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  • Title: Role of cytochrome P450 metabolites of arachidonic acid in regulation of corporal smooth muscle tone in diabetic and older rats.
    Author: Yousif MH, Benter IF.
    Journal: Vascul Pharmacol; 2007; 47(5-6):281-7. PubMed ID: 17855173.
    Abstract:
    This study examined the role of cytochrome P450 (CYP) metabolites of arachidonic acid (AA) to rat corporal smooth muscle tone. 11, 12-Epoxyeicosatrienoic acid (EET) (10(-11)-10(-6 )M) produced dose-dependent relaxation of rat (control; 10 weeks old) corpus cavernosum with a pD(2) value of 8.8+/-0.2 and a maximal relaxation of 80+/-9%, whereas 20-hydroxyeicosatetraenoic (20-HETE) did not have an effect. EET-mediated relaxation of corpus cavernosum was attenuated by 71+/-3%, 55+/-2%, 53+/-5% and 84+/-3% in the presence of nitro-L-arginine methyl ester (L-NAME) (10(-4) M), an inhibitor of nitric oxide (NO) synthase, iberiotoxin (5 x 10(-8) M), an inhibitor of calcium-activated potassium (BK) channels, glibenclamide (10(-5) M), an inhibitor of ATP-sensitive K(+) channels or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (10(-5) M), an inhibitor of soluble guanylyl cyclase, respectively. EET-mediated relaxation of rat corpus cavernosum was significantly less in the streptozotocin (STZ)-treated (diabetic) and 30 weeks old (older) animals compared to control. Carbachol (10(-9)-10(-4) M)-induced relaxation was significantly reduced whereas phenylephrine (PE) (10(-9)-5 x 10(-3) M)-induced contraction was significantly increased in the cavernosum strips from old and diabetic rats compared to the control. Pre-incubation of the cavernosum strips obtained from control, older or diabetic rats with N-hydroxy-N'-(4-butyl-2-methyl-phenyl)-formamidine (HET0016), a selective inhibitor of 20-HETE synthesis, or 1-cyclohexyl-3-dodecyl urea (CDU), a specific inhibitor of soluble epoxide hydrolase (sEH) resulted in a significant attenuation of PE-induced contraction and improvement in carbachol-induced relaxation. We conclude that 11, 12-EET-induced relaxation of the rat corpus cavernosum involves activation of cGMP/NO pathway as well as activation of ATP-sensitive K(+) channels and BK channels. These results also suggest that inhibition of 20-HETE production or reduction of EET inactivation may have therapeutic potential to prevent erectile dysfunction associated with diabetes and aging.
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