Novel guanylyl cyclase inhibitor potently inhibits cyclic GMP accumulation in endothelial cells and relaxation of bovine pulmonary artery.
The aim of the present study was: 1) to determine the effects of the novel selective inhibitor of guanylyl cyclase, ODQ (1H-[1,2,4]oxadiazolo[4,3,-a]quinoxaline-1-one) on basal and agonist-stimulated cyclic GMP levels in cultured porcine aortic endothelial cells and bovine pulmonary artery strips; 2) to determine its effects on agonist-induced relaxations of bovine pulmonary artery strips; and 3) to compare pulmonary artery cyclic GMP levels with vessel relaxation. ODQ (1 nM-30 microM) inhibited cyclic GMP accumulation in endothelial cells stimulated with S-nitrosoglutathione, nitroprusside and 3-morpholine-sydnonimine at IC50 values of 40 to 100 nM. Complete suppression of cyclic GMP generation was observed at approximately 10 microM. Relaxation of pulmonary artery strips induced by S-nitrosoglutathione, nitroprusside, glycerol trinitrate, nitrite (all endothelium-independent), bradykinin and the Ca++ ionophore A23187 (endothelium-dependent) were antagonized by ODQ (1-10 microM) in a concentration-dependent way. A consistent feature of the inhibitor was that maximal relaxant effects also were reduced. Basal levels and agonist-induced increases in arterial tissue cyclic GMP were inhibited in the same concentration range. However, tissue cyclic GMP production correlated poorly with pulmonary artery relaxation in that relaxations induced by S-nitrosoglutathione were only inhibited in part (50%), whereas rises in cyclic GMP were abolished completely by ODQ (10 microM). Furthermore, at 1 microM, ODQ had no effect on relaxation induced by endothelium-dependent agonists, but prevented entirely stimulation of cyclic GMP accumulation in arterial tissue. These results suggest that ODQ inhibits nitrovasodilator-induced and endothelium-dependent relaxation through inhibition of guanylyl cyclase activation, but also point to the presence of a cyclic GMP-independent component of relaxation in bovine pulmonary artery.
Brunner
F
F
Institut für Pharmakologie und Toxikologie, Universität Graz, Austria.
Schmidt
K
K
Nielsen
E B
EB
Mayer
B
B
D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000096:biosynthesis*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005978:Glutathione / Q000031:analogs & derivatives / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors*; D005996:Nitroglycerin / Q000494:pharmacology; D009603:Nitroso Compounds / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D011810:Quinoxalines / Q000494:pharmacology*; D026422:S-Nitrosoglutathione; D013552:Swine; D014664:Vasodilation / Q000187:drug effects*
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D009603:Nitroso Compounds; D010069:Oxadiazoles; D011810:Quinoxalines; D026422:S-Nitrosoglutathione; D006162:Guanylate Cyclase; D005996:Nitroglycerin; D005978:Glutathione; D006152:Cyclic GMP