Soluble Guanylate Cyclase Redox State Under Hypoxia or Hypoxia/Reoxygenation in Isolated Monkey Coronary Arteries

• Published in: Journal of Pharmacological Sciences 2014/06/20, Vol.125(2), pp.169-175
• Main Authors: Tawa, Masashi, Geddawy, Ayman, Shimosato, Takashi, Iwasaki, Hirotaka, Imamura, Takeshi, Okamura, Tomio
• Format: Article
• Language: English
• Subjects: Animals; Benzoates - antagonists & inhibitors; Benzoates - pharmacology; Biphenyl Compounds - antagonists & inhibitors; Biphenyl Compounds - pharmacology; cGMP; coronary artery; Coronary Vessels - enzymology; Coronary Vessels - metabolism; Coronary Vessels - physiopathology; Cyclic GMP - metabolism; Female; Guanylate Cyclase - metabolism; Hydrocarbons, Fluorinated - antagonists & inhibitors; Hydrocarbons, Fluorinated - pharmacology; hypoxia; Hypoxia - enzymology; Hypoxia - metabolism; Hypoxia - physiopathology; In Vitro Techniques; Macaca; Male; Nitric Oxide - metabolism; Nitric Oxide - physiology; Oxidation-Reduction; Oxidative Stress; Pyrazoles - antagonists & inhibitors; Pyrazoles - pharmacology; Pyridines - antagonists & inhibitors; Pyridines - pharmacology; reoxygenation; Solubility; soluble guanylate cyclase; Superoxide Dismutase - pharmacology; Superoxides - metabolism; Vasodilation - drug effects
• ISSN: 1347-8613; 1347-8648
• DOI: 10.1254/jphs.14046FP

Hypoxia or hypoxia/reoxygenation impairs nitric oxide (NO)-mediated relaxation through the increase in superoxide generation in monkey coronary arteries. Soluble guanylate cyclase (sGC), the target enzyme of NO, has been shown to change from the NO-sensitive reduced form to the NO-insensitive oxidized/heme-free form under substantial oxidative stress, so the present study investigated whether hypoxia or hypoxia/reoxygenation influences sGC redox equilibrium. In isolated monkey coronary arteries without endothelium, the relaxation caused by the sGC stimulator BAY 41-2272 (Emax: 93.3% ± 2.2%) was somewhat impaired under hypoxia (Emax: 86.3% ± 2.6%) or hypoxia/reoxygenation (Emax: 86.1% ± 3.2%), whereas that by the sGC activator BAY 60-2770 (Emax: 86.0% ± 3.2%) was significantly augmented under hypoxia (Emax: 94.4% ± 1.3%) or hypoxia/reoxygenation (Emax: 95.5% ± 1.1%). In addition, cGMP formation in response to BAY 41-2272 and BAY 60-2770 was inhibited and stimulated, respectively, under hypoxia or hypoxia/reoxygenation. The effects of hypoxia or hypoxia/reoxygenation on BAY 41-2272– and BAY 60-2770–induced vasorelaxation were completely canceled by the treatment with the superoxide dismutase mimetic tempol. These findings suggest that sGC redox equilibrium in the coronary artery is shifted towards the NO-insensitive form under hypoxia or hypoxia/reoxygenation and that superoxide seems to play an important role in this shift. [Supplementary Figures: available only at http://dx.doi.org/10.1254/jphs.14046FP]