The possible involvement of histamine (HA) in the stress-induced increase in plasma renin activity (PRA) was investigated in male rats. Intracerebroventricular (ICV) infusion of histamine (HA; 3.8-60 micrograms) increased PRA dose-dependently, and the Kd (dissociation konstant) of HA was estimated to approximately 30 micrograms. ICV infusion of HA (30 micrograms) as well as 5 min of restraint stress increased plasma renin activity (PRA) 2- and 3-fold, respectively (p less than 0.01). These effects were abolished by prior ICV infusion of the H2-receptor antagonists cimetidine (100 micrograms) and ranitidine (125 micrograms) (p less than 0.01), which reduced the PRA to subbasal levels (p less than 0.05). When administered alone the H2-receptor antagonists had no effect on PRA. In contrast, the H1-receptor antagonist mepyramine (100 micrograms) increased the basal PRA level (p less than 0.01) and slightly augmented the HA- and stress-induced increase in PRA (p less than 0.05). HA as well as restraint stress increased the plasma levels of dopamine, norepinephrine and epinephrine almost 2-fold (p less than 0.01). The effect of the two stimuli was prevented by prior ICV infusion of mepyramine or cimetidine (p less than 0.01). Pretreatment with the beta-adrenergic receptor blocker propranolol (7 mg/kg i.p.) abolished the HA-induced and inhibited by 70% the stress-induced PRA increase. The results indicate that histaminergic neurons participate in the cerebral regulation of renin secretion. The H2-receptor-mediated PRA-increasing effect of HA involves activation of sympathetic nerves. In addition, HA seems to exert a minor inhibiting effect on PRA via H1-receptors.