The pathogenesis of histamine-induced coronary spasm was examined angiographically and morphometrically in Gbttingen miniature pigs. In five of 36 consecutive pigs that were 4 to 5 months of age, coronary spasm was provoked by the intracoronary administration of histamine, and the left coronary arteries were examined histologically without endothelial denudation (group 1). Endothelial balloon denudation of the major branch of the left coronary artery was performed in 31 of 36 pigs and five died during the procedure. The remaining 26 pigs were randomly allotted to one of two groups, one fed a cholesterol-supplemented (group 2, n = 13) and one fed a regular low-cholesterol diet (group 3, n = 13). After 3 months, serum cholesterol increased significantly from 57 ± 6 to 222 ± 27 mg/dl (p < .01) in group 2, but remained unchanged (48 + 5 to 55 6 mg/dl) in group 3. Percent narrowing of the coronary diameter induced by 10 μ/kg ic histamine after administration of the H2 blocker cimetidine (60 mg/kg iv) was 39 ± 3% and 24 ± 2% (p < .05 between groups 2 and 3) at the nondenuded site and 78 ± 3% and 74 ± 4% at the denuded site in groups 2 and 3, respectively (p < .01 between nondenuded and denuded sites). Histamine-induced percent narrowing of the coronary diameter after cimetidine in group 1, 2, and 3 pigs correlated well with the degree of intimal thickness on an exponential curve (r = .92, p < .001). Since percent narrowing at the intact site was 27% (n = 19) in all three groups, predicted histamine-induced percent narrowing at the spastic site, applying the geometric theory, was 33 ± 3%. Accordingly, enhanced constriction of the coronary artery with intimal thickening in response to histamine can largely be explained by the acquired hyperresponsiveness of the vascular wall to autacoids. This phenomena, not related to the level of serum cholesterol, may be uniquely linked to the basic pathology of evolution of atherosclerosis.