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cGMP/Protein Kinase G-Dependent Potentiation of Glutamatergic Transmission Induced by Nitric Oxide in Immature Rat Rostral Ventrolateral Medulla Neurons in Vitro

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.)

Although both nitric oxide (NO) and glutamate within the rostral ventrolateral medulla (RVLM) are important mediators of the central cardiovascular regulation, little is known about the functional interactions between these two mediators. Herein, we investigated the possible role of NO on the glutamatergic transmission of RVLM neurons. Whole-cell patch-clamp recordings were performed on visualized RVLM neurons in the brainstem slice preparation of rats. We found that bath application of L-arginine, the substrate for NO production, significantly increased the amplitude of excitatory postsynaptic currents (EPSCs). This enhancement was completely abolished by coadministration of the NO synthase inhibitor 7-nitroindazole and mimicked by the NO donors 3-morpholinylsydnoneimine and spermine NONOate. Bath application of a NO-sensitive guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, or a protein kinase G (PKG) inhibitor, Rp-8-bromo-guanosine 3',5'-cyclic monophosphorothioate, fully prevented the L-arginine-, 3-morpholinylsydnoneimine-, and N-[4-[1-(3-aminopropyl)-2-hydroxy-2-nitrosohydrazino]-butyl]-1,3-propanediamin (spermine NONOate)-induced synaptic potentiation. Direct activation of PKG with 8-(4-chlorophenylthio)-cGMP mimicked the action of NO donors. Furthermore, the augmentation by spermine NONOate of EPSC was accompanied by a reduction of the paired-pulse facilitation and synaptic failure rate of EPSCs. Spermine NONOate also significantly increased the frequency of both spontaneous and miniature EPSCs without altering their amplitude distribution. Pretreatment with the N-type Ca²⁺ channel blocker -conotoxin GVIA selectively blocked the spermine NONOate-induced synaptic potentiation. These results suggest that NO acts presynaptically to elicit a synaptic potentiation on the RVLM neurons through an enhancement of presynaptic N-type Ca²⁺ channel activity leading to facilitating glutamate release. The presynaptic action of NO is mediated by a cGMP/PKG-coupled signaling pathway.

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

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