Pathogenesis of coronary artery spasm induced by histamine in miniature pigs was studied angio-graphically in in vivo and in vitro conditions. Endothelial balloon denudation was performed and the animals were fed laboratory chow for 3 months, after which coronary artery spasm was repeatedly provoked by histamine given intracoronarily. Regional hypercontraction of the coronary artery was documented by selective coronary arteriography, and the resulting myocardial ischemia was confirmed by ECG-ST changes. To evaluate coronary artery spasm without the influence of blood constituents and neural control and to quantitate the pharmacophysiological characteristics of hista-mine-induced coronary constriction in the coronary spasm, the same heart was isolated and perfused with Krebs-Henseleit solution under a constant perfusion pressure of 90 mm Hg. Histamine (10∼s M) reduced the diameter of the coronary artery of the isolated heart by 29 ± 4 and 67 ± 3% (p < 0.001) in nondenuded and denuded areas, respectively. These figures were similar to data obtained angio-graphically in vivo after the administration of histamine 10 μg/kg. The constriction of the denuded areas in response to histamine was topologically the same in vivo and in vitro. The degree of focal constriction induced by histamine, defined as a percent of stenoses from the mean diameter of the areas of proximal and distal to the spastic site, was similar in in vivo (10 μg/kg i.e.) and in vitro (10-5 M) conditions. KC1 (40 mM) reduced both the denuded and nondenuded coronary artery diameter by 67 ± 3% and 68 ± 3% (NS), respectively. The dose-response relation of the coronary diameter to histamine was not influenced by pretreatment with the nerve transmitter blockers guanethidine (3 × 10-6 M), atropine (10-6 M), and tetrodotoxin (3 × 10-7+ M). Phenylephrine (10-5 M) did not potentiate constriction of the denuded areas. In Ca+2 free solution with EGTA (2 mM), in which 118 mM KC1 did not constrict the coronary diameter, histamine (10-5 M) reduced the coronary diameter by 17 ± 2 and 19 ± 1% (NS) in nondenuded and denuded areas, respectively. Mepyramine, an Hi-receptor blocker, abolished the constrictive response to histamine. The intima was invariably thickened along the spastic portion and was coated by endothelial cells, visible microscopically. Thus, focally potentiated constriction of the coronary artery to histamine was reproducible in isolated pig hearts perfused with electrolyte solution containing 2.6 mM Ca2+. This suggests alterations in the influx of Ca2+ in the presence of H1-receptor stimulation in vascular smooth muscle of the vessel wall with intimal thickening.