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 inhi bitor 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 wer e studied in cytosolic extracts from both tissues in which the cyclic GMP p roduction was stimulated by S-nitroso-N-acetylpenicillamine (SNAP). 2 In endothelium-intact aortic rings, SNAP (100 mu M), 2,2'-(hydroxynitroso hydrazino)bis-ethanamine (DETA NONOate; 100 mu M), or carbachol (10 mu M) i ncreased cyclic GMP levels about 4 fold. These effects were abolished by OD Q (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) redu ced these effects by about 50%. 5 In extracts from cardiomyocytes, increases by SNAP (100 mu M) of cyclic G MP levels were attenuated by myoglobin dependent on concentration: at 300 m u M myoglobin, SNAP (100 mu M) increased cyclic GMP levels only 3 fold. Inh ibitory 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 hig h concentrations, can diminish their effects on sGC. Such a scavenger funct ion 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).