Effect of OS-0544, a selective estrogen receptor modulator, on endothelial function and increased sympathetic activity in ovariectomized rats.
Estrogens are known to contribute to endothelial function and sympathetic activity, both of which are strongly associated with the pathogenesis of ischemic heart disease. In addition, estrogens improve impaired lipid profile, a risk factor of endothelial dysfunction. In this study, we investigated the effects of OS-0544, a structurally new selective estrogen receptor modulator (SERM), on endothelial function, sympathetic activity, and plasma cholesterol level in ovariectomized (OVX) rats. Female Sprague-Dawley rats were ovariectomized and orally treated with OS-0544 (or OS-0689, the (R)-enantiomer of OS-0544), or 17beta-estradiol (E2) for 4 weeks, starting the next days after ovariectomy or for 1 week, starting 6 weeks after ovariectomy. Ovariectomy significantly increased vasopressin-induced mean blood pressure (AVP-MBP) (57+/-3.3 mm Hg vs. 46+/-3.5 mm Hg, P<0.05) and decreased acetylcholine (Ach)-induced maximum vasorelaxation response (69+/-5.6% vs. 81+/-4.0%, P<0.05). OS-0544 significantly inhibited AVP-MBP elevation (46+/-3.5 mm Hg vs. 57+/-3.3 mm Hg, P<0.05) and decreased Ach-induced maximum vasorelaxation response (90+/-3.3% vs. 69+/-5.6%, P<0.05) in OVX rats. In addition, OS-0689 as well as E2 significantly reduced (up to 67%) the increase in sympathetic activity in OVX rats. Moreover, like E2, OS-0544 significantly decreased plasma cholesterol level in OVX rats. These results demonstrate that OS-0544 has vascular protective effect on vascular function after ovariectomy. It is therefore believed that OS-0544 has vascular protective effect in postmenopausal woman.
Discovery Pharmacology I, Pharmacology Research Laboratories, Dainippon Sumitomo Pharmaceutical Co., Ltd., Osaka, Japan. akihisa-ikeno@ds-pharma.co.jp
Akihisa
A
Ikeno
Hisao
H
Minato
Chie
C
Kohayakawa
Jun-ichi
J
Tsuji
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology*; D005260:Female; D007189:Indans / Q000494:pharmacology*; D010052:Ovariectomy; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013141:Spiro Compounds / Q000494:pharmacology*; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects; D014667:Vasopressins / Q000494:pharmacology
C478564:3-(4-(1- piperidinoethoxy)phenyl)spiro(indene- 1,1'-indane)-5,5'-diol; D007189:Indans; D010880:Piperidines; D020845:Selective Estrogen Receptor Modulators; D013141:Spiro Compounds; D014667:Vasopressins; D002784:Cholesterol; D000109:Acetylcholine