Adrenal steroidogenesis closely correlated with increases in adrenal blood flow. Many reports have studied the regulation of adrenal blood flow in vivo and in perfused glands, but until recently few studies have been conducted on isolated adrenal blood arteries. The present study examined vasomotor responses of small isolated bovine small adrenal cortical arteries to histamine, an endogenous vasoactive compound, and its mechanism of action. In U46619-precontracted arteries, histamine (10^-9-5x10^-6 M) elicited concentration-dependent relaxations. The relaxations were blocked by the H1-receptor antagonist diphenhydramine (10 µM) or mepyramine (1 µM) (maximal relaxations of 18±6% and 22±6% respectively vs. 55±5% of control), but only partially inhibited by by the H2-receptor antagonist cimetidine (10 µM) and the H3 -receptor antagonist thioperamide (1 µM). Histamine-induced relaxations were also blocked by the nitric oxide synthase inhibitor N-nitro-L-arginine (L-NA, 30 µM; maximal relaxation of 13±7%) and eliminated by endothelial removal and L-NA combined with the cyclooxgenase inhibitor indomethacin (10 µM). In the presence of adrenal zona glomerulosa (ZG) cells, histamine did not induce further relaxations compared to histamine alone. Histamine (10^-7-10^-5 M) concentration-dependently increased aldosterone production by adrenal ZG cells. Compound 48/80 (10 µg/ml), a mast cell degranulator, induced significant relaxations (93±0.6%), which were blocked by L-NA plus indomethacin and endothelium removal, partially inhibited by the combination of the H1, H2 and H3-receptor antagonists, but not affected by the mast cell stabilizer sodium cromyoglycate (1 mM). These results demonstrate that histamine causes direct vasodilation of small adrenal cortical arteries, which is largely mediated by endothelial NO and prostaglandins via H1-receptors. The potential role of histamine in linking adrenal vascular events and steroid secretion requires further investigation.