Effects of hydrogen peroxide on relaxation through the NO/sGC/cGMP pathway in isolated rat iliac arteries.
The production of reactive oxygen species, including hydrogen peroxide (H(2)O(2)), is increased in diseased blood vessels. Although H(2)O(2) leads to impairment of the nitric oxide (NO)/soluble guanylate cyclase (sGC)/cGMP signaling pathway, it is not clear whether this reactive molecule affects the redox state of sGC, a key determinant of NO bioavailability. To clarify this issue, mechanical responses of endothelium-denuded rat external iliac arteries to BAY 41-2272 (sGC stimulator), BAY 60-2770 (sGC activator), nitroglycerin (NO donor), acidified NaNO(2) (exogenous NO) and 8-Br-cGMP (cGMP analog) were studied under exposure to H(2)O(2). The relaxant response to BAY 41-2272 (pD2: 6.79 ± 0.10 and 6.62 ± 0.17), BAY 60-2770 (pD2: 9.57 ± 0.06 and 9.34 ± 0.15) or 8-Br-cGMP (pD2: 5.19 ± 0.06 and 5.24 ± 0.08) was not apparently affected by exposure to H(2)O(2). In addition, vascular cGMP production stimulated with BAY 41-2272 or BAY 60-2770 in the presence of H(2)O(2) was identical to that in its absence. On the other hand, nitroglycerin-induced relaxation was markedly attenuated by exposing the arteries to H(2)O(2) (pD2: 8.73 ± 0.05 and 8.30 ± 0.05), which was normalized in the presence of catalase (pD2: 8.59 ± 0.05). Likewise, H(2)O(2) exposure impaired the relaxant response to acidified NaNO(2) (pD2: 6.52 ± 0.17 and 6.09 ± 0.16). These findings suggest that H(2)O(2) interferes with the NO-mediated action, but the sGC redox equilibrium and the downstream target(s) of cGMP are unlikely to be affected in the vasculature.
a Department of Pharmacology , Shiga University of Medical Science , Otsu , Shiga , Japan.
Masashi
M
Tawa
a Department of Pharmacology , Shiga University of Medical Science , Otsu , Shiga , Japan.
Takashi
T
Shimosato
a Department of Pharmacology , Shiga University of Medical Science , Otsu , Shiga , Japan.
Hirotaka
H
Iwasaki
a Department of Pharmacology , Shiga University of Medical Science , Otsu , Shiga , Japan.
Takeshi
T
Imamura
a Department of Pharmacology , Shiga University of Medical Science , Otsu , Shiga , Japan.
Tomio
T
Okamura
D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D007083:Iliac Artery / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D009924:Organ Culture Techniques; D010084:Oxidation-Reduction; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000071756:Soluble Guanylyl Cyclase; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; C528797:4-(((4-carboxybutyl) (2- (5-fluoro-2-((4'-(trifluoromethyl) biphenyl-4-yl)methoxy)phenyl)ethyl) amino)methyl)benzoic acid; D001565:Benzoates; D001713:Biphenyl Compounds; D006845:Hydrocarbons, Fluorinated; D011720:Pyrazoles; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP
cGMP; hydrogen peroxide; nitric oxide; soluble guanylate cyclase; vasorelaxation