L-643,441 is a highly potent histamine H2-receptor antagonist in guinea-pig atria, acting via a unique mechanism. Unlike ranitidine, the onset of action of this compound was slow and its inhibitory action persisted after repeated washing of the tissues. Preincubation of atria with ranitidine, however, protected the H2-receptor from the apparently irreversible antagonism of L-643,441. H2-receptor antagonism produced by L-643,441 was not surmountable by increasing the concentration of dimaprit. The compound did not alter the response of this tissue to isoproterenol or affect basal atrial rate under conditions in which maximal H2-receptor blockade was achieved. In dogs, L-643,441 was effective both orally and i.v. in inhibiting gastric acid secretion evoked by histamine, gastrin, 2-deoxy-D-glucose and food. Orally, it was equipotent with ranitidine against histamine-induced secretion, but the duration of action of L-643,441 was substantially longer.