Cytochrome P450 epoxygenases provide a novel mechanism for penile erection.
Erectile dysfunction (ED) is estimated to affect more than 30 million American men and 152 million men worldwide. Therapeutic agents targeting the nitric oxide/cyclic GMP signaling pathway have successfully treated patients with ED; however, the efficacies of these treatments are significantly lower in specific populations such as patients with diabetes. The goal of this study was to discover and identify new endothelium-derived relaxing factors involved in the regulation of erectile function, providing alternative therapeutic targets for treatment of ED. Immunoblotting results showed that protein expressions of epoxygenases from cytochrome P450 (CYP)2B, 2C and 2J subfamilies, as well as NADPH CYP reductase were present in rat corpora cavernosa, which was confirmed by immunohistochemical analysis. Furthermore, CYP2C was localized in cavernosal endothelial cells using double immunolabeling. CYP epoxygenase activity was analyzed by reverse-phase high-pressure liquid chromatography; and the results showed that 11,12- epoxyeicosatrienoic acid (EET) was the major product metabolized by CYP epoxygenases in rat corpora cavernosa. Inhibition of EETs function by injection of an EETs antagonist into rat penis significantly decreased intracavernosal pressure-induced by electrical stimulation of the major pelvic ganglion in vivo. In conclusion, our results suggest that EETs, produced by CYP epoxygenases, in penile endothelial cells serve as vasodilators. Inhibition of this pathway attenuated erectile function, suggesting that EETs are required for normal erection.
Jin
Liming
L
Department of Physiology,Medical College of Georgia, Augusta, Georgia, USA. ljin8@jhmi.edu
Foss
Clare E
CE
Zhao
Xueying
X
Mills
Thomas M
TM
Wang
Mong-Heng
MH
McCluskey
Lynnette P
LP
Yaddanapud
Ganesh S S
GS
Falck
John R
JR
Imig
John D
JD
Webb
R Clinton
RC
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000145:classification / Q000502:physiology*; D004558:Electric Stimulation; D004790:Enzyme Induction; D008297:Male; D008861:Microsomes / Q000201:enzymology; D009251:NADPH-Ferrihemoprotein Reductase / Q000032:analysis / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology; D010410:Penile Erection / Q000502:physiology*; D010413:Penis / Q000201:enzymology* / Q000502:physiology; D011312:Pressure; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000502:physiology
C494022:14,15-eicosa-5-enoic acid; D001095:Arachidonic Acids; D009569:Nitric Oxide; C046783:11,12-epoxy-5,8,14-eicosatrienoic acid; D003577:Cytochrome P-450 Enzyme System; C507848:CYP2C9 protein, rat; D009251:NADPH-Ferrihemoprotein Reductase; D015126:8,11,14-Eicosatrienoic Acid