title: Effects of atipamezole, detomidine and medetomidine on release of steroid hormones by porcine adrenocortical cells in vitro.
abstract: The 4-substituted imidazole type alpha2-adrenoceptor ligands atipamezole, detomidine, and medetomidine were screened for actions on the release of aldosterone by a suspension of porcine adrenocortical cells with deoxycorticosterone (1 microM) as substrate. Progesterone, pregnenolone or corticosterone (all at 1 microM) were also used as substrates. With pregnenolone as substrate, drug-induced effects on the output of nine steroids (aldosterone, corticosterone, cortisol, deoxycortisol, testosterone, progesterone, 17alpha-hydroxyprogesterone, androstenedione, dehydroepiandrosterone) were monitored simultaneously. The alpha2-adrenoceptor antagonist atipamezole was a potent inhibitor of aldosterone release (range 10-1000 nM). The sedative alpha2-adrenoceptor agonists medetomidine and detomidine also inhibited aldosterone release (range 10-1000 nM). With pregnenolone as substrate, the inhibition induced by 4-substituted imidazoles of the release of corticosterone and cortisol was more pronounced than that of aldosterone. Androstenedione and deoxycortisol release was enhanced. The 4-substituted imidazoles atipamezole, detomidine, and medetomidine inhibited mitochondrial cytochrome P450(11beta/18) in vitro. This inhibition was unrelated to their alpha2-adrenoceptor actions. The 4-substituted imidazole type alpha2-adrenoceptor ligands used to control sedation/anaesthesia can alter the steroid-based defence mechanisms of the body.
authors.affiliation: D.L.O.-Central Veterinary Institute (CDI-DLO), Department of Biochemistry and Toxicology, Lelystad, Netherlands. l.p.jager@id.dlo.nl
authors.forename: L P
authors.initials: LP
authors.lastname: Jager
authors.forename: G J
authors.initials: GJ
authors.lastname: De Graaf
authors.forename: H C
authors.initials: HC
authors.lastname: Widjaja-Greefkes
mesh_terms: D000302:Adrenal Cortex / Q000187:drug effects* / Q000378:metabolism; D000305:Adrenal Cortex Hormones / Q000378:metabolism*; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D012739:Gonadal Steroid Hormones / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D020926:Medetomidine; D011485:Protein Binding; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000378:metabolism; D013552:Swine
chemical_list: D000305:Adrenal Cortex Hormones; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D012739:Gonadal Steroid Hormones; D007093:Imidazoles; D018341:Receptors, Adrenergic, alpha-2; C050701:atipamezole; C041255:detomidine; D020926:Medetomidine