Angiotensin II and EDH Pathways Underlie the Vascular Sympatho-Modulation by 5-HT in Female Rats.

The vascular 5-HT sympatho-modulation may involve inhibitory or potentiating pathways: nitric oxide (NO), endothelium-dependent hyperpolarization (EDH)-K+ channels, prostanoids, angiotensin II (Ang-II), or endothelin. Compared to males, female rats show differences in the serotonergic sympatho-regulation; therefore, we aimed to study the involvement of indirect pathways via 5-HT1D-mediated inhibition and 5-HT2A/3-mediated potentiation of vascular noradrenergic neurotransmission in females. An i.v. bolus of different inhibitors/blockers of modulators/mediators (NO, K+ channels, prostanoids, Ang-II, or endothelin) was administered prior to the infusion of the agonists, L-694,247 (5-HT1D), TCB-2 (5-HT2A), or 1-PBG (5-HT3), in female pithed rats. In these conditions, the vascular sympathetic outflow was electrically stimulated to assess the vasopressor responses. The L-694,247 vascular sympatho-inhibition was abolished by a non-selective K+ channel blocker, tetraethylammonium. The 1-PBG sympatho-excitatory vascular effect was not modified by any of the inhibitors tested, whereas TCB-2 sympatho-potentiation was blocked solely by losartan (Ang-II type 1 receptor antagonist). Moreover, Ang-II levels were increased after TCB-2 infusion in females. The EDH pathway mediates the 5-HT1D-induced sympatho-inhibition, while the 5-HT2A-evoked sympatho-excitatory effect is associated with Ang-II. In contrast, the 5-HT3 sympatho-potentiation does not involve any indirect pathway. These findings advance current understanding of the complex interactions between 5-HT and vascular homeostasis in female rats.