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Flushing is one of the most common vasodilation-related adverse effects associated with Ca 2+ channel antagonist treatment. This symptom is known to occur more frequently in women than men. The present study aimed at investigating the effect of ovariectomy on nifedipine-induced flushing in mice. Ovariectomy markedly increased the tail skin temperature, a parameter of skin flushing, induced by nifedipine at a dose showing no influence on blood pressure. This event was blocked by estradiol replacement. Estrogen withdrawal is, therefore, included in the risk factors for nifedipine-induced flushing and this risk is lessened by estrogen replacement.

The possible cyclosporin A application for rheumatoid arthritis that develops preferentially in middle-aged women raises concerns about adverse effects of cyclosporin A, including neurotoxicity in patients with climacterium. The present study was aimed at elucidating the effect of cyclosporin A on the convulsive activity and gamma-aminobutyric acid (GABA) neural activity of the hippocampus in ovariectomized rats, as a menopause/climacterium model. Ovariectomy markedly aggravated the effect of repeated administration of cyclosporin A (40 mg/kg, once a day for 5 or 6 days), convulsions and reduction of the basal GABA levels and aminooxyacetic acid-evoked GABA accumulation. These aggravations were blocked by estradiol replacement. The present findings demonstrated that ovariectomy increased the susceptibility to cyclosporin A-induced convulsions by accelerating an inhibitory action of cyclosporin A on GABA neural activity in the hippocampus, this being blocked by estrogen replacement. Menopause/climacterium is, therefore, included in the risk factors for cyclosporin A-induced neurotoxicity and this risk is lowered by estrogen replacement therapy.

Statins have pleiotropic vascular protective effects that are independent of their cholesterol-lowering effects. The aim of the present study was to determine if statins have anti-flushing actions in an animal model of forced exercise-induced temperature dysregulation in menopausal hot flushes, and to clarify the critical role of statins in regulating vascular reactivity in the tail arteries of ovariectomized rats. Administration of fluvastatin or pravastatin (3 mg/kg/day for 7 days, p.o.) significantly ameliorated the flushing of tail skin in ovariectomized mice, and the effect of each statin was comparable with that of estrogen replacement (1 mg/kg/week for 3 weeks, i.m.). In phenylephrine-pre-contracted rat-tail arteries, ovariectomy inhibited acetylcholine-induced relaxation, but augmented sodium nitroprusside-induced relaxation. These ovariectomy-altered vasodilator responses were restored by fluvastatin treatment as well as by estrogen replacement. Nitrite/nitrate levels in the plasma of ovariectomized animals showed significantly lower values than those in sham-operated animals; this ovariectomy-reduced production of nitric oxide was improved by fluvastatin treatment. These data provide the first experimental evidence that statins such as fluvastatin and pravastatin exert anti-flushing effects by improving vasomotor dysfunction through nitric oxide-mediated mechanisms in ovariectomized animals. Thus, therapeutic methods that target improvement of vasomotor dysfunction could be novel strategies for reducing menopausal hot flushes.

Flushing is one of the most common vasodilation-related adverse effects associated with both nitrates and phosphodiesterase type 5 (PDE5) inhibitors. The present study aimed to investigate the effects of orchidectomy and ovariectomy on isosorbide dinitrate-, sildenafil-, vardenafil- and tadalafil-induced flushing of tail-skin in mice. Both orchidectomy and ovariectomy markedly increased the tail-skin temperature, a good parameter of flushing, induced by isosorbide dinitrate (500 microg/kg, i.p.). These observations suggest that both testosterone withdrawal and estrogen withdrawal are risk factors for isosorbide dinitrate-induced flushing. In contrast, sildenafil (100 mg/kg, p.o.)-, vardenafil (10 mg/kg, p.o.)- and tadalafil (40 mg/kg, p.o.)-induced flushing of tail-skin in mice was aggravated by ovariectomy but not by orchidectomy. Orchidectomized male mice, but not ovariectomized female mice, showed significantly lower levels of PDE5 mRNA expression in tail artery compared with those of sham-operated mice. The present findings suggest that estrogen withdrawal, but not testosterone withdrawal, is a risk factor for PDE5 inhibitor-induced flushing. These gender differences in the vascular adverse reactions of PDE5 inhibitors may be interpreted as occurring due to differences in the levels of PDE5 mRNA expression in peripheral arteries.