title: Restoration of endothelial function via enhanced nitric oxide synthesis after long-term treatment of raloxifene in adult hypertensive rats.
abstract: Raloxifene (CAS 84449-90-1, RAL), a selective estrogen receptor modulator (SERM) effective for the prevention of post-menopausal osteoporosis, also has been shown to acutely stimulate nitric oxide (NO) synthesis associated with improved endothelium-dependent relaxation. The effect of a 3-month RAL treatment (10 mg/kg/d) on basal blood pressure, measured via the carotid artery, and its challenge with increasing doses of intravenous bradykinin (1, 3 and 10 nmol/kg) was investigated. Furthermore, aortic NO bioavailability and relaxation in 9-month-old male and female ovarectomized (OVX) spontaneously hypertensive rats (SHR) was tested. Calcium ionophore stimulated NO release from aortic endothelial cells and aortic superoxide (O2-) production was directly assessed by using electrochemical nanosensors. Relaxation studies were performed with acetylcholine (10(-8) to 10(-5) mol/L) following precontraction with phenylephrine (10(-7) mmol/L). Whereas basal blood pressure (BP) was not significantly decreased in RAL treated SHR, the dose-dependent challenge with bradykinin induced an enhanced BP reduction in either gender. In contrast to female animals, aortic segments from RAL treated male animals showed significantly improved relaxaSHR) to 360 +/- 15 nmol/L. Vice versa, O2- was decreased from 110 +/- 15 to 22 +/- 1 nmol/L. In female SHR, ovarectomy 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). The results show that long-term treatment with RAL has beneficial affects on the cardiovascular system in old male and female OVX SHR via an increased NO bioavailability.
authors.affiliation: Aventis Pharma Deutschland GmbH, DG Cardiovascular Diseases, Frankfurt/Main, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Leitzbach
authors.forename: Nadine
authors.initials: N
authors.lastname: Weckler
authors.forename: Maria
authors.initials: M
authors.lastname: Madajka
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Malinski
authors.forename: Gabriele
authors.initials: G
authors.lastname: Wiemer
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Linz
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001920:Bradykinin / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology*; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009569:Nitric Oxide / Q000096:biosynthesis*; D010052:Ovariectomy; D020849:Raloxifene Hydrochloride / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D020845:Selective Estrogen Receptor Modulators / Q000627:therapeutic use*; D013481:Superoxides / Q000378:metabolism
chemical_list: D020845:Selective Estrogen Receptor Modulators; D013481:Superoxides; D009569:Nitric Oxide; D020849:Raloxifene Hydrochloride; D001920:Bradykinin