Cardiovascular effects of overexpression of endothelial nitric oxide synthase in the rostral ventrolateral medulla in stroke-prone spontaneously hypertensive rats

Kyushu University, Hukuoka, Fukuoka, Japan
Hypertension (Impact Factor: 6.48). 03/2002; 39(2):264-8. DOI: 10.1161/hy0202.102701
Source: PubMed


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.

Download full-text


Available from: Takuya Kishi, Oct 01, 2015
  • Source
    • "It is likely that the RVLM NO effect on BP depends on the source of NO and its effect on local sympathoinhibitory (GABA) and sympathoexcitatory (L-glutamate) neuromodulators . For example, although GABA inhibition is implicated in the NO-dependent CB 1 R-mediated pressor response (Ibrahim and Abdel-Rahman, 2012), eNOS-derived NO mediates increases in the RVLM GABA level and hypotension (Kishi et al., 2001Kishi et al., , 2002). More studies are warranted to delineate the mechanisms of the differential role of RVLM NO in modulating sympathetic activity/BP and to investigate the possibility that GPR18- dependent NO generation enhances RVLM GABA release/ signaling in future studies. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Systemic administration of the GPR18 agonist abnormal cannabidiol (Abn CBD) lowers blood pressure (BP). Whether GPR18 is expressed in the CNS and plays a role in BP control is not known despite the abundance of the GPR18 ligand N-arachidonoyl glycine (NAGly) in the CNS. Therefore, we first determined if GPR18 is expressed in the presympathetic tyrosine hydroxylase (TH) immunoreactive (ir) neurons of the brainstem cardiovascular regulatory nuclei. Second, we investigated the impact of GPR18 activation and/or blockade on BP and heart rate (HR) and neurochemical modulators of sympathetic activity/BP. Immunofluorescence findings revealed GPR18 expression in TH-ir neurons in the rostral ventrolateral medulla (RVLM). Intra-RVLM GPR18 activation (Abn CBD) and blockade (O-1918) elicited dose-dependent reductions and elevations in BP, respectively, along with respective increases and decreases in HR in conscious male Sprague-Dawley rats. RVLM GPR18 activation increased neuronal adiponectin (ADN) and NO and reduced reactive oxygen species (ROS) levels while GPR18 blockade reduced neuronal ADN and increased oxidative stress (ROS) in the RVLM. Finally, we hypothesized that the negligible hypotensive effect caused by the endogenous GPR18 ligand NAGly could be due to concurrent activation of CB1R in the RVLM. Our findings supported this hypothesis because NAGly-evoked hypotension was doubled following RVLM CB1R blockade (SR141716). These findings are the first to demonstrate GPR18 expression in the RVLM, and to suggest sympathoinhibitory role for this receptor. The findings yield new insight into the role of a novel cannabinoid receptor (GPR18) in central BP control.
    Full-text · Article · Jan 2014 · Journal of Pharmacology and Experimental Therapeutics
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Aug 2012 · Frontiers in Physiology
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Dec 2011 · Hypertension Research
Show more