Published online before print February 23, 2004, doi: 10.1161/01.HYP.0000120848.76987.ef
(Hypertension. 2004;43:820.)
© 2004 American Heart Association, Inc.
Scientific Contributions |
Transmission of Arterial Baroreflex Signals Depends on Neuronal Nitric Oxide Synthase
From the Department of Neurology, Laboratory of Neurobiology, VAMC and University of Iowa, Iowa City, Iowa.
Correspondence Dr William T. Talman, Department of Neurology, University of Iowa, Iowa City, IA 52242. E-mail william-talman{at}uiowa.edu
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Abstract |
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Because inhibition of neuronal nitric oxide synthase in the nucleus tractus solitarii blocks cardiovascular responses to activation of local glutamate receptors, and because glutamate is a neurotransmitter of baroreceptor afferent nerves, we sought to test the hypothesis that neuronal nitric oxide synthase inhibition would block baroreflex transmission and cause hypertension. We determined reflex heart rate responses to intravenous phenylephrine and sodium nitroprusside in 5 anesthetized rats before and after bilateral microinjection (100 nL) of the neuronal nitric oxide synthase inhibitor AR-R 17477 (7.5 nmol) into the nucleus tractus solitarii. The inhibitor significantly increased mean arterial pressure without affecting heart rate, and it significantly reduced the gain of the baroreflex. After administration of the inhibitor, reflex responses of heart rate to changes in mean arterial pressure were always less than those responses to the same, or less, change in mean arterial pressure in the same animal without administration of the inhibitor. Microinjection of saline (100 nL) bilaterally into the nucleus tractus solitarii did not lead to hypertension or change baroreflex responses. These data support the hypothesis and suggest that neuronal nitric oxide synthase is critical to transmission of baroreflex signals through the nucleus tractus solitarii.
Key Words: baroreceptor reflex • nitric oxide • nitric oxide synthase • rat
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Introduction |
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As the primary site of termination of baroreceptor and other cardiovascular and visceral afferent nerve fibers,1–3 the nucleus tractus solitarii (NTS) plays a critical role in regulation of arterial pressure (AP) and peripheral blood flow. Stimulation of NTS leads to marked changes in AP and regional blood flow,4 and lesions lead to acute hypertension in humans5 and experimental animals.6 Changes in AP regulation may be persistent with chronic perturbations of transmission in NTS.7
There is broad support for the hypothesis that glutamate (Glu) is a transmitter released from baroreceptor afferent nerve terminals in NTS,8,9 but Glu likely also participates in processing other cardiovascular signals such as those from chemoreceptor afferents.10 Changes in responsiveness to Glu injected into NTS in hypertensive rats11 suggest that alterations in Glu transmission may play a role in the genesis of some forms of hypertension. Thus, improved understanding of glutamatergic neurotransmission in the NTS in normotensive rats could shed new light not only on basic mechanisms of AP control but also on mechanisms that could contribute to hypertension.
Recent studies indicate that nitric oxide (NO·) may participate in generating responses elicited by Glu. For example, NO· may exert presynaptic and postsynaptic effects and may play a role in cardiovascular regulation at the level of NTS.12 Furthermore, responses to injection of NO· donors into NTS of anesthetized and awake animals mimic those elicited by injection of Glu agonists in anesthetized rats.13–15 However, it is not clear that NO· contributes to cardiovascular signal transduction in NTS16,17 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 NO·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 receptors19 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.
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Methods |
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All methods were reviewed and approved by institutional animal care and use committees of the University of Iowa and the Iowa City VAMC and complied with standards established in the Guide for Care and Use of Laboratory Animals (National Academy Press, Washington, DC, 1996). Adult male Sprague-Dawley rats were anesthetized with halothane (2%) delivered by inhalation with 100% oxygen, and they were instrumented with cannulae placed in a femoral artery and vein for recording AP and heart rate (HR) and for delivering drugs intravenously. The trachea was cannulated and the animals were artificially ventilated for the remainder of the experiments. As we have previously described,14 we then exposed the dorsal surface of the brain stem. After completion of this instrumentation, we discontinued halothane and maintained anesthesia with chloralose (20 mg/kg per hour after a loading dose of 40 mg/kg IV) for the remainder of the study. In 5 animals, we evaluated baroreflexes before and after inhibition of nNOS. The baroreflex was tested before administration of the nNOS inhibitor and again 10 minutes after administration of the selective nNOS inhibitor AR-R 1747721 (7.5 nmol; a gift from Astra Zeneca, Worcester, Mass) through glass micropipettes placed stereotaxically at predetermined14 coordinates in the nucleus. Baroreflex testing was begun while AP was still elevated from nNOS inhibition but after maximal elevation of AP. Testing was completed over the next 50 minutes. We confirmed that blockade by AR-R17477 of cardiovascular responses to injection of NMDA (3 pmol) into the NTS, as we have previously reported,22 persisted for 1 hour after injection of the inhibitor. We determined reflex decreases in HR in response to pressor effects of phenylephrine (0.05 to 2.5 µg in 0.1 to 5 µL of saline intravenous) and reflex tachycardic responses to depressor effects of nitroprusside (0.1 to 5 µg in 0.1 to 5 µL of saline intravenous). Each animal received multiple doses of each agent. Doses were delivered in random order and the 2 agents were randomly administered. Responses of mean AP (MAP) and HR to each agent were allowed to return to baseline before administration of the next dose. After quantifying changes in MAP and HR before and after inhibition of nNOS in NTS, we statistically analyzed only baroreflex responses before injections into NTS with those after injection of AR-R 17477 in the same 5 animals. In those animals, we analyzed baroreflex responses by subjecting all data from each animal to regression analysis (see later) to determine if nNOS inhibition significantly altered the gain of baroreflex responses. In 3 additional animals, we compared baroreflex responses before and after injection of saline bilaterally into NTS as a sham inhibitor of nNOS. Injection of saline into NTS did not affect baroreflex responses in those 3 animals.
Data, expressed as mean±SEM, were analyzed by paired t test. Random coefficient regression analysis was used to estimate the mean linear regression function for the relationship of change in HR with change in MAP for the control condition and the treated condition, and to compare the mean slope between control and treatment. A line was fit using data points derived for each animal, and the mean regression line was estimated from the individual lines. Changes were considered statistically significant at P
0.05.
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Results |
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Bilateral injection of the nNOS inhibitor (Figure 1) increased MAP from 100.8±5.4 mm Hg to 145.2±5.3 mm Hg (n=5; P<0.001) without significantly changing HR (before blockade 341.4±9.6 bpm; after blockade 357.4±14.6 bpm; P=0.154). Microinjection of saline (100 nL) bilaterally into NTS of 3 animals did not lead to hypertension (data not shown).
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We determined reflex bradycardic responses to pressor effects of intravenous phenylephrine and reflex tachycardic responses to depressor effects of intravenous sodium nitroprusside before and after bilateral microinjection (100 nL) of AR-R 17477 (Figure 2) into NTS in 5 animals or saline into NTS in 3 animals. Bilateral injections of saline into NTS did not change baroreflex responses when compared with responses in animals that had received no injection into NTS (see Methods; data not shown). In animals that had received bilateral injections of AR-R 17477, we began tests of baroreflex function before MAP had returned to basal values, but MAP gradually returned toward baseline in each animal before completion of testing. However, regardless of the level of MAP before administration of each dose of phenylephrine or nitroprusside, HR responses to comparable changes in MAP were always less after administration of AR-R17477 than they had been before administration of AR-R17477 into the NTS. Therefore, regression analysis (Figure 3) revealed a significant reduction in the gain of responses after nNOS inhibition (R=
0.1; P<0.05) versus control (R=0.9).
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Discussion |
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This study demonstrates that injection of an inhibitor of nNOS bilaterally into the NTS attenuates baroreflex responses to changes in blood pressure and leads to acute neurogenic hypertension without associated changes in HR, findings that have long been known to occur after acute interruption of the baroreflex by disturbances of NTS function.6,23 Thus, the data support the hypothesis. 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 studies19 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.
Evidence for potential interactions between Glu and NO· is abundant. Activation of Glu receptors in brain leads to synthesis and release of NO·.24,25 Glu may act through these effects on NO· to activate sGC and increase cGMP, which may contribute to cellular responses to Glu itself.26,27 Some studies have shown that destruction of Glu receptors eliminated activation of sGC by Glu, even though the same neuronal pools of the enzyme could still be activated by an NO· donor acting "downstream" of the Glu receptor.26 Thus, some responses to Glu may depend on a link to NO· synthesis. Although influences of NMDA receptor activation on NO· production were described first, it is now clear that kainate, metabotropic (ACPD responsive), and 
-amino-3-hydroxy-5-methylisoxozole-proprionic acid receptor agonists have similar influences on production of NO·.28–31 However, antagonists of Glu receptors may themselves effect release of NO·;32 and in some systems NO·, which may act presynaptically and postsynaptically,33,34 may provide a feedback mechanism influencing release of Glu.35 Little is known of the physiological significance of joint actions of Glu and NO· in NTS, but one study suggests that NO· release also may be linked to Glu receptor activation in that nucleus.36
The current study supports others that have begun to show that NO·, like Glu, may participate in cardiovascular signal transduction in NTS. For example, NOS is transported bidirectionally from nodose ganglion neurons37 and is found in neurons and vagus nerve terminals in NTS.38–42 Staining for nNOS and nNOS mRNA is greatest in cardiovascular and gastrointestinal subnuclei of NTS,40 and NO· may be synthesized in vagus nerve terminals in NTS.40,41 Furthermore, we have found that nNOS immunoreactivity and Glu immunoreactivity, a marker of glutamatergic neurons, are colocalized in NTS dendrites and axons.43
Abundant evidence suggests that nitroxidergic input to NTS may play a role in physiological control by that nucleus. Diminished neuronal activity as a result of nNOS inhibition suggests that NO· released from vagus nerve terminals may tonically influence activity of neurons in NTS.44 Injection of an nNOS inhibitor 7-nitroindazole (7-NI) into NTS has been shown45 to block Glu. Furthermore, microinjection into NTS of S-nitrosothiols, which may act as donors of NO·, elicits depressor and bradycardic responses like those produced by Glu.14 Actions of S-nitrosothiols, like those produced by NO·, may, at least in part, be mediated through activation of sGC in that effects of the S-nitrosothiols are blocked by methylene blue,46 used to block activation of sGC by NO·.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-[1.2.4]oxadiazolo[4,3,-a]quinoxalin-l-one (ODQ) of guanylate cyclase48,49 support earlier findings with methylene blue.
The similarity between physiological responses to Glu and NO· and in the distribution of Glu and No· terminals in NTS suggests a possible link between the actions of the 2 compounds. One study even suggested that the 2 may act on the same neurons in NTS.12 We have found a high degree of homology in the immunostaining for nNOS and for Glu in the cardiovascular NTS,43 as well as for nNOS and NMDA receptors50 and for nNOS and -amino-3-hydroxy-5-methylisoxozole-proprionic acid receptors51 in that nucleus.
Previous studies have used other NOS inhibitors in their efforts to define the role of NOS in central cardiovascular transmission through the NTS. Nonselective inhibitors injected into NTS have not consistently attenuated the baroreflex.16,45 Such nonselective inhibitors would be expected to inhibit both eNOS and nNOS. In that eNOS may contribute to inhibition of baroreflex activity in NTS,52 the inconsistent findings could have been the result of action on nNOS and eNOS. Others have sought to selectively inhibit nNOS by injection of 7-NI into the NTS and have demonstrated attenuation of baroreflex responses to changes in blood pressure.53 However, some evidence suggests that 7-NI, a highly hydrophobic compound, is not selective for nNOS under some conditions.54,55 Although there are other studies that support selectivity of 7-NI under a variety of conditions,56 we chose to use an agent, AR-R 17477, with acknowledged selectivity for nNOS and relatively little action on eNOS.21 The inhibitor was injected into NTS and baroreflex studies performed over approximately 1 hour, a period of time over which we have shown that responses to Glu agonists are blocked by AR-R 17477. Thus, although not directly studied here, blockade of the baroreflex with nNOS inhibition correlates temporally with blockade of responses to Glu agonists in NTS and supports a link between these 2 transmitter mechanisms in central baroreflex control within NTS.
Perspectives
This study has implications for understanding central cardiovascular reflex control in health and disease. The findings provide another example of chemical, not structural, changes in brain leading to hypertension, and they support the possibility that disturbed NO· synthesis could contribute to hypertension and altered baroreflex function in humans. Identifying that nitroxidergic transmission may contribute to transduction of naturally occurring baroreflex signals through NTS provides a potentially important insight into integrative and transduction mechanisms not only in NTS but also in other central sites.
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Acknowledgments |
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We gratefully acknowledge the support of the Veterans Affairs Medical Center Medical Media Service in preparation of figures for this paper and that from Dr Miriam B. Zimmerman, who assisted in regression analysis of baroreflex function. AR-R 17477 was a generous gift from Astra Zeneca. The work was supported in part by Veterans Affairs Merit Review Tab 14 and National Institutes of Health R01 59593.
Received December 2, 2003; first decision December 11, 2003; accepted January 21, 2004.
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References |
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1. Kalia M, Mesulam M-M. Brain stem projections of sensory and motor components of the vagus complex in the cat: II. laryngeal, tracheobronchial, pulmonary, cardiac, and gastrointestinal branches. J Comp Neurol. 1980; 193: 467–508.[CrossRef][Medline] [Order article via Infotrieve]
2. Panneton WM, Loewy AD. Projections of the carotid sinus nerve to the nucleus of the solitary tract in the cat. Brain Res. 1980; 191: 239–244.[CrossRef][Medline] [Order article via Infotrieve]
3. Wallach JH, Loewy AD. Projections of the aortic nerve to the nucleus tractus solitarius in the rabbit. Brain Res. 1980; 188: 247–251.[CrossRef][Medline] [Order article via Infotrieve]
4. Yin M, Lee CC, Ohta H, Talman WT. Hemodynamic effects elicited by stimulation of the nucleus tractus solitarii. Hypertension. 1994; 23: I73–I77.[Medline] [Order article via Infotrieve]
5. Montgomery BM. The basilar artery hypertensive syndrome. Arch Intern Med. 1961; 108: 559–569.
6. Doba N, Reis DJ. Acute Fulminating Neurogenic Hypertension Produced by Brainstem Lesions in the Rat. Circ Res. 1973; 32: 584–593.
7. Kishi T, Hirooka Y, Sakai K, Shigematsu H, Shimokawa H, Takeshita A. Overexpression of eNOS in the RVLM causes hypotension and bradycardia via GABA release. Hypertension. 2001; 38: 896–901.
8. Talman WT, Perrone MH, Reis DJ. Evidence for L-glutamate as the neurotransmitter of baroreceptor afferent nerve fibers. Science. 1980; 209: 813–815.
9. Gordon FJ, Talman WT. Role of excitatory amino acids and their receptors in bulbospinal control of cardiovascular function. In: Kunos G, Ciriello J, eds. Central Neural Mechanisms in Cardiovascular Regulation, Vol 2. New York: Birkhauser; 1992: 209–225.
10. Vardhan A, Kachroo A, Sapru HN. Excitatory amino acid receptors in commissural nucleus of the NTS mediate carotid chemoreceptor responses. Am J Physiol Regul Integr Comp Physiol. 1993; 264: R41–R50.
11. Talman WT, Lewis SJ. Altered cardiovascular responses to glutamate and acetylcholine microinjected into the nucleus tractus solitarii of the SHR. Clin Exp Hypertension. 1991; A13: 661–668.
12. Tagawa T, Imaizumi T, Harada S, Endo T, Shiramoto M, Hirooka Y, Takeshita A. Nitric oxide influences neuronal activity in the nucleus tractus solitarius of rat brainstem slices. Circ Res. 1994; 75: 70–76.
13. Machado BH, Bonagamba LGH. Microinjection of S-nitrosocysteine into the nucleus tractus solitarii of conscious rats decreases arterial pressure but L-glutamate does not. Eur J Pharmacol. 1992; 221: 179–182.[CrossRef][Medline] [Order article via Infotrieve]
14. Ohta H, Bates JN, Lewis SJ, Talman WT. Actions of s-nitrosocysteine in the nucleus tractus solitarii are unrelated to release of nitric oxide. Brain Res. 1997; 746: 98–104.[CrossRef][Medline] [Order article via Infotrieve]
15. Talman WT. Kynurenic acid microinjected into the nucleus tractus solitarius of rat blocks the arterial baroreflex but not responses to glutamate. Neurosci Lett. 1989; 102: 247–252.[CrossRef][Medline] [Order article via Infotrieve]
16. Harada S, Tokunaga S, Momohara M, Masaki H, Tagawa T, Imaizumi T, Takeshita A. Inhibition of nitric oxide formation in the nucleus tractus solitarius increases renal sympathetic nerve activity in rabbits. Circ Res. 1993; 72: 511–516.
17. Zanzinger J, Czachurski J, Seller H. Effects of nitric oxide on sympathetic baroreflex transmission in the nucleus tractus solitarii and caudal ventrolateral medulla in cats. Neurosci Lett. 1995; 197: 199–202.[CrossRef][Medline] [Order article via Infotrieve]
18. Garthwaite J. Glutamate, nitric oxide and cell-cell signalling in the nervous system. TINS. 1991; 14: 60–67.[CrossRef][Medline] [Order article via Infotrieve]
19. Talman WT, Nitschke Dragon D, Ohta H, Lin L-H. Nitroxidergic influences on cardiovascular control by NTS: a Link with Glutamate. Ann N Y Acad Sci. 2001; 940: 169–178.[Medline] [Order article via Infotrieve]
20. Lin L-H, Edwards RH, Fremeau RT, Fujiyama F, Kaneko T, Talman WT. Vesicular Glutamate Transporter Colocalizes with Neuronal Nitric Oxide Synthase in Rat Nucleus Tractus Solitarii. Neurosci. 2003; 144: 662–670.
21. Johansson C, Deveney AM, Reif D, Jackson DM. The neuronal selective nitric oxide inhibitor AR-R 17477, blocks some effects of phencyclidine, while having no observable behavioural effects when given alone. Pharmacol Toxicol. 1999; 84: 226–233.[Medline] [Order article via Infotrieve]
22. Talman WT, Chianca DA, Jr., Nitschke Dragon D, Lin L-H. Differential involvement of neuronal nitric oxide in mediating cardiovascular responses to activation of NMDA and metabotropic receptors in the nucleus tractus solitarii of rats. FASEB J. 2003; 17: A888.
23. Talman WT, Perrone MH, Reis DJ. Acute hypertension after the local injection of kainic acid into the nucleus tractus solitarii of rats. Circ Res. 1981; 48: 292–298.
24. Garthwaite J, Charles SL, Chess-Williams R. Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain. Nature. 1988; 336: 385–388.[CrossRef][Medline] [Order article via Infotrieve]
25. Garthwaite J, Garthwaite G, Palmer RMJ, Moncada S. NMDA receptor activation induces nitric oxide synthesis from arginine in rat brain slices. Eur J Pharmacol. 1989; 172: 413–416.[CrossRef][Medline] [Order article via Infotrieve]
26. Garthwaite J, Garthwaite G. Cellular origins of cyclic GMP responses to excitatory amino acid receptor agonists in rat cerebellum in vitro. J Neurochem. 1987; 48: 29–39.[Medline] [Order article via Infotrieve]
27. De Vente J, Bol JGJM, Berkelmans HS, Schipper J, Steinbusch HWM. Immunocytochemistry of cGMP in the cerebellum of the immature, adult, and aged rat: the involvement of nitric oxide. A micropharmacological study. Eur J Neurosci. 1990; 2: 845–862.[CrossRef][Medline] [Order article via Infotrieve]
28. Garthwaite J, Southam E, Anderton M. A kainate receptor linked to nitric oxide synthesis from arginine. J Neurochem. 1989; 53: 1952–1954.[CrossRef][Medline] [Order article via Infotrieve]
29. Kiedrowski L, Costa E, Wroblewski JT. Glutamate receptor agonists stimulate nitric oxide synthase in primary cultures of cerebellar granule cells. J Neurochem. 1992; 58: 335–341.[CrossRef][Medline] [Order article via Infotrieve]
30. Southam E, East SJ, Garthwaite J. Excitatory amino acid receptors coupled to the nitric oxide/cyclic GMP pathway in rat cerebellum during development. J Neurochem. 1991; 56: 2072–2081.[Medline] [Order article via Infotrieve]
31. Okada D. Two pathways of cyclic GMP production through glutamate receptor-mediated nitric oxide synthesis. J Neurochem. 1992; 59: 1203–1210.[CrossRef][Medline] [Order article via Infotrieve]
32. Marin P, Quignard J-F, Lafon-Cazal M, Bockaert J. Non-classical glutamate receptors, blocked by both NMDA and non-NMDA antagonists, stimulate nitric oxide production in neurons. Neuropharmacol. 1993; 32: 29–36.[CrossRef][Medline] [Order article via Infotrieve]
33. Larkman AU, Jack JJ. Synaptic plasticity: hippocampal LTP. Curr Opin Neurobiol. 1995; 5: 324–334.[CrossRef][Medline] [Order article via Infotrieve]
34. Hawkins RD, Zhuo M, Arancio O. Nitric oxide and carbon monoxide as possible retrograde messengers in hippocampal long-term potentiation. J Neurobiol. 1994; 25: 652–665.[CrossRef][Medline] [Order article via Infotrieve]
35. Segieth J, Getting SJ, Biggs CS, Whitton PS. Nitric oxide regulates excitatory amino acid release in a biphasic manner in freely moving rats. Neurosci Lett. 1995; 200: 101–104.[CrossRef][Medline] [Order article via Infotrieve]
36. Di Paola ED, Vidal MJ, Nisticò G. L-Glutamate evokes the release of an endothelium-derived relaxing factor-like substance from the rat nucleus tractus solitarius. J Cardiovasc Pharmacol. 1991; 17: S269–S272.
37. Fong AY, Talman WT, Lawrence AJ. Axonal transport of NADPH-diaphorase and [(3)H]nitro-L-arginine binding, but not [(3)H]cGMP binding, by the rat vagus nerve. Brain Res. 2000; 878: 240–246.[CrossRef][Medline] [Order article via Infotrieve]
38. Kristensson K, Aldskogius M, Peng Z-C, Olsson T, Aldskogius H, Bentivoglio M. Co-induction of neuronal interferon-gamma and nitric oxide synthase in rat motor neurons after axotomy: a role in nerve repair or death? J Neurocytol. 1994; 23: 453–459.[CrossRef][Medline] [Order article via Infotrieve]
39. Lawrence AJ, Castillo-Melendez M, McLean KJ, Jarrott B. The distribution of nitric oxide synthase-, adenosine deaminase- and neuropeptide Y-immunoreactivity through the entire rat nucleus tractus solitarius: Effect of unilateral nodose ganglionectomy. J Chem Neuroanat. 1998; 15: 27–40.[CrossRef][Medline] [Order article via Infotrieve]
40. Lin L-H, Cassell MD, Sandra A, Talman WT. Direct evidence for nitric oxide synthase in vagal afferents to the nucleus tractus solitarii. Neurosci. 1998; 84: 549–558.[CrossRef][Medline] [Order article via Infotrieve]
41. Lin L-H, Sandra A, Boutelle S, Talman WT. Up-regulation of nitric oxide synthase and its mRNA in vagal motor nuclei following axotomy in rat. Neurosci Lett. 1997; 221: 97–100.[CrossRef][Medline] [Order article via Infotrieve]
42. Ruggiero DA, Mtui EP, Otake K, Anwar M. Central and primary visceral afferents to nucleus tractus solitarii may generate nitric oxide as a membrane-permeant neuronal messenger. J Comp Neurol. 1996; 364: 51–67.[CrossRef][Medline] [Order article via Infotrieve]
43. Lin L-H, Emson PC, Talman WT. Apposition of neuronal elements containing nitric oxide synthase and glutamate in the nucleus tractus solitarii of rat: a confocal microscopic analysis. Neurosci. 2000; 96: 341–350.[CrossRef][Medline] [Order article via Infotrieve]
44. Ma S, Abboud FM, Felder RB. Effects of L-arginine-derived nitric oxide synthesis on neuronal activity in nucleus tractus solitarius. Am J Physiol Regul Integr Comp Physiol. 1995; 268: R487–R491.
45. Lo WJ, Liu HW, Lin HC, Ger LP, Tung CS, Tseng C-J. Modulatory effects of nitric oxide on baroreflex activation in the brainstem nuclei of rats. Chin J Physiol. 1996; 39: 57–62.[Medline] [Order article via Infotrieve]
46. Lewis SJ, Ohta H, Machado BH, Bates JN, Talman WT. Microinjection of S-nitrosocysteine into the nucleus tractus solitarii decreases arterial pressure and heart rate via activation of soluble guanylate cyclase. Eur J Pharmacol. 1991; 202: 135–136.[CrossRef][Medline] [Order article via Infotrieve]
47. Lewis SJ, Machado BH, Ohta H, Talman WT. Processing of cardiopulmonary afferent input within the nucleus tractus solitarii involves activation of soluble guanylate cyclase. Eur J Pharmacol. 1991; 203: 327–328.[CrossRef][Medline] [Order article via Infotrieve]
48. Lin HC, Wan FJ, Tseng C-J. Modulation of cardiovascular effects produced by nitric oxide and ionotropic glutamate receptor interaction in the nucleus tractus solitarii of rats. Neuropharmacol. 1999; 38: 935–941.[CrossRef][Medline] [Order article via Infotrieve]
49. Chianca DA, Jr., Lin L-H, Nitschke Dragon D, Talman WT. NMDA Receptors in the Nucleus Tractus Solitarii are Linked to Soluble Guanylate Cyclase. Am J Physiol Heart Circ Physiol. 2004; In press.
50. Lin L-H, Talman WT. N-methyl-D-aspartate receptors on neurons that synthesize nitric oxide in rat nucleus tractus solitarii. Neurosci. 2000; 100: 581–588.[CrossRef][Medline] [Order article via Infotrieve]
51. Lin L-H, Talman WT. Colocalization of GluR1 and neuronal nitric oxide synthase in rat nucleus tractus solitarii neurons. Neurosci. 2001; 106: 801–809.[CrossRef][Medline] [Order article via Infotrieve]
52. Paton JF, Deuchars J, Ahmad Z, Wong LF, Murphy D, Kasparov S. Adenoviral vector demonstrates that angiotensin II-induced depression of the cardiac baroreflex is mediated by endothelial nitric oxide synthase in the nucleus tractus solitarii of the rat. J Physiol (Lond). 2001; 531: 2–58.
53. Murakami H, Liu JL, Yoneyama H, Nishida Y, Okada K, Kosaka H, Morita H, Zucker IH. Blockade of neuronal nitric oxide synthase alters the baroreflex control of heart rate in the rabbit. Am J Physiol Regul Integr Comp Physiol. 1998; 274: 181–186.
54. Fabricius M, Rubin I, Bundgaard M, Lauritzen M. NOS activity in brain and endothelium: relation to hypercapnic rise of cerebral blood flow in rats. Am J Physiol. 1996; 271: H2035–H2044.[Medline] [Order article via Infotrieve]
55. Zagvazdin Y, Sancesario G, Wang YX, Share L, Fitzgerald ME, Reiner A. Evidence from its cardiovascular effects that 7-nitroindazole may inhibit endothelial nitric oxide synthase in vivo. Eur J Pharmacol. 1996; 303: 61–69.[CrossRef][Medline] [Order article via Infotrieve]
56. Moore PK, Bland-Ward PA. 7-nitroindazole: An inhibitor of nitric oxide synthase. Methods Enzymol. 1996; 268: 393–398.[Medline] [Order article via Infotrieve]
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T. J. Scislo, N. Tan, and D. S. O'Leary Differential role of nitric oxide in regional sympathetic responses to stimulation of NTS A2a adenosine receptors Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H638 - H649. [Abstract] [Full Text] [PDF]
|
|
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|
|
A. C. R. Dias, M. Vitela, E. Colombari, and S. W. Mifflin Nitric oxide modulation of glutamatergic, baroreflex, and cardiopulmonary transmission in the nucleus of the solitary tract Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H256 - H262. [Abstract] [Full Text] [PDF]
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K. Ito, Y. Hirooka, Y. Sagara, Y. Kimura, K. Kaibuchi, H. Shimokawa, A. Takeshita, and K. Sunagawa Inhibition of Rho-Kinase in the Brainstem Augments Baroreflex Control of Heart Rate in Rats Hypertension, October 1, 2004; 44(4): 478 - 483. [Abstract] [Full Text] [PDF]
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