Contribution of peroxynitrite to fatal cardiovascular depression induced by overproduction of nitric oxide in rostral ventrolateral medulla of the rat

• Published in: Neuropharmacology 2002-10, Vol.43 (5), p.889-898
• Main Authors: Chan, S.H.H, Wang, L.-L, Ou, C.-C, Chan, J.Y.H
• Format: Article
• Language: English
• Subjects: Animals; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Blotting, Western; Cardiology. Vascular system; Cardiovascular depression; Cardiovascular Diseases - chemically induced; Cardiovascular Diseases - mortality; Clinical manifestations. Epidemiology. Investigative techniques. Etiology; Cyclic GMP - metabolism; Depression, Chemical; Fatality; Guanylate Cyclase - metabolism; Hemodynamics - drug effects; Inducible nitric oxide synthase; Male; Medical sciences; Medulla Oblongata - cytology; Medulla Oblongata - drug effects; Medulla Oblongata - metabolism; Microinjections; Muscle Tonus - drug effects; Muscle, Smooth, Vascular - drug effects; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide - toxicity; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase - biosynthesis; Nitric Oxide Synthase Type II; Peroxynitrite; Peroxynitrous Acid - metabolism; Peroxynitrous Acid - toxicity; Rats; Rats, Sprague-Dawley; Rostral ventrolateral medulla; Superoxide anion; Survival Analysis; Time Factors
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/S0028-3908(02)00146-6

We evaluated the contribution of peroxynitrite to the fatal cardiovascular depression induced by overproduction of nitric oxide (NO) after activation of inducible NO synthase (iNOS) in the rostral ventrolateral medulla (RVLM), the origin of sympathetic vasomotor tone. In Sprague–Dawley rats maintained under propofol anesthesia, microinjection of E. coli lipopolysaccharide (LPS) bilaterally into the RVLM elicited significant hypotension, bradycardia, reduction in sympathetic vasomotor tone and mortality. There was also a discernible elevation of iNOS expression in the ventrolateral medulla, followed by a massive production of nitrotyrosine, an experimental index for peroxynitrite. Co-administration bilaterally into the RVLM of the selective iNOS inhibitor, S-methylisothiourea (50, 100 or 250 pmol), an active peroxynitrite decomposition catalyst, 5,10,15,20-tetrakis- ( N-methyl-4′-pyridyl)-porphyrinato iron (III) (10 or 50 pmol), a peroxynitrite scavenger, l-cysteine (5, 50 or 100 pmol), or a superoxide dismutase mimetic, Mn(III)-tetrakis-(4-benzoic acid) porphyrin (1 or 10 pmol), significantly prevented mortality, reduced nitrotyrosine production and reversed the NO-induced cardiovascular suppression after application of LPS into the RVLM. We conclude that the formation of peroxynitrite by a reaction between superoxide anion and NO is primarily responsible for the fatal cardiovascular depression induced by overproduction of NO after activation of iNOS at the RVLM.