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

Area of Science:

• Cardiovascular Physiology
• Neuropharmacology
• Serotonergic Signaling

Background:

• Vascular serotonin (5-HT) modulates sympathetic activity through various pathways, including nitric oxide (NO), endothelium-dependent hyperpolarization (EDH)-K+ channels, prostanoids, angiotensin II (Ang-II), and endothelin.
• Significant sex-based differences exist in serotonergic sympatho-regulation, particularly in female rats.
• Understanding these sex-specific mechanisms is crucial for comprehending vascular homeostasis.

Purpose of the Study:

• To investigate the involvement of indirect pathways in 5-HT-mediated vascular sympatho-modulation in female rats.
• To elucidate the roles of 5-HT1D-mediated inhibition and 5-HT2A/3-mediated potentiation of vascular noradrenergic neurotransmission.
• To identify specific mediators involved in these 5-HT pathways in females.

Main Methods:

• Experiments were conducted in female pithed rats.
• Intravenous administration of inhibitors/blockers for NO, K+ channels, prostanoids, Ang-II, or endothelin.
• Infusion of 5-HT receptor agonists (L-694,247 for 5-HT1D, TCB-2 for 5-HT2A, 1-PBG for 5-HT3) followed by electrical stimulation of vascular sympathetic outflow to measure vasopressor responses.

Main Results:

• 5-HT1D-induced sympatho-inhibition was abolished by a non-selective K+ channel blocker (tetraethylammonium), indicating mediation via the EDH pathway.
• 5-HT2A-mediated sympatho-potentiation was blocked by losartan (Ang-II type 1 receptor antagonist), and Ang-II levels increased post-TCB-2 infusion, linking 5-HT2A to Ang-II.
• 5-HT3-induced sympatho-excitatory effects were not affected by any tested inhibitors, suggesting no involvement of indirect pathways.

Conclusions:

• The EDH pathway is essential for 5-HT1D-induced sympatho-inhibition in female rats.
• The 5-HT2A receptor-mediated sympatho-excitatory effect is associated with angiotensin II.
• The 5-HT3 receptor-mediated sympatho-potentiation operates independently of the studied indirect pathways.