Sympathetic neurons lie outside the blood-brain barrier and are exposed to circulating regulatory peptides. Angiotensin II (AngII) produces sustained increases in sympathetic excitability via AT1 receptors, with little desensitisation. Therefore, we used a Leica SP5 confocal microscope with photon-counting avalanche photodiodes and a resonant scanner with capture time of 0.5µs/pixel to image AngII linked to Alexa-647 fluorophore (AngII-A647) or Alexa-488 (AngII-A488) binding to AT1 receptors expressed by sympathetic neurons from guinea-pig coeliac ganglion. We also used fluorescence correlation spectroscopy (FCS) to measure AngII-A647 diffusion through extracellular space and close to neurons expressing AT1 receptors. AngII-A647 or AngII-A488 (10-100nM) binding to sympathetic neurons occured in distinct membrane microdomains. After 60 minutes continuous exposure to the peptide, little internalisation was observed, and most binding microdomains remained fixed in their location. Sequential exposure of neurons to AngII-A488 following AngII-A647 revealed that some microdomains binding AngII-A647 also bound AngII-A488, some did not, while some AngII-A488 bound to domains not previously labelled by AngII-647. These inaccessible domains presumably had flipped rather than fully internalised. FCS showed that diffusion coefficients varied from 120µm2/s in free space to less than 1µm2/s at binding domains. Optically-measured binding kinetics around binding domains were no faster than those in extra-cellular connective tissue, indicating that receptor-ligand binding is significantly limited by slow peptide diffusion. Our observations suggest that diffusion-limited kinetics combined with rapid local turn-over of membrane receptor domains facilitate prolonged excitation of sympathetic neurons by AngII.