Effects of calmodulin and lipoxygenase inhibitors on LH (lutropin)- and LHRH (luliberin)-agonist-stimulated steroidogenesis in rat Leydig cells.
The results of this study, carried out with purified rat Leydig cells, indicate that there are no major differences in the stimulating effects of lutropin (LH) and luliberin (LHRH) agonists on steroidogenesis via mechanisms that are dependent on Ca2+. This was demonstrated by using inhibitors of calmodulin and the lipoxygenase pathways of arachidonic acid metabolism. All three calmodulin inhibitors used (calmidazolium, trifluoperazine and chlorpromazine) were shown to block LH- and LHRH-agonist-stimulated steroidogenesis. This probably occurred at the step of cholesterol transport to the mitochondria. Similarly, three lipoxygenase inhibitors (nordihydroguaiaretic acid, BW755c and benoxaprofen), inhibited both LH- and LHRH-agonist-stimulated steroidogenesis. The amounts of the inhibitors required were similar for LH- and LHRH-agonist-stimulated steroidogenesis. Steroidogenesis stimulated by the Ca2+ ionophore A23187 was also inhibited, but higher concentrations of the inhibitors were required. Indomethacin (a cyclo-oxygenase inhibitor) increased LHRH-agonist-stimulated steroidogenesis;this is consistent with the role of the products of arachidonic acid metabolism via the alternative, lipoxygenase, pathway. The potentiation of LH-stimulated testosterone production by LHRH agonist was unaffected by indomethacin or by lipoxygenase inhibitors at concentrations that inhibited LH-stimulated testosterone production by 75-100%. It was not possible to eliminate a role of calmodulin in modulating the potentiation, although higher concentrations of the inhibitors were generally required to negate the potentiation than to inhibit LH- or LHRH-agonist-stimulated testosterone production.
D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D000818:Animals; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007985:Leydig Cells / Q000187:drug effects / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors; D007986:Luteinizing Hormone / Q000494:pharmacology*; D008297:Male; D011422:Propionates / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D013739:Testosterone / Q000096:biosynthesis*; D014268:Trifluoperazine / Q000494:pharmacology
D002147:Calmodulin; D007093:Imidazoles; D016859:Lipoxygenase Inhibitors; D011422:Propionates; D011720:Pyrazoles; C011677:benoxaprofen; D014268:Trifluoperazine; D013739:Testosterone; C031938:calmidazolium; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D007986:Luteinizing Hormone; D007213:Indomethacin