Histaminergic neurons of the brain have been implicated in genetic hypertension. We investigated the effect of inhibition of histamine synthesis by alpha-fluoromethylhistidine (alpha-FMH), the irreversible inhibitor of histidine decarboxylase, on the development and maintenance of hypertension in spontaneously hypertensive rats. Young (3-week-old) and adult (7-week-old) rats were treated with alpha-fluoromethylhistidine for 29 and 13 days, respectively. Treatment of spontaneously hypertensive rats and normotensive Wistar-Kyoto rats with alpha-fluoromethylhistidine led to a pronounced decrease in the histidine decarboxylase activity and in the histamine concentration in the brain (hypothalamus, brainstem, cortex-midbrain). In adult spontaneously hypertensive rats, the development of hypertension was not influenced by alpha-fluoromethylhistidine. In young spontaneously hypertensive rats, alpha-fluoromethylhistidine led to a transient delay in the development of hypertension which was followed by a transient tendency to increased blood pressure. It is concluded that histaminergic neurons of the brain play only a subordinate role, if any at all, in the development of hypertension in spontaneously hypertensive rats.