We studied the effects of a 2-week period of oral raloxifene therapy on the cardiac level of nitric oxide (NO) and on the susceptibility to angina in ovariectomized rats. Ovariectomy decreased the activity of Ca2+-dependent nitric oxide synthase (NOS) in the left ventricle, an effect restored by raloxifene (0.2–5 mg kg−1 day−1) or 17β-oestradiol (0.3 mg kg−1 day−1). Ovariectomy led to a significant ST segment depression after the injection of (1) ornithine-vasopressin (0.5 IU kg−1, i.v.) or (2) epinephrine (10 μg kg−1, i.v.), followed 30 s later by phentolamine (15 mg kg−1, i.v.); both effects were reversed by raloxifene or 17β-oestradiol treatment. Inhibition of nitric oxide synthase (with NG-nitro-l-arginine methyl ester [l-NAME]; 5 mg kg−1, s.c.) augmented the ST segment depression in the ovariectomized rat and abolished the anti-ischaemic effect of 17β-oestradiol or raloxifene. Thus, an oestrogen deficiency down-regulates the cardiac constitutive nitric oxide synthase, which increases the susceptibility of the heart to ishaemia because both actions can be blocked by exogenous administration of the natural oestrogen 17β-oestradiol or the selective oestrogen-receptor modulator (SERM) raloxifene. In the present in vivo system, raloxifene exerts oestrogen-agonist properties.