Renal Sympathetic Hyperactivity in Diabetes Is Modulated by 5-HT_1D Receptor Activation via NO Pathway

Area of Science:

• Cardiovascular Physiology
• Neuroendocrinology
• Renal Pathophysiology

Background:

• The renal sympathetic nervous system plays a crucial role in maintaining cardiovascular homeostasis.
• Sympathetic nerve activity to the kidneys is modulated by serotonin (5-HT).
• Diabetes mellitus is associated with significant cardiovascular complications.

Purpose of the Study:

• To investigate if diabetes alters renal sympathetic nerve activity and its modulation by serotonin.
• To elucidate the specific serotonin receptor subtypes and signaling pathways involved in these modulations in a diabetic state.

Main Methods:

• Utilized an in situ autoperfusion model in anaesthetized alloxan-induced diabetic rats.
• Measured systemic blood pressure (SBP), heart rate (HR), and renal perfusion pressure (RPP).
• Electrically stimulated renal sympathetic outflow and administered various serotonin agonists and antagonists, including 5-HT, 5-CT, L-694,247, LY310762, and ODQ.

Main Results:

• Diabetic rats exhibited significantly higher renal sympathetic nerve stimulation-induced increases in RPP compared to normoglycaemic controls.
• Intraarterial administration of 5-HT and 5-CT (5-HT1/5/7 agonist) attenuated these increases.
• Selective 5-HT1D receptor agonism (L-694,247) mimicked this inhibition, which was blocked by a 5-HT1D antagonist (LY310762) and reversed by a guanylyl cyclase inhibitor (ODQ).

Conclusions:

• Diabetes mellitus enhances sympathetic nervous system-induced vasoconstriction in the renal vasculature.
• Prejunctional 5-HT1D receptors, acting via the nitric oxide pathway, are involved in inhibiting noradrenergic vasoconstriction in diabetic rats.
• These findings highlight a potential mechanism contributing to cardiovascular complications in diabetes.