Nitroxidergic Influences on Cardiovascular Control by NTS: A Link with Glutamate

Abstract

Glutamate (GLU) receptor activation, which is important in cardiovascular reflex transmission through the nucleus tractus solitarii (NTS), leads to release of nitric oxide (NO·) from central nitroxidergic neurons. Therefore, we hypothesized that GLU and NO· are linked in cardiovascular control by NTS. We first sought to determine if NO· released into NTS led to cardiovascular changes like those produced by GLU and found that the nitrosothiol S‐nitrosocysteine, but not NO· itself or other NO· donors, elicited such responses in anesthetized rats. The responses were dependent on activation of soluble guanylate cyclase but, not being affected by a scavenger of NO·, likely did not depend on release of NO· into the extracellular space. Responses to ionotropic GLU agonists in NTS, like those to S‐nitrosocysteine, were inhibited by inhibition of soluble guanylate cyclase. Inhibition of neuronal NO· synthase (nNOS) also inhibited responses to ionotropic GLU agonists. The apparent physiologic link between GLU and NO· mechanisms in NTS was further supported by anatomical studies that demonstrated frequent association between GLU‐containing nerve terminals and neurons containing nNOS. Furthermore, GLU receptors were often found on NTS neurons that were immunoreactive for nNOS. The anatomical relationships between GLU and nNOS and GLU receptors and nNOS were more pronounced in some subnuclei of NTS than in others. While seen in subnuclei that are known to receive cardiovascular afferents, the association was even more prominent in subnuclei that receive gastrointestinal afferents. These studies support a role for nitroxidergic neurons in mediating cardiovascular and other visceral reflex responses that result from release of GLU into the NTS.

Neuronal Nitric Oxide Synthase

“…They suggest that nNOS is critical to normal transmission of baroreflex signals through NTS and participates in tonic regulation of blood pressure by NTS. 6 The data support our earlier studies 19 that demonstrated attenuation of responses to Glu agonists injected into the NTS. Because Glu is a neurotransmitter released in NTS on stimulation of the arterial baroreflex, attenuation of that reflex by nNOS inhibition would be consistent with a role for nNOS in mediating baroreflex responses through Glu receptors in the NTS.…”

“…24 In addition, methylene blue inhibits actions of inotropic, but not metabotropic, Glu agonists. 19 The biological relevance of this blockade has been supported by studies showing that methylene blue also blocks the Bezold Jarisch reflex. 47 Other studies of a more selective blocker lH-[1.…”

“…[13][14][15] However, it is not clear that NO⅐ contributes to cardiovascular signal transduction in NTS 16,17 or, if it does, to what extent its contribution is linked to actions of Glu in the nucleus. Garthwaite points to the need for studies to help elucidate the link between Glu and NO⅐ 18 in the brain in general.We have recently shown that inhibition of neuronal nitric oxide synthase (nNOS) in NTS blocks cardiovascular responses to activation of glutamate receptors 19 and that in NTS glutamatergic nerve processes lie closely apposed to neuronal elements that contain nNOS. 20 Therefore, through the current study, we sought to test the hypothesis that baroreflex transmission in NTS depends on nNOS whose inhibition would lead to hypertension.…”

“…We have recently shown that inhibition of neuronal nitric oxide synthase (nNOS) in NTS blocks cardiovascular responses to activation of glutamate receptors 19 and that in NTS glutamatergic nerve processes lie closely apposed to neuronal elements that contain nNOS. 20 Therefore, through the current study, we sought to test the hypothesis that baroreflex transmission in NTS depends on nNOS whose inhibition would lead to hypertension.…”

Central nitric oxide modulates hindquarter vasodilation elicited by AMPA receptor stimulation in the NTS of conscious rats

“…The vasodilation produced by microinjection of glutamate in the NTS can be reduced by systemic administration of prazosin and N G -nitro-L-arginine methyl ester (L-NAME) (4). The origin and pathway involved in this neurogenic vasodilation is still unclear (4), but it was suggested that this vasodilation is caused by peripheral release of preformed nitrosyl factors during sympathetic stimulation (6, 7).Interactions between nitric oxide (NO) and glutamatergic transmission within the NTS on cardiovascular regulation have been shown by anatomic and physiological studies (24,25,27,29,34,36,41). All of the substrates necessary for NO production are present in the NTS.…”