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1 We determined whether gender and/or oestrogen deficiency affect endothelium-dependent hyperpolarization and relaxation in mesenteric arteries isolated from middle-aged (44-45 week old) rats. 2 The hyperpolarizing response to acetylcholine (ACh) was significantly greater in females than in males. Ovariectomy caused a marked reduction in ACh-induced hyperpolarization in female arteries, and this was improved by 17β-oestradiol replacement therapy. 3 ACh-induced relaxations in female arteries were not significantly different from those observed in male rats, and were unaffected by ovariectomy, regardless of whether indomethacin was present. However, when endothelial nitric oxide synthase (eNOS) was blocked with N[sup G]-nitro-L-arginine, the sensitivity and maximum relaxant response to ACh was significantly higher in intact females compared with males and ovariectomized females. Treatment with 17β-oestradiol prevented the reduced vasorelaxant response in ovariectomized females. 4 Immunohistochemical examination for eNOS showed no apparent difference in eNOS protein expression in the endothelium of arteries between intact and ovariectomized females. 5 Since circulating concentrations of oestrogen were essentially low in middle-aged female rats, the present results suggest that subtle changes from a critical concentration of oestrogen at this age may strongly affect the vascular actions of endothelium-derived hyperpolarizing factor without effect on eNOS expression and activity. [ABSTRACT FROM AUTHOR]