Serotonin receptor‐mediated vasorelaxation occurs primarily through 5‐HT ₄ activation in bovine lateral saphenous vein

Abstract

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‐HT ₄, and 5‐HT ₇. 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‐HT ₄, or 5‐HT ₇ 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‐HT ₄ receptor agonist resulted in the greatest potency (−log EC ₅₀) value (6.30) compared with 5‐HT _2B and 5‐HT ₇ receptor agonists (4.21 and 4.66, respectively). To confirm the involvement of 5‐HT ₄ in 5‐HT‐mediated vasorelaxation, blood vessels were exposed to either DMSO (solvent control) or a selective 5‐HT ₄ antagonist (1 × 10 ⁻⁵ M) for 5‐min prior to the phenylephrine pre‐contraction and 5‐HT additions. Antagonism of the 5‐HT ₄ 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‐HT ₄, providing strong evidence that 5‐HT‐mediated vasorelaxation occurs through 5‐HT ₄ activation in bovine peripheral vasculature.