Sex influence on serotonergic modulation of the vascular noradrenergic drive in rats

Abstract

[EN] Background and Purpose: In male rats, the serotonergic system modulates sympa-thetic outflow at vascular levels, causing sympatho-inhibition and sympatho-excitation, mainly via 5-HT 1D/1A and 5-HT 3 receptors, respectively. However, sexinfluence on vascular serotonergic regulation has not yet been elucidated. This studyaimed to analyse the 5-HT sympatho-modulatory role in female rats, characterisingthe 5-HT receptors involved.Experimental Approach: Female Wistar (14- to 16-week-old) rats were prepared forsympathetic stimulation. Mean blood pressure (MBP) and heart rate (HR) were con-tinuously measured. Vasopressor responses were obtained by electrical stimulationof the sympathetic outflow (0.1–5 Hz) or i.v. noradrenaline (0.01–0.5 μg kg 1). 5-HT-related drug effects on adrenergic system were determined. Age-matched male ratswere used as control.Key Results: Basal MBP in females was lower than in male rats, whereas electrical-induced increases in MBP were similar. In females, 5-HT exerted a dose-dependentinhibition on the sympathetic-evoked vasoconstrictions, that was reproduced bysome agonists; 5-CT (5-HT1/5/7) and L-694,247 (5-HT1D ), whereas the selective5-HT2A/2B/2C (α-methyl-5-HT) and 5-HT 3 agonist (1-PBG) increased the electrically-produced vasopressor responses. None of the other drugs tested (targeting5-HT1A/1B/1F , 5-HT 2B/2C , 5-HT 4, 5-HT5A or 5-HT 7) modified these vasoconstrictions.Only 1-PBG (5-HT3) modified the vasoconstrictions induced by exogenousnoradrenaline.Conclusions and Implications: In female rats, vascular serotonergic sympatholyticeffects are due to prejunctional 5-HT 1D receptor activation, whereas pre and/orpostjunctional 5-HT3 and prejunctional 5-HT 2A receptor activation is involved in thepotentiating effect of vascular sympathetic neurotransmission. These findings may open novel sex-differential therapeutic strategies for treating cardiovascularconditions.