Heart failure is associated with a sympatho-excitation and a suppression of baroreceptor mediated reflexes in response to the decreased arterial pressure and cardiac output. Previously we reported that nitric oxide (NO) mediated, in part, the attenuation of the renal sympatho-inhibition arising from stimulation of the cardiopulmonary reflex in a model of heart hypertrophy induced by caffeine/isoprenaline [1]. The aim of this study was to determine the isoform of nitric oxide synthase (NOS) that might be involved. To that end, the heart hypertrophy model was used and the impact of a relatively selective neuronal NOS (nNOS) blocker on the cardiopulmonary reflex mediated inhibition of RSNA was examined. Groups of male Wistar rats (n=6) were maintained on a normal diet and tap water or on caffeine water (61.54mg/l) and isoprenaline subcutaneous injections (5mg/kg) for 2 weeks to induce cardiac damage [2]. Following anaesthesia, (1ml chloralose/urethane, 16.5/250mg/ml, i.p.), the femoral artery and femoral vein were cannulated for measurement of blood pressure (BP) and heart rate (HR) and saline infusion. The left kidney was exposed by a flank incision and the renal nerves placed on recording electrodes. All animals were subjected to two periods of volume expansion (VE) at a rate of 0.25% of body weight per minute for 30 min. Following the first period of VE, 30 min was allowed after which the nNOS inhibitor S-methyl thiocitrulline (SMTC) was administered at 10mg/min/kg for 40 min. Thereafter, the animals were subjected to a second period of VE. Data were presented as a mean value over each 5 min ± S.E.M and subjected to ANOVA. Significance was taken at P<0.05. Heart rate, at 6±0.51 Hz, was decreased (P<0.01) by 8 and 9% in the normal and heart hypertrophy groups during the first VE, and by 6 and 4% in the second VE. Blood pressure, at 90±8 mmHg, was unchanged in the normal group throughout both VEs, while it was decreased (P<0.01) by 9 and 7% in the heart hypertrophy group during the first and second VE, respectively. VE in the normal group resulted in a 49% decrease (P<0.001) in RSNA at 30 min, but by contrast, RSNA did not change in the heart hypertrophy group. During the second VE, RSNA was decreased by 83 and 61% in the normal and heart hypertrophy group, respectively, which were responses larger (both P<0.001) than those obtained in the absence of SMTC. The RSNA suppression during VE illustrates the cardiopulmonary reflex and its absence in the heart hypertrophy group implies a deficit in the reflex. Inhibition of nNOS with SMTC enhanced the reflex RSNA suppression to VE in the normal rats and re-established the VE induced renal sympatho-inhibition in the heart hypertrophy rats. These observations suggest that nNOS contributes to the generation of NO which attenuates the cardiopulmonary reflex.