Tetrahydrobiopterin restores diastolic function and attenuates superoxide production in ovariectomized mRen2.Lewis rats.

After oophorectomy, mRen2.Lewis rats exhibit diastolic dysfunction associated with elevated superoxide, increased cardiac neuronal nitric oxide synthase (nNOS) expression, and diminished myocardial tetrahydrobiopterin (BH₄) content, effects that are attenuated with selective nNOS inhibition. BH₄ is an essential cofactor of nNOS catalytic activity leading to nitric oxide production. Therefore, we assessed the effect of 4 wk BH₄ supplementation on diastolic function and left ventricular (LV) remodeling in oophorectomized mRen2.Lewis rats compared with sham-operated controls. Female mRen2.Lewis rats underwent either bilateral ovariectomy (OVX) (n = 19) or sham operation (n = 13) at 4 wk of age. Beginning at 11 wk of age, OVX rats were randomized to receive either BH₄ (10 mg/kg · d) or saline, whereas the sham rats received saline via sc mini-pumps. Loss of ovarian hormones reduced cardiac BH₄ when compared with control hearts; this was associated with impaired myocardial relaxation, augmented filling pressures, increased collagen deposition, and thickened LV walls. Additionally, superoxide production increased and nitric oxide decreased in hearts from OVX compared with sham rats. Chronic BH₄ supplementation after OVX improved diastolic function and attenuated LV remodeling while restoring myocardial nitric oxide release and preventing reactive oxygen species generation. These data indicate that BH₄ supplementation protects against the adverse effects of ovarian hormonal loss on diastolic function and cardiac structure in mRen2.Lewis rats by restoring myocardial NO release and mitigating myocardial O₂⁻ generation. Whether BH₄ supplementation is a therapeutic option for the management of diastolic dysfunction in postmenopausal women will require direct testing in humans.