TY - JOUR T1 - 3-Morpholinylsydnonimine Inhibits Glutamatergic Transmission in Rat Rostral Ventrolateral Medulla via Peroxynitrite Formation and Adenosine Release JF - Molecular Pharmacology JO - Mol Pharmacol SP - 492 LP - 501 DO - 10.1124/mol.104.000554 VL - 66 IS - 3 AU - Chiung-Chun Huang AU - Samuel H. H. Chan AU - Kuei-Sen Hsu Y1 - 2004/09/01 UR - http://molpharm.aspetjournals.org/content/66/3/492.abstract N2 - We have previously reported that, depending on the dose, nitric oxide (NO)-generating agents exert a dual facilitatory and inhibitory action on glutamatergic transmission on the rostral ventrolateral medulla (RVLM) neurons. The molecular mechanisms underlying the NO-mediated synaptic inhibition have not yet been defined. Here we show that the amplitude of excitatory postsynaptic currents (EPSCs) was reversibly reduced by the NO donors 3-morpholinylsydnoneimine (SIN-1) (1 mM) and spermine NONOate (1 mM). This effect was antagonized by an active peroxynitrite decomposition catalyst 5,10,15,20-tetrakis(4-sulfonatophenyl)prophyrinato iron (III) chloride, Gi/o-coupled receptor blockers, N-ethylmaleimide and pertussis toxin, A1 adenosine receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine, or adenosine deaminase. However, NO-sensitive guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, GABAB receptor antagonist (2S)-(+)-5,5-dimethyl-2-morpholineacetic acid (SCH50911), or cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A) had no effect on the inhibitory action of SIN-1 on EPSCs. Perfusion of adenosine mimicked and subsequently occluded the action of SIN-1. Inhibition of EPSC amplitude by SIN-1 was associated with an increase in the paired-pulse ratio of EPSCs. Furthermore, SIN reduced the frequency of spontaneous EPSCs without altering their amplitude of distribution. Pretreatment with N-type Ca2+-channel blocker ω-conotoxin GVIA selectively blocked SIN-1–induced inhibition of EPSCs. These results suggest that a higher dose of SIN-1 acts presynaptically to elicit a synaptic depression on the RVLM neurons through an inhibition of presynaptic N-type Ca2+-channel activity, leading to reduced glutamate release. The presynaptic action of SIN-1 is mediated by the formation of peroxynitrite, which subsequently acts to release adenosine to activate A1 adenosine receptors. ER -