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

Abstract

Background and purpose: In male rats, the serotonergic system modulates sympathetic outflow at vascular levels, causing sympatho-inhibition and sympatho-excitation, mainly via 5-HT_1D/1A and 5-HT₃ receptors, respectively. However, sex influence on vascular serotonergic regulation has not yet been elucidated. This study aimed to analyse the 5-HT sympatho-modulatory role in female rats, characterising the 5-HT receptors involved.

Experimental approach: Female Wistar (14- to 16-week-old) rats were prepared for sympathetic stimulation. Mean blood pressure (MBP) and heart rate (HR) were continuously measured. Vasopressor responses were obtained by electrical stimulation of 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 rats were 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-dependent inhibition on the sympathetic-evoked vasoconstrictions, that was reproduced by some agonists; 5-CT (5-HT_1/5/7) and L-694,247 (5-HT_1D), whereas the selective 5-HT_2A/2B/2C (α-methyl-5-HT) and 5-HT₃ agonist (1-PBG) increased the electrically-produced vasopressor responses. None of the other drugs tested (targeting 5-HT_1A/1B/1F, 5-HT_2B/2C, 5-HT₄, 5-HT_5A or 5-HT₇) modified these vasoconstrictions. Only 1-PBG (5-HT₃) modified the vasoconstrictions induced by exogenous noradrenaline.

Conclusions and implications: In female rats, vascular serotonergic sympatholytic effects are due to prejunctional 5-HT_1D receptor activation, whereas pre and/or postjunctional 5-HT₃ and prejunctional 5-HT_2A receptor activation is involved in the potentiating effect of vascular sympathetic neurotransmission. These findings may open novel sex-differential therapeutic strategies for treating cardiovascular conditions.