Evidence for a critical role of nitric oxide in the tonic excitation of rabbit renal sympathetic preganglionic neurones.

Hakim, Manfaluthy; Hirooka, Yoshitaka; Coleman, Matthew; Bennett, Max R.; Dampney, R.A.L.

doi:10.1113/jphysiol.1995.sp020527

Cited by 53 publications

(35 citation statements)

References 18 publications

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“…4,6,7 Other studies 3,5,6 suggest a sympathoexcitatory and pressor role for NO in the RVLM. Our laboratory 13 demonstrated recently that this controversy might be resolved by recognizing the differential roles of NOS isoforms at the RVLM in cardiovascular regulation.…”

Section: Discussionmentioning

confidence: 99%

“…Key Words: blood pressure Ⅲ heart rate Ⅲ hypertension Ⅲ nervous system, sympathetic Ⅲ nitric oxide synthase A part from its well-known function as an endotheliumderived relaxing factor that promotes relaxation of peripheral vasculature, 1 recent studies 2 also assign a role to nitric oxide (NO) in central circulatory regulation. One of the potential sites in the central nervous system for NO to exert its modulatory action on cardiovascular functions is the rostral ventrolateral medulla (RVLM), [3][4][5][6][7][8] which provides the sympathetic drive that maintains vascular vasomotor tone. 9 Of the 3 isoforms of nitric oxide synthase (NOS), it is generally contended 10 -12 that whereas both the neuronal (nNOS) and endothelial (eNOS) isoforms are expressed constitutively, the activity of inducible NOS (iNOS) is induced principally by inflammatory stimuli.…”

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confidence: 99%

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Reduced Functional Expression and Molecular Synthesis of Inducible Nitric Oxide Synthase in Rostral Ventrolateral Medulla of Spontaneously Hypertensive Rats

Chan

Ling-lin

et al. 2001

Circulation

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Background-We demonstrated recently that the prevalence of neuronal (nNOS) over inducible (iNOS) nitric oxide synthase activity at the rostral ventrolateral medulla (RVLM), the medullary origin of sympathetic neurogenic vasomotor tone, and the associated dominance of sympathoexcitation over sympathoinhibition underlie the maintenance of sympathetic vasomotor outflow by the endogenous NO. Here, we evaluated the hypothesis that a significant downregulation of iNOS at the RVLM may play a crucial role in the genesis of augmented sympathetic vasomotor tone during hypertension. Methods and Results-Spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats anesthetized with propofol were used. Compared with SHR, the hypotension, bradycardia, or depression in sympathetic vasomotor tone induced by bilateral microinjection of lipopolysaccharide (5 or 10 ng) into the RVLM of WKY rats exhibited significantly shorter-onset latency, appreciably steeper slope, and a greater incidence of mortality. All these effects of lipopolysaccharide (10 ng) were significantly blunted by coadministration of the selective iNOS inhibitor S-methylisothiourea (250 pmol). Reverse transcription-polymerase chain reaction and Western blot analyses further revealed significantly lower iNOS mRNA and protein levels at the ventrolateral medulla in SHR under basal conditions or on activation by lipopolysaccharide (10 ng). Conversely, nNOS mRNA and protein levels remained constant in the RVLM and were comparable in both strains of rats. Conclusions-We conclude that a significant downregulation in both functional expression and molecular synthesis of iNOS at the RVLM may underlie the augmented sympathetic vasomotor tone during hypertension. Key Words: blood pressure Ⅲ heart rate Ⅲ hypertension Ⅲ nervous system, sympathetic Ⅲ nitric oxide synthase A part from its well-known function as an endotheliumderived relaxing factor that promotes relaxation of peripheral vasculature, 1 recent studies 2 also assign a role to nitric oxide (NO) in central circulatory regulation. One of the potential sites in the central nervous system for NO to exert its modulatory action on cardiovascular functions is the rostral ventrolateral medulla (RVLM), [3][4][5][6][7][8] which provides the sympathetic drive that maintains vascular vasomotor tone. 9 Of the 3 isoforms of nitric oxide synthase (NOS), it is generally contended 10 -12 that whereas both the neuronal (nNOS) and endothelial (eNOS) isoforms are expressed constitutively, the activity of inducible NOS (iNOS) is induced principally by inflammatory stimuli. In a recent study, 13 however, we demonstrated that both nNOS and iNOS in the RVLM are tonically active under physiological conditions at the levels of functional expression and molecular synthesis. Furthermore, the prevalence of nNOS over iNOS activity at the RVLM and the associated dominance of sympathoexcitation over sympathoinhibition may underlie the maintenance of sympathetic vasomotor outflow and stable arterial pressure by the endogenous NO.A ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Reduced Functional Expression and Molecular Synthesis of Inducible Nitric Oxide Synthase in Rostral Ventrolateral Medulla of Spontaneously Hypertensive Rats

Chan

Ling-lin

et al. 2001

Circulation

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“…22 In the CNS, nNOS is thought to play an important role in regulating BP via SNA, but its actual role is unclear. NO derived from nNOS has been suggested to both decrease and increase SNA in rats 23,24 and rabbits 25,26 and to decrease SNA in cats, 27 whereas it has been shown to have no or little effect on SNA in rabbits 28 and humans. 29 Thus, it is possible that in the CNS, NO released by nNOS has different effects depending on the center where it is released.…”

Section: Kurihara Et Al November 1998 859mentioning

confidence: 99%

Role of nNOS in Blood Pressure Regulation in eNOS Null Mutant Mice

et al. 1998

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Abstract-The role of neural nitric oxide synthase (nNOS) in regulating blood pressure (BP) remains uncertain. Recently it was reported that in mice lacking functional endothelial NOS (eNOS) genes (Ϫ/Ϫ), acute administration of a nonselective NOS inhibitor, N w -nitro-L-arginine, decreased mean BP, suggesting that NO released by non-eNOS isoforms increases BP. Because the inducible NOS isoform is not constitutively expressed and when induced causes hypotension, we hypothesize that it is NO produced by nNOS that increases BP in the absence of eNOS activity. To test this hypothesis, we studied the acute effect of selective and nonselective nNOS inhibitors on BP and cerebellar NOS activity in eNOS (Ϫ/Ϫ), wild-type (ϩ/ϩ), and heterozygous (ϩ/Ϫ) mice as well as in ϩ/ϩ mice with renovascular hypertension. Because it is not known whether the decrease in BP caused by acute NOS inhibition in Ϫ/Ϫ mice can occur chronically, we also studied the effect of chronic NOS inhibition on both BP and cerebellar NOS activity. eNOS (Ϫ/Ϫ) mice had higher BP than ϩ/ϩ or ϩ/Ϫmice, and acute administration of the selective nNOS inhibitor 7-nitroindazole (7-NI) decreased their mean BP from 137Ϯ13 to 124Ϯ12 mm Hg (PϽ0.01). In ϩ/ϩ, ϩ/Ϫ, or renovascular hypertensive ϩ/ϩ mice, 7-NI caused a small but insignificant rise from 105Ϯ5 to 110Ϯ6 mm Hg, from 115Ϯ9 to 119Ϯ13 mm Hg, and from 146Ϯ6 to 150Ϯ6 mm Hg, respectively. Fifteen minutes after administration of 7-NI, cerebellar NOS activity decreased by 70%; however, this inhibitory effect was brief, since 2 hours after 7-NI administration NOS returned toward control values. Chronic oral or intraperitoneal administration of 7-NI did not inhibit cerebellar NOS activity, whereas the nonselective NOS inhibitor N G -nitro-L-arginine methyl ester (L-NAME) decreased this activity by 50%. Therefore, we studied the effect of chronic L-NAME administration (4 weeks) on BP. In Ϫ/Ϫ mice, chronic L-NAME administration decreased BP from 135Ϯ4 to 120Ϯ3 mm Hg (PϽ0.05), whereas in ϩ/ϩ and ϩ/Ϫmice, as expected, it increased BP from 109Ϯ2 to 125Ϯ3 mm Hg (PϽ0.001) and from 107Ϯ6 to 119Ϯ5 mm Hg (PϽ0.02), respectively. After L-NAME administration was stopped, BP returned to baseline. These results suggest that in eNOS Ϫ/Ϫ mice, NO derived from nNOS increases BP both acutely and chronically. (Hypertension. 1998;32:856-861.) Key Words: nitric oxide Ⅲ blood pressure Ⅲ nitric oxide synthase, neural Ⅲ nitric oxide synthase, endothelial I t is well known that nitric oxide (NO) plays an important role in regulating blood pressure (BP).1-4 Three isoforms of the enzyme responsible for NO formation, nitric oxide synthase (NOS), have been identified: neuronal (nNOS), inducible (iNOS), and endothelial (eNOS).4,5 eNOS is expressed in endothelial cells and produces NO, which dilates blood vessels. It is stimulated by a variety of receptor agonists and by shear stress produced by flowing blood.3,4 Recently, 2 groups acting independently developed mice lacking functional eNOS genes (eNOS Ϫ/Ϫ mice).6,7 These mutant mice showed elevated B...

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“…RVLM (Hakim et al, 1995;Zanzinger et al, 1995;Hirooka et al, 1996;Kagiyama et al, 1997;. Studies using immunohistochemistry, NADPH-diaphorase staining, or autoradiography further demonstrate the presence of neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS in the RVLM (Vincent and Kimura, 1992;Chang et al, 2001).…”

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confidence: 99%

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

Huang

Chan²,

Hsu

2003

Mol Pharmacol

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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 Larginine, 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 3Ј,5Ј-cyclic monophosphorothioate, fully prevented the L-arginine-, 3-morpholinylsydnoneimine-, and N-[4-[1-(3-(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 Ca 2ϩ 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 Ca 2ϩ channel activity leading to facilitating glutamate release. The presynaptic action of NO is mediated by a cGMP/PKG-coupled signaling pathway.It is well known that rostral ventrolateral medulla (RVLM) neurons play an important role in cardiovascular, respiratory, and nociceptive functions (Dampney, 1994). Both electrophysiological and anatomical studies showed that a subset of RVLM neurons directly innervates preganglionic vasomotor neurons in the intermediolateral cell columns of the spinal cord, which are involved in the regulation of vasomotor and cardiac tone (Morrison et al., 1991;Deuchars et al., 1995). In addition, the RVLM neurons are tonically active in vivo and receive convergent excitatory and inhibitory inputs from multiple sources (Mtui et al., 1995;Guyenet et al., 1996). However, little is known regarding the physiological regulation of the tonic excitation of these neurons.Nitric oxide (NO), an unstable diatomic radical synthesized from L-arginine by nitric-oxide synthase (NOS), is recognized as an important signaling molecule mediating a variety of physiological processes, including synaptic transmission and synaptic plasticity (Garthwaite, 1991). In addition, considerable evidence suggests that NO i...

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Evidence for a critical role of nitric oxide in the tonic excitation of rabbit renal sympathetic preganglionic neurones.

Cited by 53 publications

References 18 publications

Reduced Functional Expression and Molecular Synthesis of Inducible Nitric Oxide Synthase in Rostral Ventrolateral Medulla of Spontaneously Hypertensive Rats

Reduced Functional Expression and Molecular Synthesis of Inducible Nitric Oxide Synthase in Rostral Ventrolateral Medulla of Spontaneously Hypertensive Rats

Role of nNOS in Blood Pressure Regulation in eNOS Null Mutant Mice

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

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