Mechanisms of chronic intermittent hypoxia‐induced enhancement of paraventricular nucleus glutamatergic tone (1130.21)

Abstract

Sleep apnea increases risk for cardiovascular diseases in part by increasing sympathetic nerve activity (SNA). Chronic intermittent hypoxia (CIH), a rodent model that mimics repetitive hypoxemias that occur in patients with sleep apnea, increases mean arterial pressure (MAP) through a hypothalamic PVN dependent mechanism. The goal of this study was to determine effects of CIH on glutamatergic NMDA receptor tone and investigate the underlying mechanisms. After 7 days of CIH, male Sprague‐Dawley rats were anesthetized and PVN NMDA receptors were blocked bilaterally with AP5. Compared to normoxic controls, CIH exposed rats had greater reductions of renal SNA (CIH: ‐17±7 vs control: 2±2%) and MAP (CIH: ‐8±3 mmHg vs control: ‐3±1 mmHg). CIH decreased PVN expression of NMDA receptor subunits NR1 (72% of control, n=5, P<0.05), NR2A (33% of control, n=2), and NR2B (49% of control, n=6, P<0.05), but increased expression of the excitatory amino acid transporter 2 (158% of control, n=2), suggesting a possible compensatory mechanism to maintain excitatory neurotransmission. CIH reduced expression of postsynaptic density protein 95 (PSD‐95, 73% of control, n=5, P<0.05), a critical adaptor protein that links NMDA receptors to neuronal nitric oxide synthase (nNOS) activation. Interestingly, CIH did not change PVN expression of nNOS (105% vs control, n=3). We conclude that support of SNA and MAP after 7 days of CIH involves increased NMDA receptor‐dependent glutamatergic tone in PVN, which involves reduced expression of NMDA receptors offset by reduced glutamate uptake. A further contribution could arise from reduced NO‐mediated inhibition caused by reduced NMDA receptor‐nNOS coupling by PSD‐95. HL 102310 & 088052 (GMT)