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This study tested the hypothesis that nitric oxide (NO) inhibits the rate-limiting catalytic step in steroidogenesis, cytochrome P450 cholesterol side-chain cleaving enzyme (CYP11A1), independent of soluble guanylyl cyclase (GC-S) stimulation. To assess CYP11A1 activity, pregnenolone levels were quantified in murine adrenocortical Y1 cells in the presence of the 3beta-hydroxy-Delta(5)-steroid dehydrogenase inhibitor, 2alpha-cyano-17beta-hydroxy4,4',17alpha-trimethylandrost-5-ene-3-one. The NO donor, (Z)-1-[2-(2-aminoethyl-N-(2ammonioethyl)amino]diazen-1-ium-1,2-diolate(deta nonoate), inhibited vasoactive intestinal peptide-, forskolinand 22alpha-hydroxycholesterol (22HC)-facilitated pregnenolonogenesis in the absence of GC-S activation and in the presence of a GC-S inhibitor, 1H[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). CYP11A1 was also heterologously expressed in monkey COS7 cells. Deta nonoate inhibited 22HC-facilitated activity of the over-expressed enzyme in the absence of GC-S activation and in the presence of ODQ. The NO-independent, GC-S agonist, 1-benzyl-3-(5'-hydroxymethyl-2'-furyl)indazole did not inhibit steroidogenesis. The IC(50) for effects of free NO on CYP11A1 was potent and in the 0.4-2 microM range. These results support the hypothesis that NO inhibits the rate-limiting enzyme in steroidogenesis independent of GC-S activation. ----------------------------------Biol Reprod. 2010 Sep;83(3):434-42. Epub 2010 May 12. Testosterone-induced modulation of nitric oxide-cGMP signaling pathway and androgenesis in the rat Leydig cells. Andric SA, Janjic MM, Stojkov NJ, Kostic TS. Reproductive Endocrinology and Signaling Group, Department of Biology and Ecology, Faculty of Sciences, University of Novi Sad, Novi Sad, Serbia.