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: 7.63). 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: In this prospective study, we examined the effect of atorvastatin treatment on baroreflex sensitivity (BRS) in subjects with type 2 diabetes. A total of 79 patients with type 2 diabetes with dyslipidaemia were recruited. A total of 46 subjects were enrolled to atorvastatin 10 mg daily and low-fat diet and 33 patients to low-fat diet only. BRS was assessed non-invasively using the sequence method at baseline, 3, 6 and 12 months. Treatment with atorvastatin increased BRS after 12 months (from 6.46 ± 2.79 ms/mmHg to 8.05 ± 4.28 ms/mmHg, p = 0.03), while no effect was seen with low-fat diet. Further sub-analysis according to obesity status showed that BRS increased significantly only in the non-obese group (p = 0.036). A low dose of atorvastatin increased BRS in non-obese subjects with type 2 diabetes and dyslipidaemia after 1-year treatment. This finding emphasizes the beneficial effect of atorvastatin on cardiovascular system, beyond the lipid-lowering effects.
    Diabetes & Vascular Disease Research 10/2013; · 3.04 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Statins (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) reduce plasma cholesterol and improve endothelium-dependent vasodilation, inflammation and oxidative stress. A 'pleiotropic' property of statins receiving less attention is their effect on the autonomic nervous system. Increased central sympathetic outflow and diminished cardiac vagal tone are disturbances characteristic of a range of cardiovascular conditions for which statins are now prescribed routinely to reduce cardiovascular events: following myocardial infarction, and in hypertension, chronic kidney disease, heart failure and diabetes. The purpose of the present review is to synthesize contemporary evidence that statins can improve autonomic circulatory regulation. In experimental preparations, high-dose lipophilic statins have been shown to reduce adrenergic outflow by attenuating oxidative stress in central brain regions involved in sympathetic and parasympathetic discharge induction and modulation. In patients with hypertension, chronic kidney disease and heart failure, lipophilic statins, such as simvastatin or atorvastatin, have been shown to reduce MNSA (muscle sympathetic nerve activity) by 12-30%. Reports concerning the effect of statin therapy on HRV (heart rate variability) are less consistent. Because of their implications for BP (blood pressure) control, insulin sensitivity, arrhythmogenesis and sudden cardiac death, these autonomic nervous system actions should be considered additional mechanisms by which statins lower cardiovascular risk.
    Clinical Science 03/2014; 126(6):401-15. · 5.63 Impact Factor
  • [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.
    Journal of Pharmacology and Experimental Therapeutics 01/2014; · 3.89 Impact Factor