Abstract
Overproduction of nitric oxide (NO) by gene transduction of endothelial NO synthase (eNOS) in rostral ventrolateral medulla (RVLM), which is responsible for maintenance of vasomotor tone, reduces arterial pressure in spontaneously hypertensive rats (SHR). This NO-induced vasodepression, however, is not sustained and is followed by rebound hypertension. Because superoxide anion () level is increased and synthesis or activity of mitochondrial manganese superoxide dismutase (SOD2) is reduced in RVLM during hypertension, we hypothesized that an interaction between NO and in RVLM, using mitochondrial respiratory enzyme complexes (MRC) as the cellular target, contributes to those cardiovascular outcomes after eNOS gene transduction in SHR. The present study assessed this hypothesis using adenoviral vectors to overexpress eNOS (AdeNOS) and/or SOD2 (AdSOD2) in RVLM of SHR or normotensive Wistar-Kyoto (WKY) rats. Microinjection of AdeNOS bilaterally into RVLM elicited 35% depression of MRC-I enzyme activity and evoked 60% and 50% increase in and peroxynitrite level in RVLM of SHR, but not WKY rats, which was reversed by cotransduced AdSOD2 or treatment with peroxynitrite decomposition catalyst. Cotransduction of AdeNOS and AdSOD2 in RVLM of SHR elicited significantly greater decreases in arterial pressure and heart rate than those promoted by the individual transgene and prevented the AdeNOS-induced rebound hypertension. We conclude that an interactive action between NO and on MRC-I in RVLM via formation of peroxynitrite contributes to the unsustained hypotensive effects of NO after overexpression of eNOS in SHR. The mitochondria-derived also mediates the rebound hypertension induced by eNOS transgene in RVLM of SHR.
Footnotes
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This study was supported by research grants NSC-97-2752-B-110-001-PAE (S.H.H.C.) and NSC-97-2752-B075-B-001-PAE (M.H.T., J.Y.H.C.) from National Science Council, and VGHKS 96G-21 from Kaohsiung Veterans General Hospital (J.Y.H.C.), Taiwan, Republic of China.
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ABBREVIATIONS: NO, nitric oxide; RVLM, rostral ventrolateral medulla; eNOS, endothelial nitric-oxide synthase; MRC, mitochondrial respiratory enzyme complex; UCP-2, uncoupling protein-2; SOD1, copper/zinc superoxide dismutase; SOD2, manganese superoxide dismutase; SOD3, extracellular superoxide dismutase; SHR, spontaneously hypertensive rat; AdeNOS, adenoviral vectors encoding endothelial nitric-oxide synthase; AdSOD2, adenoviral vectors encoding manganese superoxide dismutase; WKY, Wistar-Kyoto; GFP, green fluorescence protein; AdGFP, adenoviral vectors encoding green fluorescence protein; Adβgal, adenoviral vectors encoding β-galactosidase; pfu, plaque-forming unit; CoQ10, coenzyme Q10; NOS, nitric-oxide synthase; l-NAME, Nω-nitro-l-arginine-methyl ester; l-NIO, N5-(1-iminoethyl)-l-ornithine; FeTMPyP, 5,10,15,20-tetrakis-(N-methyl-4′-pyridyl)-porphyrinato iron (III); aCSF, artificial cerebrospinal fluid; MSAP, mean systemic arterial pressure; HR, heart rate; NCCR, NADH cytochrome c reductase; SCCR, succinate cytochrome c reductase; nNOS, neuronal nitric-oxide synthase; iNOS, inducible nitric-oxide synthase; RT, reverse transcription; PCR, polymerase chain reaction; CCO, cytochrome c oxidase.
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↵ The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
- Received May 12, 2008.
- Accepted August 19, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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