Hypertension is associated with an increase in cardiac sympathetic transmission, although the exact mechanism underlying this is unknown. The adult spontaneously hypertensive rat (SHR) has increased cardiac sympathetic activity compared to Wistar Kyoto (WKY) controls. Recent studies in 4 week old pre-hypertensive SHRs have shown increased calcium transients in isolated stellate ganglion neurons compared to age matched WKYs. In an isolated organ bath atrial preparation with intact right stellate ganglion (37±0.5oC) there was a greater heart rate response to stellate stimulation (5 and 7Hz, 30sec, 20V, 1msec) in SHRs compared to WKYs, and a significantly greater release of 3H-NE to field stimulation (5Hz, 20V, 1msec) of right atria. Whereas, ventricular weight/body weight ratios and mean arterial pressure measured via the left carotid artery (under 2% isoflurane) demonstrated that SHRs were without left ventricular hypertrophy and were normotensive at this age compared to WKYs. This neural phenotype observed might result from defective NET-1 transport in the SHR preventing rapid termination of the noradrenaline signal. A novel fluorescent assay of the noradrenaline reuptake transporter (NET) was used on isolated sympathetic postganglionic neurons. NET rate was significantly impaired in cardiac stellate sympathetic neurons from the pre-hypertensive and hypertensive SHR compared to age matched normotensive WKY. However, no reduction in transporter rate was observed at either age in the other major non-cardiac sympathetic ganglia. To test the effect of neuronal excitability on NET activity preparations were depolarised by electrical field stimulation (EFS). Electrical field stimulation potentiated the difference in NET rate observed within stellate neurons of the hypertensive SHR and age matched WKY (SHR: 2.59±0.30 au/min, n=20, WKY: 4.25±0.47 au/min, n=19, P<0.01). NET is known to be highly regulated by a number of kinase and phosphatases, modulating both its intrinsic activity and surface expression therefore allowing for a dynamic modulation of the main system responsible for the termination of the action of noradrenaline. Previous studies have indicated a role for protein kinase C inhibition in facilitating the translocation of NET to the presynaptic membrane. The PKC inhibitor calphostin C caused a significant dose dependent increase in NET activity in WKY neurons (100nM n=13, P<0.05). Similarly NET activity in SHR neurons was also increased in the presence of calphostin C compared its control (100nM n=15, P<0.05). Moreover, there was no difference in NET rate between SHR and WKY neurons after calphostin C. Therefore reduced NET activity in the SHR may be due to increased PKC expression and increased phosphorylation of NET transporters in the cytosol that prevents insertion of the transporter into the presynaptic membrane. Strategies that up regulate NET activity may help rescue the sympathetic hyperactivity observed in this model system.