Discovery of GS-biased 5-HT7 receptor agonists for treatment of Hypertension

This project investigates whether β-arrestin-biased signaling through the 5-hydroxytryptamine 7 (5-HT7) receptor mediates vascular relaxation and hypotension. The 5-HT7 receptor is known to be necessary for serotonin (5-HT) to cause concentration-dependent vascular relaxation and reductions in blood pressure, and the receptor can signal through either Gs protein pathways or β-arrestin-dependent pathways. Using the β-arrestin, selective 5-HT7 receptor agonist serodolin, Watts and team tested the specific hypothesis that activation of 5-HT7 via the β-arrestin pathway is responsible for vasorelaxation and hypotension.

Their experimental approach combined isolated tissue isometric contractility studies with in vivo anesthetized rat infusions. Isolated abdominal aorta (reported to lack functional 5-HT7) and vena cava (reported to have functional 5-HT7) from male Sprague Dawley rats were employed. Serodolin was applied across a concentration range (1 nM–10 μM) to assess effects on baseline tone and on tissues contracted with endothelin-1 (ET-1) or norepinephrine. In isolated tissues, serodolin did not alter baseline tone and failed to relax ET-1, contracted vena cava or aorta. In the abdominal aorta serodolin produced a rightward shift in the 5-HT–induced concentration, response curve consistent with 5-HT2A receptor antagonism. In the vena cava serodolin behaved functionally as a 5-HT7 receptor antagonist, shifting the 5-HT concentration, response curve left and upward and blocking relaxation to the mixed 5-HT1A/7 agonist 5-carboxamidotryptamine.

Complementing the in vitro work, the investigators infused 5-HT or serodolin intravenously into anesthetized male Sprague Dawley rats at 5, 25, and 75 μg/kg/min. Whereas 5-HT produced concentration-dependent depressor (blood pressure–lowering) responses, serodolin elicited only small, statistically insignificant depressor effects at all infusion rates. Importantly, when serodolin was present at the final infusion dose, subsequent 5-HT infusion was unable to reduce blood pressure, supporting the interpretation that serodolin blocks 5-HT–mediated hypotensive effects rather than mimicking them via β-arrestin signaling.

Collectively, the data lead Watts and colleagues to conclude that serodolin functions as a 5-HT7 antagonist with additional 5-HT2A blocking properties and does not produce vascular relaxation or hypotension through β-arrestin–dependent 5-HT7 receptor signaling. These findings indicate that β-arrestin–biased activation of 5-HT7 is not the pathway responsible for serotonin-induced vasorelaxation and hypotension in the models tested. The study clarifies the signaling mechanisms underlying 5-HT7 effects on vascular tone and blood pressure and suggests that therapeutic strategies targeting Gs-mediated 5-HT7 signaling, rather than β-arrestin-biased agonists like serodolin, may be more relevant for modulating vascular relaxation and hypotensive responses. The authors declare no competing financial interests or personal relationships influencing the reported work.