in 5-HT-mediated vasorelaxation, blood vessels were exposed to either DMSO (solvent control) or a selective 5-HT₄ antagonist (1 × 10⁻⁵ M) for 5-min prior to the phenylephrine pre-contraction and 5-HT additions. Antagonism of the 5-HT₄ receptor attenuated the vasorelaxation caused by 5-HT. Approximately 94% of the vasorelaxation occurring in response to 5-HT could be accounted for through 5-HT₄, providing strong evidence that 5-HT-mediated vasorelaxation occurs through 5-HT₄ activation in bovine peripheral vasculature.