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

3-Morpholinylsydnonimine Inhibits Glutamatergic Transmission in Rat Rostral Ventrolateral Medulla via Peroxynitrite Formation and Adenosine Release

“…In conclusion, this study provides for the first time clear evidence that higher doses of SIN-1 may inhibit presynaptic release of glutamate through the formation of peroxynitrite, which subsequently acts to release adenosine to activate presynaptic A 1 adenosine receptors. One known pathological condition that is associated with high levels of NO in the RVLM is endotoxemia (Morimoto et al, 2000;Kishi et al, 2001;Chan et al, 2002). We demonstrated previously (Chan et al, 2001) that the detrimental cardiovascular depression during the progression toward death in a rat model of experimental endotoxemia is associated with the progressive augmentation in both molecular synthesis and functional expression of the iNOS in the RVLM.…”

“…It has been known for a considerable time that NO and glutamate are both important mediators at the RVLM in central cardiovascular regulation (Shapoval et al, 1991;Zanzinger et al, 1995;Hirooka et al, 1996;Kagiyama et al, 1997;Martins-Pinge et al, 1997;Ishide et al, 2000;Chan et al, 2002;Zanzinger, 2002;Morrison, 2003). However, the functional interactions between these two mediators remain poorly understood.…”

“…There is some evidence that the effects of high concentrations of NO are related to the formation of peroxynitrite (OONO-) via a reaction between NO and superoxide anion (O 2 . ) (Blough and Zafiriou, 1985;Muijsers et al, 1997;Chan et al, 2002). Thus, the aim of the present study was to determine the effect of peroxynitrite in SIN-1-induced synaptic depression on the RVLM neurons, along with delineation of the underlying cellular mechanisms.…”

Downregulation of Angiotensin Subtype 1 Receptor in Rostral Ventrolateral Medulla During Endotoxemia

“…[12][13][14][15] On the other hand, we reported recently that NO produced by iNOS in the RVLM elicits sympathoinhibition 4,5 through GABAergic neurotransmission. 6 Furthermore, fatal cardiovascular depression associated with overproduction of NO in the RVLM during endotoxemia 4,5 engages the formation of peroxynitrite. 5 It follows that the progressive reduction in AT1R expression in the ventrolateral medulla that commenced at late stage of Phase II and persisted throughout Phase III endotoxemia would shift the balance in favor of sympathoinhibition, resulting in the significant cardiovascular depression seen during the last phase of experimental endotoxemia.…”

“…2,3 In addition, we reported recently 4 that overproduction of NO by iNOS in the rostral ventrolateral medulla (RVLM) is also a crucial determinant for the reduction in sympathetic vasomotor outflow and fatal cardiovascular depression during experimental endotoxemia. Whereas we proposed that the underlying mechanisms include formation of the cytotoxic substance peroxynitrite 5 and activation of GABAergic neurotransmission, 6 the possibility exists for the engagement of other mediators in the RVLM.…”