Nitric Oxide as an Autocrine Regulator of Sodium Currents in Baroreceptor Neurons

Li, Zhi; Chapleau, Mark W.; Bates, James N.; Bielefeldt, Klaus; Lee, Hon Chi; Abboud, François M.

doi:10.1016/s0896-6273(00)80484-5

Cited by 130 publications

(97 citation statements)

References 67 publications

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“…20,21 Indeed, the modulation of ion channels represents one of the important functional effects of NO. In the cardiac systems, NO can inactivate the cardiac ryanodine receptor Ca 2ϩ release channel 22 and plays an important role in cardiac pacemaking cells by mediating a muscarinic cholinergic attenuation of the L-type Ca 2ϩ current in mammalian sinoatrial and atrioventricular node.…”

Section: Effects Of No On Other Ion Channelsmentioning

confidence: 99%

Nitric Oxide Modulates Cardiac Na ⁺ Channel via Protein Kinase A and Protein Kinase G

Ahmmed

Dong

et al. 2001

Circulation Research

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Abstract-We directly tested the effects of nitric oxide (NO) on Na ϩ channels in guinea pig and mouse ventricular myocytes using patch-clamp recordings. We have previously shown that NO donors have no observed effects on expressed Na ϩ channels. In contrast, NO (half-blocking concentration of 523 nmol/L) significantly reduces peak whole-cell Na ϩ current (I Na ) in isolated ventricular myocytes. The inhibitory effect of NO on I Na was not associated with changes in activation, inactivation, or reactivation kinetics. At the single-channel level, the reduction in macroscopic current was mediated by a decrease in open probability and/or a decrease in the number of functional channels with no change in single-channel conductance. Application of cell permeable analogs of cGMP or cAMP mimics the inhibitory effects of NO. Furthermore, the effects of NO on I Na can only be blocked by inhibition of both cGMP and cAMP pathways. Sulfhydryl-reducing agent does not reverse the effect of NO. In summary, although NO exerts its action via the known guanylyl cyclase (GC)/cGMP pathway, our findings provide evidence that NO can mediate its function via a GC/cGMP-independent mechanism involving the activation of adynylyl cyclase (AC) and cAMP-dependent protein kinase. Key Words: nitric oxide Ⅲ cardiac Na ϩ current Ⅲ protein kinase A Ⅲ protein kinase G N itric oxide (NO) is a uniquely diffusible and reactive molecular messenger, which is found in abundance and plays important regulatory roles in different systems throughout the body. 1 In the cardiovascular system, NO is the major endothelium-derived relaxing factor (EDRF) and causes vasodilation and reduces blood pressure. 2 In addition, NO functions as an important endogenous inhibitor of vascular lesion formation. 3 The coronary endothelium is responsible for the bulk of the endogenous, physiological production of NO. 4 However, NO can also be produced within the cardiac myocytes themselves by the constitutive NO synthase. 5 NO modulates cardiac contractility both in vitro and in vivo. 6 More recently, it was shown that NO can regulate both adenylyl cyclase (AC) and guanylyl cyclase (GC) in cardiac myocytes. High levels of NO induce large increases in cGMP and a negative inotropic effect, whereas low levels of NO increase cAMP and induce a positive contractile response. 7 We have previously shown using heterologous expression systems that although Ca 2ϩ channel can be directly modulated by NO, Na ϩ channels are unaffected by direct NO modulation. 8 Here, we show that NO modulates Na ϩ channels in native cardiac myocytes. In addition, we provide evidence to demonstrate that NO modulates Na ϩ channels via second messenger pathways through activation of protein kinase G (PKG) and protein kinase A (PKA). Materials and MethodsSingle left ventricular myocytes were isolated from guinea pigs and mice (Charles River Laboratories, Wilmington, Mass) as previously described. 9 See further details in the expanded Materials and Methods section that can be found in the online data supplement av...

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Section: Effects Of No On Other Ion Channelsmentioning

confidence: 99%

Nitric Oxide Modulates Cardiac Na ⁺ Channel via Protein Kinase A and Protein Kinase G

Ahmmed

Dong

et al. 2001

Circulation Research

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“…This gaseous molecule can spread, in fact, from its site of production and act in adjacent cells, either directly or through second messengers, on various protein substrates, including ion channels. Its influence on Ca 2ϩ -activated K ϩ channels (Bolotina et al, 1994), Na ϩ channels (Li et al, 1998), and Ca 2ϩ -activated Cl Ϫ currents (Waniishi et al, 1998) has been well documented, and several reports suggest that it is also involved in the modulation of high-voltage-activated (HVA) Ca 2ϩ channels [references in Carabelli et al (2002)]. In previous studies, we have found that NO donors and cGMP analogs significantly reduce the amplitude of macroscopic currents flowing through both L-and P/Q-type Ca 2ϩ channels in rat insulinoma RINm5F cells (Grassi et al, 1999a).…”

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confidence: 99%

cGMP/Protein Kinase G-Dependent Inhibition of N-Type Ca²⁺Channels Induced by Nitric Oxide in Human Neuroblastoma IMR32 Cells

et al. 2002

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Although data from our laboratory and others suggest that nitric oxide (NO) exerts an overall inhibitory action on high-voltageactivated Ca 2ϩ channels, conflicting observations have been reported regarding its effects on N-type channels. We performed whole-cell and cell-attached patch-clamp recordings in IMR32 cells to clarify the functional role of NO in the modulation of N channels of human neuronal cells. During depolarizing steps to ϩ10 mV from V h ϭ Ϫ90 mV, the NO donor, sodium nitroprusside (SNP; 200 M), reduced macroscopic N currents by 34% ( p Ͻ 0.01). The magnitude of inhibition was similar at all voltages tested (range, Ϫ40 to ϩ50 mV). No significant inhibition was observed when SNP was applied together with the NO scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide potassium salt (300 M), or after cell treatment with the guanylate cyclase inhibitor, 1H- channel open probability by 59% and increased both the mean shut time and the null sweep probability, but it had no significant effects on channel conductance, mean open time, or latency of first openings. These data suggest that NO inhibits N-channel gating through cGMP and PKG. The consequent decrease in Ca 2ϩ influx through these channels may affect different neuronal functions, including neurotransmitter release.

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“…The left kidney was exposed through a left flank incision, and the left RGA and CG were isolated from the connective tissue and excised for dissociation and cell culture as described previously. 11,12 The ganglia were incubated in the digestive medium for 55 minutes at 37°C. Enzymatic activity was terminated by a trypsin inhibitor.…”

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confidence: 99%

Angiotensin Selectively Activates a Subpopulation of Postganglionic Sympathetic Neurons in Mice

Yan

Chapleau

Whiteis

et al. 2001

Circulation Research

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Abstract-Angiotensin II (Ang II) increases renal sympathetic nerve activity in anesthetized mice before and after ganglionic blockade, suggesting that Ang II may directly activate postganglionic sympathetic neurons. The present study directly tested this hypothesis in vitro. Neurons were dissociated from aortic-renal and celiac ganglia of C57BL/6J mice. Key Words: calcium imaging Ⅲ calcium influx Ⅲ calcium channel blockers Ⅲ protein kinase activation T he renin-angiotensin system plays an important role in the regulation of arterial blood pressure and body fluid and electrolyte homeostasis. Angiotensin II (Ang II) directly contracts vascular smooth muscle cells and enhances the renal tubular reabsorption of sodium. 1,2 In addition, Ang II stimulates the sympathetic nervous system, thereby enhancing vasoconstriction and sodium reabsorption. 3,4 Mounting evidence supports a role of the sympathetic nervous system in the long-term regulation of arterial pressure. [5][6][7][8] Ang II has been shown to modulate the sympathetic nervous system function through actions within the central nervous system (eg, at the area postrema and rostral ventrolateral medulla) and through facilitation of sympathetic ganglionic neurotransmission and neurotransmitter release from efferent sympathetic terminals. 9 We recently described biphasic effects of Ang II on renal sympathetic nerve activity (RSNA) in intact mice. 10 Intravenous administration of Ang II increased arterial pressure and evoked a biphasic change in RSNA: inhibition of highamplitude phasic bursts of RSNA secondary to the initial rise of arterial pressure followed by the activation of lowamplitude continuously discharging RSNA. The initial inhibition of RSNA was prevented by baroreceptor denervation, indicating that it was indirectly mediated by the baroreflex response to the rise in arterial pressure. Consistent with this interpretation, the ganglionic blocker hexamethonium eliminated the baseline high-amplitude phasic bursts of RSNA. However, neither denervation nor hexamethonium prevented the Ang II-induced activation of low-amplitude continuously discharging RSNA, suggesting a direct action of Ang II on postganglionic sympathetic neurons. The goal of the present study was to test this hypothesis in vitro by directly measuring Ang II-induced changes in intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) in cultured sympathetic neurons isolated from mouse aortic-renal (ARG) and celiac (CG) ganglia. Materials and Methods AnimalsAll experiments were performed on cells obtained from C57BL/6J mice (Harlan; Madison, Wis). The project had been approved by the University of Iowa Animal Care and Use Committee. Cell CulturePrimary cultures of sympathetic neurons were prepared from the ARG and CG of mice. Adult C57BL/6J mice (25 to 30 g) were Original

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Nitric Oxide as an Autocrine Regulator of Sodium Currents in Baroreceptor Neurons

Cited by 130 publications

References 67 publications

Nitric Oxide Modulates Cardiac Na ⁺ Channel via Protein Kinase A and Protein Kinase G

Nitric Oxide Modulates Cardiac Na ⁺ Channel via Protein Kinase A and Protein Kinase G

cGMP/Protein Kinase G-Dependent Inhibition of N-Type Ca²⁺Channels Induced by Nitric Oxide in Human Neuroblastoma IMR32 Cells

Angiotensin Selectively Activates a Subpopulation of Postganglionic Sympathetic Neurons in Mice

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Nitric Oxide as an Autocrine Regulator of Sodium Currents in Baroreceptor Neurons

Cited by 130 publications

References 67 publications

Nitric Oxide Modulates Cardiac Na + Channel via Protein Kinase A and Protein Kinase G

Nitric Oxide Modulates Cardiac Na + Channel via Protein Kinase A and Protein Kinase G

cGMP/Protein Kinase G-Dependent Inhibition of N-Type Ca2+Channels Induced by Nitric Oxide in Human Neuroblastoma IMR32 Cells

Angiotensin Selectively Activates a Subpopulation of Postganglionic Sympathetic Neurons in Mice

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Nitric Oxide Modulates Cardiac Na ⁺ Channel via Protein Kinase A and Protein Kinase G

Nitric Oxide Modulates Cardiac Na ⁺ Channel via Protein Kinase A and Protein Kinase G

cGMP/Protein Kinase G-Dependent Inhibition of N-Type Ca²⁺Channels Induced by Nitric Oxide in Human Neuroblastoma IMR32 Cells