title: Prostaglandins and nitric oxide mediate superoxide-induced myocardial contractile dysfunction in isolated rat hearts.
abstract: Oxygen-derived free radicals have been implicated in the pathogenesis of myocardial injury. We therefore investigated the pathophysiology of myocardial injury induced in isolated rat hearts by perfusion with superoxide radical generated by reacting 2.5 mmol/l purine, 0.03 U/ml xanthine oxidase and 300 U/ml catalase. Perfusion with superoxide significantly (P<0.05) increased left ventricular end-diastolic pressure within 15 to 20 min. During the same time period, heart rate and left-ventricular developed pressure significantly declined to 44.6+/-8.2% and 31.0+/-4.9% of control, respectively. Superoxide perfusion also significantly increased production of prostaglandins, nitric oxide (detected as nitrites) and peroxynitrite (detected immunohistochemically as nitrotyrosine). N(G)-nitro-l-arginine (100 micromol/l), a nitric oxide synthase inhibitor, attenuated superoxide-induced generation of peroxynitrite, increased synthesis of prostacyclin, and partially blocked myocardial dysfunction, as did 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (30 micromol/l), a selective inhibitor of soluble guanylate cyclase, and ONO-3708 (10 micromol/l), a selective thromboxane A(2)receptor antagonist. In contrast, nitroglycerin (4 micromol/l) and sodium nitroprusside (1 micromol/l) each exacerbated the superoxide-induced myocardial dysfunction. These results suggest that nitric oxide and related reactive species contribute to myocardial injury induced by superoxide. Moreover, they suggest that oxidative stress can be delayed or inhibited by reducing levels of nitric oxide, by inhibiting soluble guanylate cyclase, and by blocking thromboxane/prostaglandin receptors.
authors.affiliation: Department of Physiology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, Japan 113.
authors.forename: S A
authors.initials: SA
authors.lastname: Gupte
authors.forename: T
authors.initials: T
authors.lastname: Okada
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism*; D009566:Nitrates / Q000378:metabolism; D017942:Nitric Acid / Q000378:metabolism*; D019335:Nitroarginine / Q000494:pharmacology; D005996:Nitroglycerin / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011453:Prostaglandins / Q000096:biosynthesis / Q000378:metabolism*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D013481:Superoxides / Q000378:metabolism*; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D009566:Nitrates; D010069:Oxadiazoles; D010726:Phosphodiesterase Inhibitors; D010975:Platelet Aggregation Inhibitors; D011453:Prostaglandins; D011810:Quinoxalines; D014665:Vasodilator Agents; D013481:Superoxides; D009599:Nitroprusside; D005576:Colforsin; D019335:Nitroarginine; C039642:peroxynitric acid; D017942:Nitric Acid; D013928:Thromboxane A2; C049855:ONO 3708; D001219:Aspartate Aminotransferases; D005996:Nitroglycerin; D015056:1-Methyl-3-isobutylxanthine