Abstract P306: Beta-arrestin Biased Signaling Is Not Necessary For The Hypotensive Actions Of 5-HT 7 Receptor Stimulation: Use Of Serodolin

Abstract

The 5-hydroxytryptamine 7 receptor (5-HT7) is necessary for 5-HT to cause a concentration-dependent vascular relaxation and hypotension. 5-HT 7 is recognized as having biased signaling, transduced through either Gs or β-arrestin. It is unknown whether 5-HT 7 signals in a biased manner to cause relaxation/hypotension. This is important to know to maximize therapeutic effects of 5-HT 7 receptor stimulation. Here, we used the recently described β-arrestin selective 5-HT 7 receptor agonist serodolin to test the hypothesis that 5-HT 7 activation does not cause vascular relaxation or hypotension via the β-arrestin. Abdominal aorta (no functional 5-HT 7 ) and vena cava (functional 5-HT 7 ) from male Sprague Dawley rats were used in isometric contractility studies. Serodolin (1 nM - 10 uM) did not change baseline tone of either vessel when compared to vehicle control, and was unable to relax the endothelin-1 (ET-1) contracted vena cava or aorta. In the aorta, serodolin acted as a 5-HT 2A receptor antagonist, evidenced by a rightward shift in 5-HT-induced concentration response curve (pEC 50 5-HT [M]: Veh = 5.2±0.15; 100 nM Ser = 4.49±0.08). In the vena cava, serodolin acted as a 5-HT 7 receptor antagonist, by 1) shifting concentration response curve to 5-HT left and upward [% 10 uM NE contraction; Veh = 3.2±1.7; Ser (10 nM) = 58±11%; p< 0.05] and blocking relaxation of the contracted tissue to the 5-HT 1A/7 agonist 5-carboxamidotryptamine. Studies were conducted in vivo in normotensive male rats under isoflurane anesthesia. 5-HT or serodolin were infused at 5, 25 and 75 ug/kg/min, iv). 5-HT caused concentration-dependent depressor responses at the two lowest infusion rates (5-HT 7 -mediated), and pressor responses at the highest infusion rate (5-HT 2A- mediated). Serodolin caused only small depressor responses at all three infusion rates. In another group of animals serodolin was given at a dose of 1 ug/kg, sc. Over one hour, basal blood pressure was unaffected; subsequent infusion of 5-HT caused minimal changes in blood pressure. Collectively the data indicate that serodolin functions as a 5-HT 7 antagonist with additional 5-HT 2A blocking properties and that 5-HT 7 activation does not cause vascular relaxation or hypotension via the β-arrestin pathway.