Alterations in vessel wall reactivity (VR) at or adjacent to the dilation site after balloon angioplasty (BA) may vary according to the inflation protocol and the time after angioplasty and may influence outcome. In 64 atherosclerotic rabbit femoral arteries, we evaluated VR after BA with intravenous ergonovine (ERGO) (40 micrograms/min for 5 minutes) and intra-arterial nitroglycerin (NTG) (2,500 micrograms single bolus) 24-72 hours and 28 days after BA. Comparisons were made with atherosclerotic, nonangioplastied, age-matched controls. BA was standardized to three 1-minute inflations, each 1 minute apart. For each balloon size, 2.5- (appropriate size) or 3.0-mm (oversized) vessels were allocated to either 5 or 10 atm inflation pressure. For the analysis, four groups were compared: Group 1, 3.0/5; group 2, 3.0/10; group 3, 2.5/5, and group 4, 2.5 mm/10 atm. Angiographic diameters were measured at, proximal, and distal to the lesion at baseline, 10 minutes after ERGO, and 5 minutes after NTG. Angiograms were measured with electronic calipers by two blinded observers. All segments of control vessels vasoconstricted to ERGO and vasodilated to NTG (p less than 0.05 versus baseline), indicating a normal response. At 24-72 hours after dilatation, the angioplasty sites for all inflation pressure/balloon size combinations were not responsive to either ERGO or NTG. All segments distal to the dilatation sites vasoconstricted to ERGO and dilated to NTG (p less than 0.05 versus baseline), indicating a normal response. Proximal segments of vessels dilated with a 2.5-mm balloon (appropriate size) responded positively to both stimuli (p less than 0.05). Those vessels dilated with a large balloon (3.0 mm) were nonreactive in the segment proximal to the angioplasty site. Twenty-eight days later angioplasty sites dilated with a 2.5-mm balloon (appropriately sized) regained reactivity; however, segments dilated with a large balloon (3.0 mm) remained unresponsive. All proximal segments, including those from vessels dilated with a large balloon, reacted positively. All distal segments reacted appropriately. Restenosis rates were not different between the over- and appropriately sized balloon groups. These data demonstrate that immediately after angioplasty, vessels lose reactivity at the dilatation site. Those vessels dilated with the smaller-size balloon (2.5 mm) regained reactivity. For large balloons, reactivity is not regained at 28 days. For segments proximal to the site of dilatation, transient loss of reactivity is seen only when a large balloon is used. Thus, acute closure originating at the site of dilatation is not a result of spasm.(ABSTRACT TRUNCATED AT 400 WORDS)