Mitochondrial respiratory enzyme complexes in rostral ventrolateral medulla as cellular targets of nitric oxide and superoxide interaction in the antagonism of antihypertensive action of eNOS transgene.
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 (O(2)(*-)) 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 O(2)(*-) 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 O(2)(*-) 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 O(2)(*-) 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 O(2)(*-) also mediates the rebound hypertension induced by eNOS transgene in RVLM of SHR.
Kung
Ling-Chang
LC
Department of Neurology, Antai Tian-Sheng Memorial Hospital, Pintong, Taiwan, Republic of China.
Chan
Samuel H H
SH
Wu
Kay L H
KL
Ou
Chen-Chun
CC
Tai
Ming-Hon
MH
Chan
Julie Y H
JY
D000818:Animals; D001483:Base Sequence; D001794:Blood Pressure; D017931:DNA Primers; D006339:Heart Rate; D008526:Medulla Oblongata / Q000201:enzymology / Q000378:metabolism*; D008928:Mitochondria / Q000201:enzymology* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013481:Superoxides / Q000378:metabolism*; D014161:Transduction, Genetic; D019076:Transgenes
D017931:DNA Primers; D013481:Superoxides; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III