Serotonin can stimulate vasorelaxation in ovine lateral saphenous veins precontracted with ergovaline

Authors: Klotz, James; CHECURA, CELINA - Clemson University; GREENE, MASLYN - Clemson University; JI, HUIHUA - University Of Kentucky; DUCKETT, SUSAN - Clemson University

Submitted to: Journal of Animal Science
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/31/2025
Publication Date: 4/15/2025
Citation: Klotz, J.L., Checura, C.M., Greene, M.A., Ji, H., Duckett, S.K. 2025. Serotonin can stimulate vasorelaxation in ovine lateral saphenous veins precontracted with ergovaline. Journal of Animal Science. 103. Article skaf108. https://doi.org/10.1093/jas/skaf108.
DOI: https://doi.org/10.1093/jas/skaf108

Interpretive Summary: Serotonin is a neurotransmitter that can be found in all of the major organ systems and has roles in numerous physiological processes throughout the body ranging from learning, memory, mood, sleep, appetite, gastrointestinal motility and cardiovascular function. It is able to achieve this "jack of all trades" potential in part due to the variety of different serotonin receptors that exist throughout the body. Ergot alkaloids are toxins that can be found in forages and cereal grains that livestock consume. Livestock that are exposed to these toxins can develop an illness generally referred to as ergotism. Ergot alkaloids can also bind to serotonin receptors and disrupt their normal function. One of the symptoms of ergotism associated with serotonin receptor interference is a chronic vasoconstriction where the lumen (were the blood flows) of blood vessels shrinks and limits blood flow. This study sought to understand how serotonin regulates vascular tone in sheep lateral saphenous veins and arteries and how this is influenced by the ergot alkaloid ergovaline. Blood vessels were precontracted with a chemical that causes vasoconstriction and it was found that serotonin caused further contraction in the artery, but resulted in substantial relaxation in the vein. This relaxation occurred also when veins were precontracted with the ergot alkaloid ergovaline. One specific serotonin receptor was identified as responsible for this relaxation and its function was not influenced by the presence of ergovaline. This is a very significant finding. This is the first report of direct observation of relaxation of a blood vessel that was previously exposed to ergovaline. This work will open the door to numerous lines of research that will have the potential to develop mitigation solutions for fescue toxicosis and many different forms of ergotism around the world. While this work primarily benefits other researchers, it is only a step away from benefiting livestock producers.

Technical Abstract: Herbivores that consume ergot alkaloids frequently suffer from vasoconstriction that can result in a myriad of symptoms that can range from necrosis of peripheral tissues to fetal intra-uterine growth restriction. The ergot alkaloid ergovaline is a potent vasoconstrictor. Previous research has shown that ergovaline can bind serotonin (5-HT) receptors. Three experiments were conducted to evaluate 5-HT as vasorelaxant in the ovine saphenous artery and vein. Blood vessels were collected from mixed breed market lambs (n = 23) at slaughter, cleaned of surrounding adipose and connective tissue, sliced into 2-mm cross-sections, and mounted in a multimyograph. Experiment 1: artery and vein cross-sections were precontracted with 0.0001 M phenylephrine for 15 min, exposed to concentrations of 5-HT that ranged from 1x10-9 to 1x10-4 M for a 5-min interval. Response data were normalized to the 0.0001 M phenylephrine response and were analyzed as a completely randomized design in SAS. The lateral saphenous vein (n = 5 lambs) relaxed to increasing concentrations of 5-HT (P < 0.05) with 65 – 75 % relaxation occurring at 1x10-7 M through 1x10-4 5-HT. Conversely, the lateral saphenous artery (n = 6 lambs) contracted in response to increasing concentrations of 5-HT (P < 0.05) resulting in a 255% increase from the phenylephrine response by the 1x10-4 M addition. Experiment 2: saphenous veins from additional lambs (n = 5) were treated the same, but in place of increasing concentrations of 5-HT, saphenous veins were exposed to increasing concentrations of selective 5-HT receptor agonists to determine the receptor subtypes involved in the previously observed vasorelaxation. Agonists for receptors 5-HT2B (BW 723C86), 5-HT4 (BIMU-8), and 5-HT7 (LP44) were used. While all three 5-HT receptor subtypes resulted in vasorelaxation (P < 0.05), the 5-HT2B agonist only stimulated a maximal relaxation of 32% compared to the agonists for 5-HT4 and 5-HT7 that resulted in maximal relaxation of 68% and 50%, respectively. Experiment 3: saphenous arteries and veins were collected from market rams (n = 7) and precontracted with 1.0 'M ergovaline for 30 min. The lateral saphenous vein relaxed to increasing concentrations of 5-HT (P < 0.05) with 87 % relaxation occurring by 1 x 10-6 M 5-HT. Conversely, the lateral saphenous artery contracted in response to increasing concentrations of 5-HT (P < 0.05) resulting in a 43% increase from the ergovaline response by the 1 x 10-4 M addition. The differing responses across vessel are likely a result of different receptor populations and this should be verified in future research. This is the first reported observation of stimulated relaxation of a blood vessel constricted by ergovaline. The agonist for 5-HT4 produced the greatest relaxation in the ovine lateral saphenous vein, does not appear to be antagonized by ergovaline, and should be targeted in subsequent research focused on mitigation of ergot alkaloid-induced vasoconstriction.