Abstract P620: Renal Nerve Denervation Modulates GABA-ergic Input into Paraventricular Nucleus of the Hypothalamus and Exerts a Long Term Antihypertensive Effect in Hypertensive Mice Associated with Chronic Kidney Disease

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Background: Sympathoexcitation plays an important role in the pathogenesis of hypertension with chronic kidney disease (CKD). In hypertension, the paraventricular nucleus of the hypothalamus (PVN) in the brain controls the sympathetic outflow through GABA-ergic mechanisms. The renal nerve denervation (RDN) exerts a certain long term antihypertensive effect; however the precise mechanism is not fully elucidated. We aimed to clarify whether RDN modulates sympathetic outflow through GABA-ergic mechanisms in the PVN in hypertensive mice with CKD. Methods and Results: In 5/6-nephrectomized ICR-mice (Nx) at 4-weeks after nephrectomy, systolic BP (SBP) was significantly increased (vs. Sham, 143±2 vs. 109±2mmHg, n=12-24, p<0.01), accompanied by sympathoexcitation (urinary norepinephrine (uNE): vs. Sham, 424±26 vs. 226±17μg/24hrs, n=12-24, p<0.01). We performed RDN or sham operation and divided into 3 groups (Sham-sham, Nx-sham, and Nx-RDN, n=12 for each). At 2-weeks after RDN, SBP was significantly decreased (123±2 vs. 136±2 mmHg, n=12 for each, p<0.01), and urinary sodium excretions were increased (0.64±0.04 vs. 0.47±0.03 mmol/24hrs, n=8 for each, p<0.01) in Nx-RDN compared with those in Nx-sham. The uNE levels were not different between two groups. At 6-weeks after RDN, SBP was kept decreasing (125±1 vs. 140±3 mmHg, n=12 for each, p<0.01) and uNE levels were also decreased (386±32 vs. 541±35 μg/24hrs, n=12 for each, p<0.01) in Nx-RDN compared with those in Nx-sham. The urinary sodium excretions were not different between two groups. Bicuculline (GABA-A receptor antagonist, 50pmol) microinjection into PVN increased mean arterial pressure (MAP) and lumbar sympathetic nerve activity (LSNA) in all groups. The pressor responses and the change in LSNA were significantly attenuated in Nx-sham (vs. Sham-sham, [[Unable to Display Character: ∆]]MAP/baseline MAP [%], 33±4 vs. 66±6 %; [[Unable to Display Character: ∆]]LSNA (%baseline), 57±7 vs. 112±8 %, p<0.01, n=6 for each), but were enhanced in Nx-RDN at 6-weeks after RDN (vs. Nx-sham, [[Unable to Display Character: ∆]]MAP/baseline MAP [%], 60±6 vs. 33±4 %; [[Unable to Display Character: ∆]]LSNA (%baseline), 94±5 vs. 57±7 %, p<0.05, n=6 for each). Conclusion: These data indicate that augmented GABA-ergic input into PVN induced by RDN, at least in the late phase, is involved in antihypertensive action in hypertensive mice with CKD.