Renin secretion is controlled locally in the kidneys as well as via central neuronal mechanisms. The neuronal mechanisms are not fully understood but may involve the neurotransmitter histamine (HA) since centrally infused HA stimulates renin secretion. This, however, does not prove that HA is of any physiological importance for the regulation of renin secretion. Dehydration is a physiological stimulus of renin secretion and, therefore, we studied the possible role of hypothalamic histaminergic neurons in dehydration-induced renin secretion in conscious male rats. In addition, we expanded on our previous investigations of HA-induced renin secretion. Twenty-four hours of dehydration induced a 3-fold increase in plasma renin activity (PRA). Pretreatment with the HA synthesis inhibitor alpha-fluoromethylhistidine inhibited the dehydration-induced PRA secretion by 80% whereas pretreatment with the H1 receptor antagonist mepyramine (MEP) or the H2 receptor antagonist ranitidine (RAN) inhibited the PRA response to dehydration by approximately 40%. In euhydrated control rats, none of the HA-blocking agents had any significant effect on basal PRA secretion. Central administration of HA stimulated PRA almost 2-fold and the maximum concentration of PRA was reached after 15 min. Pretreatment with the H1 receptor antagonist MEP or the H2 receptor antagonist RAN totally inhibited the HA-induced PRA secretion. We conclude that HA activates renin secretion via H1 and H2 receptors and that HA seems to be a physiological mediator of dehydration-induced renin secretion via activation of H1 and H2 receptors. The effect is probably indirect and may among others involve the catecholaminergic and serotonergic systems.