Female sex hormones decrease constitutive endothelin-1 release via endothelial sigma-1/cocaine receptors: an action independent of the steroid hormone receptors.
Cardiovascular disease is rare in premenopausal women compared to men. The authors investigate sex hormone-induced endothelin-1 (ET-1) release and the involvement of classic sex hormone receptors as well as the ability of sigma-1/cocaine receptors to respond to sex hormones. ET-1 release was measured in the supernatant of endothelial cells after treatment with beta-estradiol, progesterone, testosterone, or combined with their antagonists, and with the sigma-1 receptor ligand ditolylguanidine (DTG), or haloperidol, a sigma-1 receptor antagonist. Binding assays were performed using 2.5 x 10(-8) M [3H]DTG. Female sex hormones decreased ET-1 release whereas testosterone increased it, sex hormone antagonists only slightly attenuated or had no effect on the respective hormone's effect. DTG totally blocked the female sex hormone-induced inhibition on ET-1 release, whereas testosterone-induced stimulation was not affected. However, haloperidol blocked both. [3H]DTG binding was displaced by beta -estradiol but not by testosterone. DTG-binding sites account for 513 +/- 114 per cell, KD 8.79 nM. These data suggest that besides classic steroid hormone receptors, sigma-1/cocaine receptors mediate the effects of female sex hormones on ET-1 release, an up to now unknown signalling pathway. Results also suggest that female and male sex hormones may bind to different sites on sigma-1 receptors, exerting opposite pharmacological effects.
Wilbert-Lampen
U
U
Medizinische Klinik und Poliklinik I, Klinikum Grosshadern, Ludwig-Maximilians Universität, München, Germany. uwilbert@med.uni-muenchen.de
Seliger
C
C
Trapp
A
A
Straube
F
F
Plasse
A
A
D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D011374:Progesterone / Q000494:pharmacology; D011955:Receptors, Drug / Q000502:physiology*; D011987:Receptors, Steroid / Q000187:drug effects / Q000502:physiology*; D017480:Receptors, sigma / Q000187:drug effects / Q000502:physiology*; D013552:Swine; D013739:Testosterone / Q000494:pharmacology
D002352:Carrier Proteins; D019332:Endothelin-1; D011955:Receptors, Drug; D011987:Receptors, Steroid; D017480:Receptors, sigma; C061445:cocaine receptor; D013739:Testosterone; D011374:Progesterone; D004958:Estradiol