Cardiovascular Effects of Overexpression of Endothelial Nitric Oxide Synthase in the Rostral Ventrolateral Medulla in Stroke-Prone Spontaneously Hypertensive Rats

Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Hypertension (Impact Factor: 6.48). 03/2002; 39(2):264-8. DOI: 10.1161/hy0202.102701
Source: PubMed

ABSTRACT We have previously demonstrated that the overexpression of endothelial NO synthase (eNOS) in the rostral ventrolateral medulla (RVLM) decreases blood pressure, heart rate, and sympathetic nerve activity via an increase in gamma-amino butyric acid release in normotensive Wistar-Kyoto rats (WKY). Stroke-prone spontaneously hypertensive rats (SHRSP) appear to have reductions of NO production and GABA release in the RVLM. The aim of this study was to determine whether the effects of the increase in NO production in the RVLM in SHRSP are different from those in WKY. We transfected adenovirus vectors encoding either eNOS (AdeNOS) or beta-galactosidase (Adbetagal) into the RVLM of both strains. In the AdeNOS-treated group, mean arterial blood pressure and heart rate in the conscious state were significantly decreased at day 7 after the gene transfer in both strains. The decreases in mean arterial blood pressure and heart rate were significantly greater in SHRSP than in WKY. Urinary norepinephrine excretion was also decreased to a greater degree in SHRSP than in WKY after the gene transfer. The pressor response evoked by bicuculline into the RVLM of WKY was greater than that of SHRSP in the nontransfected group. However, in the AdeNOS-treated group, the pressor response did not differ between SHRSP and WKY after the gene transfer. These results indicate that the increase in NO production evoked by the overexpression of eNOS in the RVLM causes greater depressor and sympathoinhibitory responses in SHRSP than in WKY by improving an inhibitory action of GABA on the RVLM neurons.

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    • "In the brain, the balance between excitatory and inhibitory amino acids determines the neural activity (Li et al., 2002; Garthwaite, 2008). In hypertensive rats, inhibitory amino acid γ-amino butylic acid (GABA) in the RVLM is decreased (Kishi et al., 2002), which in part contributes to the activation of the SNS. NO in the RVLM increases GABA release (Kishi et al., 2001). "
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    ABSTRACT: Activation of the sympathetic nervous system (SNS) has an important role in the pathogenesis of hypertension, and is determined by the brain. Previous many studies have demonstrated that oxidative stress, mainly produced by angiotensin II type 1 (AT(1)) receptor and nicotinamide adenine dinucleotide phosphate (NAD (P) H) oxidase, in the autonomic brain regions was involved in the activation of the SNS of hypertension. In this concept, we have investigated the role of oxidative stress in the rostral ventrolateral medulla (RVLM), which is known as the cardiovascular center in the brainstem, in the activation of the SNS, and demonstrated that AT(1) receptor and NAD (P) H oxidase-induced oxidative stress in the RVLM causes sympathoexcitation in hypertensive rats. The mechanisms in which brain oxidative stress causes sympathoexcitation have been investigated, such as the interactions with nitric oxide (NO), effects on the signal transduction, or inflammations. Interestingly, the environmental factors of high salt intake and high calorie diet may also increase the oxidative stress in the brain, particularly in the RVLM, thereby activating the central sympathetic outflow and increasing the risk of hypertension. Furthermore, several orally administered AT(1) receptor blockers have been found to cause sympathoinhibition via reduction of oxidative stress through the inhibition of central AT(1) receptor. In conclusion, we must consider that AT(1) receptor and the related oxidative stress production in the brain cause the activation of SNS in hypertension, and that AT(1) receptor in the brain could be novel therapeutic target of the treatments for hypertension.
    Frontiers in Physiology 08/2012; 3:335. DOI:10.3389/fphys.2012.00335 · 3.53 Impact Factor
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    • "Controversy remains as to whether endogenous nitric oxide (NO) decreases SNA. Some reports show that NO decreased the activities of RVLM neurons and sympathetic outflow.43, 44 In contrast, Kimura et al.45 reported that NO produced by inducible NOS in the RVLM contributed to high BP of SHR. "
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    ABSTRACT: Accentuated sympathetic nerve activity (SNA) is a risk factor for cardiovascular events. In this review, we investigate our working hypothesis that potentiated activity of neurons in the rostral ventrolateral medulla (RVLM) is the primary cause of experimental and essential hypertension. Over the past decade, we have examined how RVLM neurons regulate peripheral SNA, how the sympathetic and renin-angiotensin systems are correlated and how the sympathetic system can be suppressed to prevent cardiovascular events in patients. Based on results of whole-cell patch-clamp studies, we report that angiotensin II (Ang II) potentiated the activity of RVLM neurons, a sympathetic nervous center, whereas Ang II receptor blocker (ARB) reduced RVLM activities. Our optical imaging demonstrated that a longitudinal rostrocaudal column, including the RVLM and the caudal end of ventrolateral medulla, acts as a sympathetic center. By organizing and analyzing these data, we hope to develop therapies for reducing SNA in our patients. Recently, 2-year depressor effects were obtained by a single procedure of renal nerve ablation in patients with essential hypertension. The ablation injured not only the efferent renal sympathetic nerves but also the afferent renal nerves and led to reduced activities of the hypothalamus, RVLM neurons and efferent systemic sympathetic nerves. These clinical results stress the importance of the RVLM neurons in blood pressure regulation. We expect renal nerve ablation to be an effective treatment for congestive heart failure and chronic kidney disease, such as diabetic nephropathy.
    Hypertension Research 12/2011; 35(2):132-41. DOI:10.1038/hr.2011.208 · 2.66 Impact Factor
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    • "Others, such as acetylcholine (Shao & Feldman 2001) and serotonin may also act on ligand-gated ion channels to exert rapid changes in membrane potential, but the effect of these latter neurotransmitters—as well as that of others—discussed below, is principally exerted on metabotropic receptors that are coupled to G proteins (Martin 1992; Pelat et al. 1999; Padley et al. 2005). Cannabinoids (Padley et al. 2003), gases such as nitric oxide (Zanzinger et al. 1995; Kishi et al. 2002; Gao et al. 2008) and other novel mediators are also part of the environment that influences the long-and short-term activity of cardiorespiratory neurons. The 'simplistic' understanding of how G-proteincoupled receptors (GPCRs) work is clouded by the discovery that dimerization (both between the same receptor type and between different receptor types) can lead to activation of entirely different signal transduction pathways with effects that are the reverse of those normally seen (e.g. "
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    ABSTRACT: Central neurons in the brainstem and spinal cord are essential for the maintenance of sympathetic tone, the integration of responses to the activation of reflexes and central commands, and the generation of an appropriate respiratory motor output. Here, we will discuss work that aims to understand the role that metabotropic neurotransmitter systems play in central cardiorespiratory mechanisms. It is well known that blockade of glutamatergic, gamma-aminobutyric acidergic and glycinergic pathways causes major or even complete disruption of cardiorespiratory systems, whereas antagonism of other neurotransmitter systems barely affects circulation or ventilation. Despite the lack of an 'all-or-none' role for metabotropic neurotransmitters, they are nevertheless significant in modulating the effects of central command and peripheral adaptive reflexes. Finally, we propose that a likely explanation for the plethora of neurotransmitters and their receptors on cardiorespiratory neurons is to enable differential regulation of outputs in response to reflex inputs, while at the same time maintaining a tonic level of sympathetic activity that supports those organs that significantly autoregulate their blood supply, such as the heart, brain, retina and kidney. Such an explanation of the data now available enables the generation of many new testable hypotheses.
    Philosophical Transactions of The Royal Society B Biological Sciences 10/2009; 364(1529):2537-52. DOI:10.1098/rstb.2009.0092 · 7.06 Impact Factor
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