Research reportActions of S-nitrosocysteine in the nucleus tractus solitarii are unrelated to release of nitric oxide
Introduction
Description of an endothelium derived relaxing factor [3]led to evidence supporting the role of a similar compound in central neurotransmission [7]. Nitric oxide (NO⋅) has been considered that centrally active agent [1]. Many studies have suggested that NO⋅ may be synthesized by central neurons, freely diffuse across membranes, and act on soluble guanylate cyclase in target cells to effect neuronal responses [40]. In such a situation the actions of NO⋅ would not depend on binding to a classic receptor. Instead, NO⋅ binds to the allosteric site of guanylate cyclase and elicits conformational changes in the enzyme, which may thus act as a `receptor' for NO⋅[33]. Although many studies support a role for authentic NO⋅ as a central messenger others suggest that S-nitrosylated thiols such as S-nitrosocysteine (SNC) may be equally or more effective than NO⋅ in activating soluble guanylate cyclase [28]and may share many features with NO⋅[30]. These compounds are synthesized by brain through reactions that would depend upon NO⋅ synthesis [16]. Although some suggest that S-nitrosothiols simply provide a pool of NO⋅ and that their biological actions depend upon their decomposition to NO⋅[9], recent studies have challenged that idea and proposed that S-nitrosothiols may be more potent in their actions than NO⋅ itself 8, 17, 28. We have previously shown that microinjection of S-nitrosocysteine into the nucleus tractus solitarii (NTS), the site of termination of cardiovascular afferent nerves, leads to reductions of arterial pressure (AP) and heart rate (HR) and that the cardiovascular responses are blocked by methylene blue, an inhibitor of soluble guanylate cyclase 21, 22. Therefore, we have used the NTS as a model system to test the hypothesis that SNC is independently active and may elicit central responses through stereoselective actions in the brain.
Section snippets
Physiological studies
Rats were prepared for experiments as described previously [22]. In brief, adult male Sprague–Dawley rats (275–350 g) were anesthetized with halothane and instrumented for recording AP, mean AP (MAP), and HR. The rats were placed in a stereotaxic frame (DKI, Tujunga, CA), a partial occipital craniotomy was performed, the dura and arachnoid incised, and the cerebellum retracted to expose the dorsal surface of the brain stem at the level of the obex. The calamus scriptorius was identified and
Results
Relative potencies were determined for l-SNC and d-SNC unilaterally microinjected into the NTS of anesthetized rats. Microinjection of 25–250 pmol of l-SNC produced dose-dependent hypotension and bradycardia (Fig. 1). Higher doses elicited progressively weaker effects. Microinjection of d-SNC (25–250 pmol) produced substantially smaller responses. Responses to the maximally effective dose (250 pmol) of l-SNC were approximately 300% greater than those to the same dose of d-SNC. The dose-response
Discussion
This study makes four pertinent observations with regard to possible participation of S-nitrosothiols in signal transduction at the level of the NTS. First, it supports previous studies that showed dose-dependent reductions of both AP and HR when SNC was microinjected into the NTS of anesthetized [22]and conscious rats [26]. Second, it shows that those responses cannot be explained by extracellular release of NO⋅ from the nitrosothiol or by generation of NO⋅ within the target cell through
Acknowledgements
All studies were approved by institutional animal care and use review committees. The work was supported by a Veterans Affairs Clinical Investigatorship (WTT) and Merit Review and in part by NIH HL23305 and 14388 and an American Heart Association Grant in Aid.
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