Failure of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-(ODQ) to inhibit soluble guanylyl cyclase in rat ventricular cardiomyocytes

1 The effects of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), an inhibitor of soluble guanylyl cyclase (sGC), were investigated in aortic rings and ventricular cardiomyocytes from rats. The production of cyclic GMP was stimulated by NO.-donors or carbachol. Additionally, the effects of ODQ were studied in cytosolic extracts from both tissues in which the cyclic GMP production was stimulated by S-nitroso-N-acetylpenicillamine (SNAP). 2 In endothelium-intact aortic rings, SNAP (100 mu M), 2,2'-(hydroxynitrosohydrazino)bis-ethanamine (DETA NONOate; 100 mu M), or carbachol (10 mu M) increased cyclic GMP levels about 4 fold. These effects were abolished by ODQ (50 mu M). 3 In cardiomyocytes, SNAP (100 mu M), DETA NONOate (100 mu M), or carbachol (10 mu M) increased cyclic GMP levels about 2 fold. These effects were not affected by ODQ (50 mu M). 4 In cytosolic extracts from aortic rings and cardiomyocytes, SNAP (100 mu M) induced about 50 fold increases in cyclic GMP levels. ODQ (50 mu M) reduced these effects by about 50%. 5 In extracts from cardiomyocytes, increases by SNAP (100 mu M) of cyclic GMP levels were attenuated by myoglobin dependent on concentration: at 300 mu M myoglobin, SNAP (100 mu M) increased cyclic GMP levels only 3 fold. Inhibitory effects of ODQ (50 mu M) were abolished by 300 mu M myoglobin. 6 It is suggested that both NO. and ODQ can bind to myoglobin which, at high concentrations, can diminish their effects on sGC. Such a scavenger function of myoglobin could explain why NO. and ODQ exert only minor effects in cardiomyocytes (with high myoglobin content), but strong effects in aortic tissue (virtually devoid of myoglobin).