The aim of this study was to use periarterial manipulation to produce an atheroma-like neo-intima in rabbits and study resting blood flow and vascular responsiveness in vivo. One common carotid artery was enclosed in a silastic collar to induce a neo-intima similar to that of human early atherosclerosis, and carotid blood flow was measured periodically over 8 days in 8 conscious rabbits. The vasodilator responses to intravenous infusions of the endothelium-dependent vasodilator, acetylcholine, and glyceryl trinitrate were measured in each artery at 2 and 7 days after surgical placement of the collar, and again following infusion of the nitric oxide synthase inhibitor, N-nitro- L-arginine (NOLA, 15 mg/kg). Histological examination of the arterial segments at completion of the study revealed significant intimal thickening of the regions of artery enclosed in the collar. Resting blood flow was lower in the collared vascular bed as compared with the control, from as early as 2 days after surgery. Acetylcholine- and glyceryl trinitrate-induced decreases in carotid resistance, however, were no different between the arteries after 2 days. At 7 days after surgery, the vasodilator response to acetylcholine was significantly impaired in the collared vascular bed when compared with the control, while the glyceryl trinitrate-induced vasodilatation was similar in the two beds. Following NOLA infusion, mean arterial pressure was significantly increased and blood flow through both arteries was reduced. After NOLA, acetylcholine-induced vasodilatation in the collared vascular bed was no longer different from the vasodilatation in the control bed. Therefore, a developing neo-intima reduces the blood flow through the collared carotid artery before any morphological changes are detected. These results suggest that the nitric oxide-mediated dilator function of resistance vessels distal to the developing lesion is compromised, in this study in the absence of hyperlipidaemia.