Localization of vesicular glutamate transporters and neuronal nitric oxide synthase in rat nucleus tractus solitarii

Lin, Leou-Chyr; Edwards, Robert H.; Fremeau, Robert T.; Fujiyama, Fumino; Kaneko, T.; Talman, William T.

doi:10.1016/j.neuroscience.2003.08.063

Cited by 40 publications

(62 citation statements)

References 45 publications

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“…59 Moreover, exogenous NO in the NTS enhances both glutamate release in vivo 60 and evoked excitatory postsynaptic potentials in vitro, 61 and both of the latter may explain the bradycardia/depressor responses (for references see above) and depressed baroreceptor reflex gain after nNOS blockade. 38,51 In addition, Dias et al 38 have described that N G -nitro-L-arginine methyl ester blockade of NOS in the NTS reduces the depressor response evoked by N-methyl-D-aspartate.…”

Section: Diversity Of Effects Of Nitrergic Mechanisms In the Nts For mentioning

confidence: 99%

Endothelial NO Synthase Activity in Nucleus Tractus Solitarii Contributes to Hypertension in Spontaneously Hypertensive Rats

et al. 2006

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Abstract-NO is implicated as a major modulator of central nervous circuits regulating cardiovascular activity. Based on previous data, we hypothesized that overactivity of endothelial NO synthase (eNOS) within the nucleus tractus solitarii (NTS) could contribute to the hypertension in the spontaneously hypertensive rat (SHR). Using real-time PCR, we found that endogenous eNOS mRNA was greater in the NTS of mature, but not juvenile prehypertensive SHRs compared with aged-matched Wistar Kyoto (WKY) rats. To test the functional significance of this, we chronically blocked eNOS activity in the NTS in the adult SHR by in vivo adenoviral-mediated gene transfer of a dominant-negative form of eNOS; data were compared with WKY rats. This resulted in a fall in arterial pressure in the SHR but not WKY rats. In both rat strains, cardiac baroreceptor reflex gain and the high-frequency spectral component of heart rate variability increased. Thus, endogenous eNOS activity in the NTS plays a major role in determining the set point of arterial pressure in the SHR and contributes to maintaining high arterial blood pressure in this animal model of human hypertension. Key Words: nitric oxide synthase Ⅲ nitric oxide Ⅲ endothelium Ⅲ blood pressure Ⅲ baroreflex Ⅲ sympathetic nervous system Ⅲ neurogenic hypertension A s described by Doba and Reis, 1 destruction of the nucleus tractus solitarii (NTS) leads to fulminating hypertension. This is highly suggestive that the NTS is a central brain stem structure that plays a vital role in maintaining the set point of arterial pressure. Equally, because baroreceptor afferents terminate in this nucleus, it is also one of the most effective central sites for modulating the gain of the baroreceptor reflex, a process that is critically important for blood pressure homeostasis. A potent neuromodulator of central cardiovascular autonomic activity is angiotensin II (Ang II). NTS microinjections of Ang II evoke concentrationdependent effects composed of either a depressor response 2,3 or a pressor/tachycardic response. 4 In addition, an Ang II antagonist increased cardiac baroreceptor reflex gain in anesthetized mature rats. 5 Because of the work of Casto and Philips, 6 it has been known that Ang II acting on Ang II type 1 receptors depresses cardiac baroreceptor reflex function in NTS. We showed that the depressant effect of Ang II type 1 receptor stimulation on cardiac baroreceptor reflex function in the NTS was mediated by NO. 7 We confirmed recently that Ang II can release NO in the NTS using electron paramagnetic resonance. 8 We also found that the effect of Ang II occurs via a Gq-PLC-IP3 pathway that releases intracellular calcium, 9 which we assume is required for activating endothelial NO synthase (eNOS). Released NO enhances inhibitory GABAergic neurotransmission in the NTS, 10 which may underlie the NO-induced cardiac baroreceptor reflex depression. 7 In conscious normotensive Wistar rats, chronic blockade of eNOS activity in NTS elevated the cardiac baroreceptor reflex gain, supporting a de...

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Section: Diversity Of Effects Of Nitrergic Mechanisms In the Nts For mentioning

confidence: 99%

Endothelial NO Synthase Activity in Nucleus Tractus Solitarii Contributes to Hypertension in Spontaneously Hypertensive Rats

et al. 2006

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“…The relative selectivity of SAP conjugates for specific neuronal types has been shown by others (Wiley andLappi, 1997, 1999;Madden et al, 1999) and was supported by our finding that treatment with SSP-SAP did not lead to loss of neurons with the biosynthetic enzyme, tyrosine hydroxylase (TH), which is essential for norepinephrine synthesis (Lin et al, 2012b). In contrast, injection into the NTS of anti-dopamine ␤-hydroxylase-SAP (anti-DBH-SAP), which led to a significant loss of TH and DBH neurons, while not affecting NTS neurons with the NK1R, also attenuated the arterial baroreflex and caused significant lability of arterial pressure (Talman et al, 2012). Our findings would be consistent with an integral role for both types of neuron in transmission or modulation of baroreflexes as has been suggested by others (Snyder et al, 1978;Gillis et al, 1980;.…”

Section: Introductionmentioning

confidence: 99%

Astrocytes in the Rat Nucleus Tractus Solitarii Are Critical for Cardiovascular Reflex Control

et al. 2013

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We have shown that an antibody to dopamine-␤-hydroxylase conjugated with saporin (anti-DBH-SAP) damages catecholamine neurons in the nucleus tractus solitarii (NTS) of rat, attenuates arterial baroreflexes, and leads to lability of arterial blood pressure, damage to cardiac myocytes, and, in some animals, sudden death. However, others have shown that injection of 6-hydroxydopamine (6-OHDA), a toxin devoid of saporin, also damaged NTS catecholamine neurons but did not lead to these cardiovascular changes. We found similar cardiovascular changes after injecting a different SAP conjugate to target NTS neurons with neurokinin (NK1) receptors. Because ribosome-inactivating proteins may be toxic to glia, we hypothesized that SAP, a ribosome-inactivating protein, might target glia whose loss could account for physiological changes. We tested this hypothesis by assessing effects on select neurons and on glia in the NTS after exposure to SAP, targeted SAP conjugates, or 6-OHDA. SAP and all SAP conjugates led to loss of immunoreactivity for glial fibrillary acidic protein, a marker for astrocytes, in the NTS while 6-OHDA did not. As reported previously, anti-DBH-SAP selectively killed noradrenergic neurons in the NTS while SAP conjugated to stabilized substance P (SSP-SAP) selectively killed neurons with NK1 receptors. In contrast, SAP produced no demonstrable neuronal damage. All injections led to activation of microglia in the NTS; however, only SAP and its conjugates attenuated cardiovascular reflexes while also producing lability of arterial pressure, damage to cardiac myocytes, and in some animals, sudden death. Thus, NTS astrocytes may play a role in mediating cardiovascular reflex transmission through the NTS.

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“…9 Still other studies provided further support for integration between NO and glutamate actions. For example, both nNOS and vesicular glutamate transporters were found within the same neuronal elements in the NTS, 10 and nerve fibers that contained nNOS have often been found in immediate apposition to NTS neurons that expressed glutamate receptors. 6 The occurrence of nNOS both in presynaptic and in postsynaptic elements in the NTS suggested that integration between NO and glutamate was going to be complex.…”

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confidence: 99%

NO and Central Cardiovascular Control

Talman

2006

Hypertension

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T he 1998 Nobel Prize in Physiology or Medicine recognized the great contributions of Robert Furchgott, Louis Ignarro, and Ferid Murad through "their discoveries concerning nitric oxide as a signaling molecule in the cardiovascular system." Furchgott's earlier work describing a vasodilatory factor that was activated by acetylcholine acting on an intact endothelium not only set the stage for subsequent recognition that NO was the endothelium-derived relaxation factor but also acted as a harbinger of much subsequent study of interactions between classic neurotransmitters and NO. Three isoforms of NO synthase (NOS), the biosynthetic enzyme for synthesis of NO, have been identified. Two are constitutive enzymes, endothelial NOS (eNOS) and neuronal NO (nNOS). Each has been identified in the nucleus tractus solitarii (NTS), the primary site of termination of baroreceptor afferent nerves, but the role of each, or for that matter the role of NO itself, in baroreflex transmission through the NTS remains very much in question. The presence of iNOS in the NTS could indicate that there had been stress in animals in which it was found.In keeping with the potential that NO may link transmitter mechanisms and may integrate vascular and neuronal functions, the work by Waki et al in this issue of Hypertension 1 provides further evidence for complex integration through NO mechanisms in the NTS and for contributions of NO in disorders of cardiovascular homeostasis. That work is the latest from the Paton/Kasparov laboratories at the University of Bristol and further supports there being a cascade of transduction events that involve NO derived from eNOS, as well as several additional putative transmitters in NTS regulation of blood pressure. One such potential transmitter is angiotensin. Particularly since the work of Casto and Phillips, 2 it has been recognized that angiotensin may act at the level of the NTS to inhibit the baroreflex. The cellular mechanisms of sympathetically mediated hypertension seen when angiotensin was introduced into the NTS have not been fully clarified, but the Bristol laboratory has begun to provide a compelling argument supported by highly innovative methods to approach the question. Using viral vectors to upregulate eNOS in the NTS, they showed previously that the enzyme played a critical role in the attenuation of the baroreflex by angiotensin, 3 a fascinating link given the presence of both angiotensin-converting enzyme and eNOS in caveolar endothelial membranes. 4 Their work also suggested that an inhibitory mechanism for that attenuation may lie in integration between eNOS-supported nitroxidergic mechanisms and GABAergic mechanisms in the NTS. 5 Thus, they provided further support for the interesting possibility that there is a link not only between signaling molecules in the brain but also between events initiated in local blood vessels and neuronal signal transduction in the NTS. Their current study associates those links with hypertension in one experimental model in which baroreflex function is ...

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Localization of vesicular glutamate transporters and neuronal nitric oxide synthase in rat nucleus tractus solitarii

Cited by 40 publications

References 45 publications

Endothelial NO Synthase Activity in Nucleus Tractus Solitarii Contributes to Hypertension in Spontaneously Hypertensive Rats

Endothelial NO Synthase Activity in Nucleus Tractus Solitarii Contributes to Hypertension in Spontaneously Hypertensive Rats

Astrocytes in the Rat Nucleus Tractus Solitarii Are Critical for Cardiovascular Reflex Control

NO and Central Cardiovascular Control

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