Calcineurin Controls Hypothalamic NMDA Receptor Activity and Sympathetic Outflow

Area of Science:

• Neuroscience
• Cardiovascular Physiology
• Pharmacology

Background:

• Hypertension is a serious side effect of calcineurin inhibitors (e.g., cyclosporine, tacrolimus/FK506).
• The precise mechanisms driving increased sympathetic outflow and hypertension due to these drugs are not fully understood.
• Calcineurin, a phosphatase, is present in the brain's paraventricular nucleus (PVN), a key regulator of sympathetic tone.

Purpose of the Study:

• To investigate if calcineurin inhibitors elevate sympathetic output and cause persistent hypertension by enhancing N-methyl-D-aspartate (NMDA) receptor activity in the PVN.
• To elucidate the role of calcineurin in regulating sympathetic vasomotor tone within the PVN.

Main Methods:

• Systemic FK506 administration in rats, followed by telemetry for blood pressure monitoring.
• Measurement of calcineurin activity, NMDA receptor phosphorylation, and synaptic trafficking in the PVN.
• Electrophysiological recordings (patch-clamp) of PVN presympathetic neurons.
• Microinjection of receptor antagonists into the PVN and systemic administration of memantine.

Main Results:

• FK506 treatment induced sustained hypertension and increased sympathetic nerve activity.
• FK506 reduced calcineurin activity and increased NMDA receptor activity in the PVN.
• Enhanced firing of PVN presympathetic neurons was observed, mediated by NMDA and AMPA receptors.
• Antagonism of NMDA or AMPA receptors in the PVN attenuated FK506-induced hypertension and sympathetic outflow.
• The NMDA receptor antagonist memantine effectively reduced FK506-induced hypertension.

Conclusions:

• Calcineurin in the PVN normally suppresses NMDA receptor activity, thereby limiting sympathetic vasomotor tone.
• Inhibition of calcineurin disrupts this suppression, leading to increased sympathetic activity and hypertension.
• Targeting NMDA receptor activity in the PVN presents a potential therapeutic strategy for calcineurin inhibitor-induced hypertension.