Failure of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (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 microM), 2,2'-(hydroxynitrosohydrazino)bis-ethana-mine (DETA NONOate; 100 microM), or carbachol (10 microM) increased cyclic GMP levels about 4 fold. These effects were abolished by ODQ (50 microM). 3. In cardiomyocytes, SNAP (100 microM), DETA NONOate (100 microM), or carbachol (10 microM) increased cyclic GMP levels about 2 fold. These effects were not affected by ODQ (50 microM). 4. In cytosolic extracts from aortic rings and cardiomyocytes, SNAP (100 microM) induced about 50 fold increases in cyclic GMP levels. ODQ (50 microM) reduced these effects by about 50%. 5. In extracts from cardiomyocytes, increases by SNAP (100 microM) of cyclic GMP levels were attenuated by myoglobin dependent on concentration: at 300 microM myoglobin, SNAP (100 microM) increased cyclic GMP levels only 3 fold. Inhibitory effects of ODQ (50 microM) were abolished by 300 microM 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).
Pharmakologisches Institut, Universität Mainz, Germany.
J W
JW
Wegener
E I
EI
Closs
U
U
Förstermann
H
H
Nawrath
D000818:Animals; D001013:Aorta, Thoracic; D002217:Carbachol / Q000494:pharmacology; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000096:biosynthesis / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors*; D006352:Heart Ventricles; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D010069:Oxadiazoles; D011810:Quinoxalines; D002217:Carbachol; D006162:Guanylate Cyclase; D006152:Cyclic GMP