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

Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan (C.-C.H., K.-S.H.); and Center for Neuroscience, National Sun Yat-sen University, Kaohsiung, Taiwan (S.H.H.C.)

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, G_i/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, GABA_B 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 -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.

Address correspondence to: Dr. Kuei-Sen Hsu, Department of Pharmacology, College of Medicine, National Cheng Kung University, 1, Ta-Hsiue Road, Tainan 701, Taiwan. E-mail: richard{at}mail.ncku.edu.tw

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