Acute vascular effects of the selective estrogen receptor modulator EM-652 (SCH 57068) in the rat mesenteric vascular bed.
OBJECTIVE
Selective estrogen receptor modulators (SERMs) represent a class of compounds that act as either estrogen receptor agonist or antagonist in a tissue-selective manner. SERMs exert beneficial effects on bone and lipids but are not associated with an increased risk of breast or uterine carcinoma. 17beta-estradiol (E2) and SERMs such as raloxifene and tamoxifen acutely relax coronary arteries. EM-652 (SCH 57068) is a 4th generation SERM acting as pure antiestrogen in the mammary gland and endometrium. The effects of SERMs on the mesenteric vasculature are unknown. In the present study, the vascular effects of EM-652 and E2 on the rat mesentery were investigated.


METHODS
Isolated perfused (5 ml/min) mesenteric vascular bed (MVB) was preconstricted with methoxamine. Increasing doses (0.1-10 microM) of EM-652 or E2 were infused into the perfusate.


RESULTS
EM-652 and E2 relaxed MVBs removed from intact and gonadectomized female and male rats. The amplitude of EM-652 responses was consistently greater than those of E2 and its potency was similar or greater than that of other SERMs. EM-652 and E2 relaxed MVB by an endothelium-independent mechanism. The estrogen receptor (ER) antagonist ICI 182,780 attenuated E2-induced relaxations but only partially block the effects of EM-652. Inhibition of the nitric oxide synthase/cGMP pathway with N(G)-nitro-arginine-methyl-ester (L-NAME) and 1H-(1,2,4)oxadiazolo(4,3-a)quinoxaline-1-one (ODQ) or of prostanoid synthesis with indomethacin failed to reduce EM-652 responses. The vascular effects of EM-652 were also unaffected by potassium channels blockers or inhibitors/scavengers of reactive oxygen species. EM-652 attenuated the vasoconstrictor responses induced by adrenergic agonists and endothelin-1.


CONCLUSIONS
EM-652 acutely relaxes the mesenteric vasculature by an endothelium-independent pathway which is partly mediated by ER, providing a novel mechanism by which this SERM may exert beneficial actions on the vascular system.
Tatchum-Talom
Rabelais
R
Department of Physiology & Lipid Research Unit, Laval University Hospital Research Center, RC 9502-2705 Blvd Laurier, G1V 4G2, Ste-Foy, Québec, Canada.
Martel
Céline
C
Labrie
Fernand
F
Marette
André
A
D000818:Animals; D006152:Cyclic GMP / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D008297:Male; D008729:Methoxamine / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology*; D015221:Potassium Channels / Q000502:physiology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D011960:Receptors, Estrogen / Q000502:physiology; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013152:Splanchnic Circulation / Q000187:drug effects* / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*
D010880:Piperidines; D015221:Potassium Channels; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009569:Nitric Oxide; C012121:ritetronium; D004958:Estradiol; D006152:Cyclic GMP; D008729:Methoxamine