Role of cytochrome P450 metabolites of arachidonic acid in regulation of corporal smooth muscle tone in diabetic and older rats.
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.
Yousif
Mariam H M
MH
Department of Pharmacology & Toxicology, Faculty of Medicine, Kuwait University, Kuwait.
Benter
Ibrahim F
IF
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000375:Aging / Q000378:metabolism*; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism* / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D054086:KATP Channels / Q000502:physiology; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000502:physiology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D010413:Penis / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar
D006893:Hydroxyeicosatetraenoic Acids; D054086:KATP Channels; D051036:Large-Conductance Calcium-Activated Potassium Channels; D016718:Arachidonic Acid; C046783:11,12-epoxy-5,8,14-eicosatrienoic acid; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D015126:8,11,14-Eicosatrienoic Acid