In order to investigate the role of the endothelium in the regulation of cerebrovascular tone, we studied selective intraluminal and extraluminal vasoactive mechanisms of acetylcholine, potassium and serotonin. We also examined the effects of removal of the endothelium on these vasoactive responses. With 0.75 g of tension, isolated rabbit basilar arteries were fixed in a perfusion system with the ability to isolate the intraluminal and extraluminal surfaces, and perfused at 8 ml-1 min-1 under a pressure of 8 mmHg. To remove the endothelium, we applied several concentrations of saponin. The endothelium was completely removed by 0.05 mg-1 ml-1 saponin, confirmed histologically. Extraluminal and intraluminal acetylcholine induced endothelium-dependent relaxations. Intraluminal potassium induced greater contraction than extraluminal potassium in both saponin denuded (p < 0.01) and intact preparations (p < 0.05, n = 8). Intraluminal and extraluminal serotonin induced symmetric contractions, and for both sides the response was enhanced by removal of the endothelium (p < 0.05, n = 6). Our results suggest that inhibitory (relaxant) contribution of the endothelium to contractile responses varies depending on the vasoactive agent. The fact that the effects of some extraluminal agents were enhanced when the endothelium was denuded, may be of some importance in potentiating the mechanism of vasospasm following subarachnoid haemorrhage.