Heart hypertrophy (HH) is an initial indicator of progression into heart failure when there is activation of the autonomic nervous system. Recently by using a caffeine/isoprenaline induced model of HH [1], we demonstrated a blunted renal sympatho-inhibition in response to saline volume expansion (VE) which was dependent on nitric oxide (NO) generation. This study investigated whether the neural regulation of fluid excretion during VE was raised in HH and if NO was involved. Groups of male Wistar rats (n=6) were fed a normal diet and tap water or caffeine water (62mg/L) plus isoprenaline (5mg/kg, sc every 72h) for two weeks. Following anaesthesia (1ml chloralose/urethane, 16.5/250mg/ml ip), a femoral artery and femoral vein were cannulated to monitor blood pressure (BP) and infuse saline. The right ureter was exposed and cannulated for urine collection. The left kidney was exposed, the renal nerves sectioned and its ureter cannulated for urine collection. At the end of surgery, inulin 2mg/ml in 0.9% NaCl was given as a bolus of 2ml and infused at 3ml/h. Two 15 min basal clearances were taken for estimation of GFR and Na+ excretion. Rats were subjected to two periods of VE, 0.25% of bw/min for 30 min during which 5min urine collections were taken, one before and one after a 60 min infusion of the NO synthase (NOS) inhibitor N-nitro-L-arginine methyl ester (L-NAME) at 10μg/min/kg for 60 min [2]. Data, means ±SEM, were compared using one- and two-way ANOVA. Significance was taken at P<0.05. BP, at 93±2 and 84±5mmHg, and GFR at 2.31±0.38 and 4.12±1.46ml/min/kg were similar in the normal and HH groups respectively. Basal Na+ excretion (UNaV) was 0.35±0.08 and 1.63±0.46μmol/min/kg (P<0.01) for the normal and HH groups, respectively. During VE, there were significant (P<0.05) 7.5-8-fold increases in UNaV which was greater in the innervated than the denervated kidney. There was a small but significantly greater increase (P<0.05) in UNaV during VE in the innervated kidney when L-NAME was infused. In the HH group, there was a significant increase in UNaV (3.5-fold) from the denervated kidney during VE, but it did not change in the innervated kidney. L-NAME infusion had no effect on basal UNaV from either kidney but during VE, there was a significantly (P<0.001) greater increase in UNaV in both the innervated and denervated kidneys. The natriuretic responses to VE were greater in denervated than innervated kidneys reflecting an action of the nerves on fluid reabsorption and were enhanced following L-NAME suggesting an inhibitory role for NO on the neural regulation of fluid excretion. In the HH group, the markedly blunted natriuretic response to VE in the innervated kidney was partly restored following L-NAME. This indicated that the neural control of fluid excretion was greater in HH due to raised NO production.