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

Authors: TROTTA, RONALD - University Of Kentucky; HARMON, DAVID - University Of Kentucky; Klotz, James

Submitted to: Physiological Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/21/2024
Publication Date: 7/1/2024
Citation: Trotta, R.J., Harmon, D.L., Klotz, J.L. 2024. Serotonin receptor-mediated vasorelaxation occurs primarily through 5-HT4 activation in bovine lateral saphenous vein. Physiological Reports. 12: Article e16128. https://doi.org/10.14814/phy2.16128.
DOI: https://doi.org/10.14814/phy2.16128

Interpretive Summary: Serotonin is a neurotransmitter or signaling molecule. It is involved in a number of different biological functions that range from mood, memory, digestion, blood clotting, and the regulation of the diameter of blood vessels (vasoconstriction or vasodilation). Livestock that graze tall fescue grass can be exposed to toxins called ergot alkaloids that are produced by a fungus that lives in the plant. Ergot alkaloids can bind with serotonin receptors and disrupt their normal function. Our laboratory has characterized the effects that ergot alkaloids and serotonin have on constriction, but not relaxation of blood vessels. There are 14 different serotonin receptors. This study sought to characterize the receptors involved in serotonin-induced relaxation of the bovine lateral saphenous vein. The results clearly show that serotonin can cause both relaxation and contraction of a blood vessel and that the relaxation is primarily caused by the stimulation of serotonin receptor subtype 4. The findings reported in this manuscript will be primarily of interest to other researchers looking to better understand how ergot alkaloids cause the negative effects seen in livestock that consume them.

Technical 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 1x10-4 M phenylephrine and exposed to increasing concentrations of 5-HT or 5-HT receptor agonists that were selective for 5-HT1B, 5-HT2B, 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 1x10-7 M 5-HT, a relaxation was observed with an 88.7% decrease (P < 0.01) from the phenylephrine maximum. At 1x10-4 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-HT2B, 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-HT2B 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 (1x10-5 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.