High-dose morphine impairs vascular endothelial function by increased production of superoxide anions.
BACKGROUND
The effects of high-dose morphine on vascular endothelial function have not been previously shown. The authors hypothesized that the pro-oxidant effect of high-dose morphine impairs vascular endothelial function.


METHODS
Mice were subjected to placebo or morphine (20 mg/kg intraperitoneal) injection for consecutive 14 days. Aortas were harvested for assessment of vasomotor function by isometric force recordings. Protein expression p47phox was determined by Western blotting. Generations of superoxide anions were detected under a confocal microscope.


RESULTS
Compared with controls, contraction response to phenylephrine was significantly enhanced in the aorta of mice treated with high-dose morphine (maximal contractions were 150 +/- 26 vs. 261 +/- 32 mg, respectively; n = 5 or 6, P = 0.04). Endothelium-dependent relaxations to acetylcholine (10 to 10 m) were significantly reduced in morphine-treated animals but were normalized by superoxide scavenging. Fluorescent densities of dihydroethidium were increased in the aorta of morphine-treated mice. Aorta of mice treated with morphine expressed higher levels of p47phox (a major subunit of nicotinamide adenine dinucleotide phosphate oxidase). In cultured endothelial cells, morphine enhanced production of reactive oxygen species.


CONCLUSIONS
Collectively, the authors' results showed that high-dose morphine impairs vascular endothelial function via attenuation of biologic activity of endothelium-derived nitric oxide. Chemical antagonism between superoxide anions generated by nicotinamide adenine dinucleotide phosphate oxidases may be the molecular mechanism responsible for the inactivation of endogenous nitric oxide after treatment with high-dose morphine.
Lam
Chen-Fuh
CF
Department of Anesthesiology, National Cheng Kung University Medical College and Hospital, Tainan City, Taiwan.
Liu
Yen-Chin
YC
Tseng
Fan-Ling
FL
Sung
Yen-Hui
YH
Huang
Chien-Chi
CC
Jiang
Meei-Jyh
MJ
Tsai
Yu-Chuan
YC
D000109:Acetylcholine / Q000008:administration & dosage; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western / Q000379:methods; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004996:Ethidium / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D007274:Injections, Intraperitoneal / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D009924:Organ Culture Techniques; D010656:Phenylephrine / Q000008:administration & dosage; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D014662:Vasoconstrictor Agents / Q000008:administration & dosage; D014665:Vasodilator Agents / Q000008:administration & dosage; D014666:Vasomotor System / Q000187:drug effects*
D000701:Analgesics, Opioid; D017382:Reactive Oxygen Species; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C067883:dihydroethidium; D013481:Superoxides; D010656:Phenylephrine; D009569:Nitric Oxide; D009020:Morphine; D004996:Ethidium; D000109:Acetylcholine