Regression of endothelial dysfunction via enhanced no synthesis by long-term raloxi-fene treatment of old male and female SHR

Abstract

Raloxifene (RAL) a selective estrogen receptor modulator (SERM), effective for the prevention of postmenopausal osteoporosis also has been shown to stimulate acutely nitric oxide (NO) synthesis associated with improved endothelium-dependent relaxation. We studied the effects of 3 month RAL treatment (10 mg/kg/d) on aortic NO bioavailability and relaxation in 9 month old male and female ovarectomized (OVX) SHR. Furthermore, basal blood pressure (BP), measured via the carotid artery, and its challenge with increasing doses of intravenous bradykinin (1, 3 and 10 nmol/kg) was investigated. Calcium ionophore stimulated NO release from aortic endothelial cells and aortic superoxide (O2-) production were directly assessed by using a porphyrinic microsensor and by chemiluminescence method, respectively. Relaxation studies were performed with acetylcholine (10-7 to 10-5 mol/L) following preconstriction with KCl (20 mmol/L). RAL significantly enhanced NO release from 125 ± 5 (placebo treated male SHR) to 360 ± 15 nmol/L. Vice versa O2- was decreased from 110 ± 15 to 22 ± 1 nmol/L. In female SHR OVX led to an increase/decrease of NO/O2- from 130 ± 5 to 180 ± 10 nmol/L and 82 ± 7 to 68 ± 3 nmol/L, respectively. These effects were significantly amplified by RAL treatment (NO:370 ± 10 and O2-:25 ± 2 nmol/L). Aortic rings from RAL treated animals of both gender showed significantly improved relaxations. In contrast to females BP was only significantly decreased in male RAL treated SHR. However, the dose-dependent bradykinin-induced BP reduction was enhanced by RAL treatment in rats of both gender. Our results show that long-term treatment with RAL has beneficial effects on the cardiovascular system in old male and female OVX SHR via an increased NO bioavailability.