Reactive hyperemia following 30 s of coronary occlusion in the isolated guinea pig heart is accompanied by a two-fold increase of nitric oxide (NO) and histamine release, which are significantly reduced in the presence of L-NAME, cimetidine and thioperamide, respectively. Great changes of histamine release occur during autoregulation. However, histamine seems much more important for metabolic dilation below the autoregulatory range. Inhibition of NO synthesis, but not blockade of histamine receptors, widens the autoregulatory range. Changes of the released NO and histamine under conditions employed in this study suggest a positive feed-back relationship between NO and histamine in the regulation of coronary circulation.