Enhanced Depressor Response to Endothelial Nitric Oxide Synthase Gene Transfer into the Nucleus Tractus Solitarii of Spontaneously Hypertensive Rats

Hirooka, Yoshitaka; Sakai, Koji; Kishi, Takuya; Izutsu, Koji; Shimokawa, Hiroaki; Takeshita, Akira

doi:10.1291/hypres.26.325

Cited by 34 publications

(30 citation statements)

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“…The reduction of blood pressure following eNOS activation may be due to decreased sympathetic nerve activity. 39 In summary, the increased expression of eNOS led to augmented baroreflex sensitivity in the brains of hypertensive rats and reduced MAP and HR, 40 as observed in our studies following Bj-PRO-10c administration. These effects result from increased eNOS expression and appear to depend on NO-induced liberation of GABA.…”

Section: Discussionsupporting

confidence: 70%

“…38 It has been suggested that the development of hypertension in SHRs involves abnormalities in the citrulline-NO cycle. 39 Although high concentrations of nNOS are present in the CNS and principally in nucleus of the solitary tract and rostral ventrolateral medulla, its expression levels do not differ between SHRs and rats with normal arterial pressures. 39 This observation suggests that there are other compensatory mechanisms for the reduction of arterial pressure that do not involve nNOS activity.…”

Section: Discussionmentioning

confidence: 93%

“…39 Although high concentrations of nNOS are present in the CNS and principally in nucleus of the solitary tract and rostral ventrolateral medulla, its expression levels do not differ between SHRs and rats with normal arterial pressures. 39 This observation suggests that there are other compensatory mechanisms for the reduction of arterial pressure that do not involve nNOS activity. The reduction of blood pressure following eNOS activation may be due to decreased sympathetic nerve activity.…”

Section: Discussionmentioning

confidence: 93%

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Brain nitric oxide production by a proline-rich decapeptide from Bothrops jararaca venom improves baroreflex sensitivity of spontaneously hypertensive rats

Lameu

Pontieri

Guerreiro³

et al. 2010

Hypertens Res

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Baroreflex sensitivity is disturbed in many people with cardiovascular diseases such as hypertension. Brain deficiency of nitric oxide (NO), which is synthesized by NO synthase (NOS) in the citrulline-NO cycle (with argininosuccinate synthase (ASS) activity being the rate-limiting step), contributes to impaired baroreflex. We recently showed that a decapeptide isolated from Bothrops jararaca snake venom, denoted Bj-PRO-10c, exerts powerful and sustained antihypertensive activity. Bj-PRO-10c promoted vasodilatation dependent on the positive modulation of ASS activity and NO production in the endothelium, and also acted on the central nervous system, inducing the release of GABA and glutamate, two important neurotransmitters in the regulation of autonomic systems. We evaluated baroreflex function using the regression line obtained by the best-fit points of measured heart rate (HR) and mean arterial pressure (MAP) data from spontaneously hypertensive rats (SHRs) treated with Bj-PRO-10c. We also investigated molecular mechanisms involved in this effect, both in vitro and in vivo. Bj-PRO-10c mediated an increase in baroreflex sensitivity and a decrease in MAP and HR. The effects exerted by the peptide include an increase in the gene expression of endothelial NOS and ASS. Bj-PRO-10c-induced NO production depended on intracellular calcium fluxes and the activation of a G i/o -protein-coupled metabotropic receptor. Bj-PRO-10c induced NO production and the gene expression of ASS and endothelial NOS in the brains of SHRs, thereby improving baroreflex sensitivity. Bj-PRO-10c may reveal novel approaches for treating diseases with impaired baroreflex function. Hypertension Research (2010Research ( ) 33, 1283Research ( -1288 doi:10.1038/hr.2010 Keywords: argininosuccinate synthase; baroreflex sensitivity; Bothrops jararaca venom; nitric oxide; proline-rich oligopeptide INTRODUCTIONThe gaseous messenger NO is involved mainly in the regulation of local and systemic vascular resistance, sodium balance and, consequently, blood pressure control, 1 but it is also a signaling molecule and modulator of brain function. 2 Recent studies relate NO with central cardiovascular control through the regulation of the cardiac and vascular autonomic system via the modulation of the central sites of cardiovascular autonomic neural integration. 3,4 NO is generated in the citrulline-NO cycle by NO synthase (NOS) using L-arginine as a substrate. Three isoforms of NOS have been described: calcium-dependent endothelial (eNOS) and neuronal (nNOS) isoforms and inducible NOS. The expression and activity

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 93%

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Brain nitric oxide production by a proline-rich decapeptide from Bothrops jararaca venom improves baroreflex sensitivity of spontaneously hypertensive rats

Lameu

Pontieri

Guerreiro³

et al. 2010

Hypertens Res

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“…4,29 -31 In addition, overexpression of eNOS in the NTS causes a greater depressor response in SHR (spontaneously hypertensive rats), which suggests that an abnormality of the NO pathway in the NTS may be related to the hypertensive mechanisms of SHR. 32 This was also supported by a study that demonstrated that insulin-stimulated production of NO in HUVECs is completely blocked by L-NAME, which is consistent with the possibility that eNOS may be acutely regulated through ligand-activated tyrosine kinase receptors, such as the insulin receptor and insulin-like growth factor-1 receptor. 14 On the basis of those findings, we question whether eNOS activation is needed in the insulin-signaling pathway to regulate cardiovascular effects in the NTS.…”

Section: Discussionsupporting

confidence: 68%

In Situ Akt Phosphorylation in the Nucleus Tractus Solitarii Is Involved in Central Control of Blood Pressure and Heart Rate

Huang

et al. 2004

Circulation

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Background-Previously, we have shown that nitric oxide (NO) plays a significant role in central cardiovascular regulation and modulates the baroreflex in the nucleus tractus solitarii (NTS) of rats. NO production is mediated by activation of NO synthase (NOS). Insulin signaling was involved in controlling peripheral blood pressure via the activation of endothelial NOS. Here, we investigated whether the insulin signal transduction pathway is involved in controlling central cardiovascular effects. Methods and Results-Insulin was injected into NTS of urethane-anesthetized male Wistar-Kyoto (WKY) rats.Unilateral microinjection (60 nL) of insulin (100 IU/mL) into the NTS produced prominent depressor and bradycardic effects in 8-and 16-week-old WKY rats. In addition, pretreatment with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and the NOS inhibitor L-NAME into the NTS caused attenuation of the cardiovascular response evoked by insulin in either 8-or 16-week-old WKY rats. Western blot analysis showed a significant increase (2.6Ϯ0.4-fold; PϽ0.05) in Akt phosphorylation after insulin injection, whereas LY294002 abolished the insulin-induced effects. In situ Akt phosphorylation was found in NTS by immunohistochemistry analysis after injection of insulin. This in situ Akt phosphorylation was abolished significantly after injection of LY294002. Conclusions-Take together, these results suggest that the insulin-PI3K-Akt-NOS signaling pathway may play a significant role in central cardiovascular regulation. Key Words: insulin Ⅲ enzymes Ⅲ nitric oxide synthase N itric oxide (NO) has been indicated to affect sympathetic nerve activity, and it modulates blood pressure and heart rate (HR) in the nucleus tractus solitarii (NTS). 1,2 However, the mechanisms for these actions have not been clarified. NO is produced by NO synthase (NOS). 3 Previously, adenovirusmediated gene delivery of endothelial NOS (eNOS) into NTS caused hypotension and bradycardia. 4 The results suggested that genes involved in the eNOS upstream signal transduction pathway might control central cardiovascular effects.Studies have shown that insulin receptors are present in the central nervous system, 5 which indicates the significant role of insulin in the central nervous system. Havrankova et al 6 have demonstrated that insulin has an effect on cardiovascular function. Other reports also showed the effects of insulin on arterial pressure and HR after peripheral injection and suggested a function of insulin in central cardiovascular control. 7,8 Recent evidence has demonstrated that the peripheral and central influence by insulin on cardiovascular regulation is due to an influence it exerts in the sympathetic nervous system. 7 Moreover, insulin receptors are shown to be immunochemically positive in the NTS. 8 These data suggested that insulin-mediated signaling in the NTS may play a significant role in the regulation of cardiovascular activity.It then becomes important to study insulin-mediated signaling in the NTS to understand how insulin regul...

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“…In addition, this mechanism is involved in the depressor and bradycardic responses evoked by NMDA receptor activation in anesthetized rats (82). To determine the effects of increased NO production in the NTS for much longer periods on blood pressure, heart rate, and urinary norepinephrine excretion, we developed an in vivo technique for eNOS gene transfer into the NTS of rats (43,44,46,107). In this study, the successful transfer of the eNOS gene into the NTS was confirmed by several methods, including immunohistochemistry, Western blot analysis, and nitrite/nitrate concentration measurements (107).…”

Section: No In the Brainmentioning

confidence: 99%

Imbalance of central nitric oxide and reactive oxygen species in the regulation of sympathetic activity and neural mechanisms of hypertension

Hirooka

Kishi

Sakai

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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109

108

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Hirooka Y, Kishi T, Sakai K, Takeshita A, Sunagawa K. Imbalance of central nitric oxide and reactive oxygen species in the regulation of sympathetic activity and neural mechanisms of hypertension. Am J Physiol Regul Integr Comp Physiol 300: R818-R826, 2011. First published February 2, 2011 doi:10.1152/ajpregu.00426.2010 and reactive oxygen species (ROS) play important roles in blood pressure regulation via the modulation of the autonomic nervous system, particularly in the central nervous system (CNS). In general, accumulating evidence suggests that NO inhibits, but ROS activates, the sympathetic nervous system. NO and ROS, however, interact with each other. Our consecutive studies and those of others strongly indicate that an imbalance between NO bioavailability and ROS generation in the CNS, including the brain stem, activates the sympathetic nervous system, and this mechanism is involved in the pathogenesis of neurogenic aspects of hypertension. In this review, we focus on the role of NO and ROS in the regulation of the sympathetic nervous system within the brain stem and subsequent cardiovascular control. Multiple mechanisms are proposed, including modulation of neurotransmitter release, inhibition of receptors, and alterations of intracellular signaling pathways. Together, the evidence indicates that an imbalance of NO and ROS in the CNS plays a pivotal role in the pathogenesis of hypertension. blood pressure; sympathetic nervous system; central nervous system; nitric oxide; oxidative stress ACTIVATION OF THE SYMPATHETIC nervous system is critically involved in the pathogenesis of hypertension, from initial occurrence to the development of target organ damage, such as heart failure, stroke, and renal failure (35,36). The importance of the effects of the renin-angiotensin system on the sympathetic nervous system in the pathogenesis of hypertension is recently highlighted (30,31). This is not surprising because both the autonomic nervous system and hormonal factors are the major regulators of blood pressure; therefore, abnormalities of either system are likely to be involved in the pathogenesis of essential hypertension (30,31,37). Esler (30) reported that the sympathetic nervous system is activated in ϳ50% of patients with hypertension, particularly in patients with essential hypertension. Central sympathetic outflow is determined by several important nuclei and their circuits in the central nervous system (CNS) (9, 81). These pathways involve many neurotransmitters and neuromodulators (16,25,38,99). In particular, the brain stem circuitry is now considered crucial for the pathogenesis of hypertension, including both excitatory and inhibitory inputs from the supramedullary nuclei and the baroreceptors (16,25,38,100,115). In this review, we focus on the role of nitric oxide (NO) and reactive oxygen species (ROS) in the brain stem as factors constituting the neural mechanisms of hypertension. Because of the close relationship between NO and ROS, we discuss the individual roles of NO and ROS in the brain stem i...

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Enhanced Depressor Response to Endothelial Nitric Oxide Synthase Gene Transfer into the Nucleus Tractus Solitarii of Spontaneously Hypertensive Rats

Cited by 34 publications

References 45 publications

Brain nitric oxide production by a proline-rich decapeptide from Bothrops jararaca venom improves baroreflex sensitivity of spontaneously hypertensive rats

Brain nitric oxide production by a proline-rich decapeptide from Bothrops jararaca venom improves baroreflex sensitivity of spontaneously hypertensive rats

In Situ Akt Phosphorylation in the Nucleus Tractus Solitarii Is Involved in Central Control of Blood Pressure and Heart Rate

Imbalance of central nitric oxide and reactive oxygen species in the regulation of sympathetic activity and neural mechanisms of hypertension

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