Role of Nitric Oxide in Central Sympathetic Outflow (original) (raw)
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Physiological Reports, 2019
We aimed to investigate the effects of nitric oxide (NO) synthesis inhibition by NO synthase inhibitor N-nitro-L-arginine-methyl ester (L-NAME) treatment on the sympathetic vasomotor nerve activity (SNA) on two sympathetic vasomotor nerves, the renal and splanchnic. NO plasma level and systemic oxidative stress were assessed. Hypertension was induced by L-NAME (20 mg/ kg per day, by gavage, for seven consecutive days) in male Wistar rats. At the end of the treatment, blood pressure, heart rate, arterial baroreflex sensitivity, renal SNA (rSNA), and splanchnic SNA (sSNA) were assessed in urethane anesthetized rats. L-NAME-treated rats presented increased blood pressure (152 AE 2 mmHg, n = 17) compared to the control group (101 AE 2 mmHg, n = 15). Both rSNA (147 AE 10, n = 15 vs. 114 AE 5 Spikes/s, n = 9) and sSNA (137 AE 13, n = 14 vs. 74 AE 13 spikes/s, n = 9) were significantly increased in the L-NAME-treated compared to the control group. A differential response on baroreflex sensitivity was found, with a significant reduction for rSNA but not for sSNA arterial baroreceptor sensitivity in L-NAME-treated rats. The adjusted regression model revealed that the reduction of systemic NO levels partially explains the variation in sSNA and blood pressure, but not rSNA. Taken together, our data show that hypertension induced by NO synthase blockade is characterized by increased SNA to the rSNA and sSNA. In addition, we found that the rats that had the greatest reduction in NO levels in plasma by L-NAME were those that developed higher blood pressure levels. The reduction in the NO level partially explains the variations in sSNA but not in rSNA.
Sympathetic activation and nitric oxide function in early hypertension
American Journal of Physiology-Heart and Circulatory Physiology, 2012
The purpose of this study was to determine if tonic restrain of blood pressure by nitric oxide (NO) is impaired early in the development of hypertension. Impaired NO function is thought to contribute to hypertension, but it is not clear if this is explained by direct effects of NO on vascular tone or indirect modulation of sympathetic activity. We determined the blood pressure effect of NO synthase inhibition with Nω-monomethyl-l-arginine (l-NMMA) during autonomic blockade with trimethaphan to eliminate baroreflex buffering and NO modulation of autonomic tone. In this setting, impaired NO modulation of vascular tone would be reflected as a blunted pressor response to l-NMMA. We enrolled a total of 66 subjects (39 ± 1.3 yr old, 30 females), 20 normotensives, 20 prehypertensives (blood pressure between 120/80 and 140/90 mmHg), 17 hypertensives, and 9 smokers (included as “positive” controls of impaired NO function). Trimethaphan normalized blood pressure in hypertensives, suggesting i...
International Journal of Hypertension
The aim of our study is to investigate the sympathetic output and baroreflex via renal sympathetic nerve activity (RSNA) recording in a model of severe hypertension which exhibits arterial, cardiac, and renal damages, the spontaneously hypertensive rat (SHR) under lowered NO bioavailability. SHR are treated from 18 to 20 weeks of age with a low dose of L-NAME, a NO synthase inhibitor, in drinking water (SHRLN) and compared to SHR and normotensive Wistar Kyoto (WKY) rats. After the two-week treatment, rats are anesthetized for RSNA, mean blood pressure (MBP), and heart rate (HR) recording. MBP is higher in SHR than in WKY and higher in SHRLN than in SHR. Compared to WKY, SHR displays an alteration in the baroreflex with a displacement of the sympathoinhibition curve to highest pressures; this displacement is greater in SHRLN rats. The bradycardic response is reduced in SHRLN compared to both SHR and WKY. In hypertensive rats, SHR and SHRLN, basal RSNA is modified, the maximal amplitu...
Canadian Journal of Physiology and Pharmacology, 2011
We evaluated the role of the sympathetic nervous system and oxidative stress in hemodynamic and autonomic control after acute inhibition of the synthesis of nitric oxide, using intravenous (i.v.) injection of 30 mg·kg -1 N G -nitro-L-arginine methyl ester (L-NAME) in adult Wistar rats. Baroreflex sensitivity (BRS) and heart rate variability (HRV) were measured as indices of cardiac autonomic control, before and after L-NAME treatment in rats with intact autonomic innervation, and in rats with chemical sympathectomy by 6-hydroxydopamine. Serum malondialdehyde (MDA) was measured as a marker of oxidative stress. In control rats, L-NAME treatment resulted in a significant rise in blood pressure, augmentation of BRS, and enhanced serum MDA. HRV showed an attenuation of total spectral power and high frequency spectral power, along with a rise of the low to high frequency ratio (LF:HF). Administration of L-NAME produced a pressor response even in sympathectomised rats, but augmented BRS was not observed, and the high frequency spectral power showed an increase, in addition to a significant decline of LF:HF and serum MDA. We therefore conclude that even though pressor response was unaffected, reversal of cardiac autonomic responses and decline in oxidative stress following sympathectomy in L-NAME-treated rats reflects a significant role for sympathetic innervation in acute L-NAME-induced hypertension.
Central depressor action of nitric oxide is deficient in genetic hypertension
American Journal of Hypertension, 1996
This observation indicates that NO is normally produced at a CNS site@ where it has a tonic blood pressure lowering effect. The current study tests the hypothesis &hat a deficient NOS activity in the CNS may contribute to the pressure elevation in genetically hypertensive rats. NO administered intracerebroventricularly (ICV) caused a greater fall in mean arterial pressure (MAP; femoral artery) in hypertensive (SHRSP) than in nor-(motensive (WKYJ rats, -66.1 f 3.4 mm Hg u -23.7 i 3.9 mm Hg, respectively. Yet when endogenous NO was increased by stimulating NOS with ICV calcium, the depressor response was less in SHRSP than in WKY, 13.7 + 1.1 mm Hg u 26.7 f 19 mm Hg. Likewise, when NOS was blocked with N"'-nitro+arginine methyl ester (L-NAME), the resultant pressor response was less in SHRSP than in WKY,13.8 f: 1.1 mm Hg D 22.2 at 1.1 mm Hg. Blockade of the action of cGMP, a mediator of the -&ion of NO, caused a pressor response c4 5o IC X.9 mm Hg and 22.6 f 8.7 mm Hg !I-' < .01) in the hypertensive and normotensive rats, respectively. I&&olytic ablation of the anteroventral third cerebral ventricle (A v'3VJ did not alter blood pressure responses to NO or to agents that alter NOS activity. We conclude that a deficit in NOS a&&y in some other central cardiovascular regulatory area may contribute to tire elevated arterial pressure of these genetically hypertensive rats. Am J Hypertens 1996; 9~237-241 KEY WORDS: Nitric oxide, cyclic guanosine monophosphate (cCrv2P1, wJ-nitro-t-arginine methyl ester (LNAME), anteroventral third cerebral ventricle (AV3VJ, stroke-prone spontaneously hypertensive rat.
Neuroscience, 1997
The hypothesis was tested that the activation of postganglionic sympathetic neurons contributes to the peripheral vasoconstriction and the blood pressure increase which are observed in rats after systemic blockade of nitric oxide synthase by substituted -arginine analogues. Single and multifibre postganglionic sympathetic activity supplying hindlimb hairy skin and the activity in the caudal lumbar sympathetic trunk supplying mainly hindlimb skeletal muscle were recorded in anaesthetized, paralysed and artificially ventilated Wistar rats before, during and up to 1 h after intravenous injection of a supramaximal dose (10 or 35 mg/kg) of N G -nitro--arginine methyl ester. This elicited a sustained rise of arterial blood pressure, a long-lasting decrease in heart rate and vasoconstriction in hindlimb skin and skeletal muscle as measured by laser Doppler flowmetry. With intact buffer nerves all sympathetic neurons analysed responded with a decrease in their ongoing activity in parallel with the vasoconstriction and the increased blood pressure, except for one neuron which was unresponsive. These responses were probably mediated by the arterial baroreceptors, since it was shown that N G -nitro--arginine methyl ester did not impair the function of both the afferent and the efferent limb of the reflex. Furthermore, baroreceptor denervation almost abolished the inhibitory responses in sympathetic neurons. In baroreceptor denervated animals, with a latency of about 15 min after N G -nitro--arginine methyl ester there was an increase in sympathetic activity without a further increase in blood pressure.
Inhibition of nitric oxide synthase evokes central sympatho-excitation in healthy humans
Journal of Physiology-london, 2009
Animal studies have indicated that nitric oxide is a key signalling molecule involved in the tonic restraint of central sympathetic outflow from the brainstem. Extension of these findings to humans has been difficult because systemic infusion of nitric oxide synthase (NOS) inhibitors increases blood pressure due to inhibition of endothelial NOS, resulting in activation of the arterial baroreflex and subsequent inhibition of central sympathetic outflow. To overcome this confounding inhibitory influence of the baroreflex, in the current study we directly measured skin sympathetic nerve activity (SNA), which is not under baroreceptor control. Healthy, normotensive humans were studied before, during a 60 min intravenous infusion of the NOS inhibitor N G -nitro-l-arginine methyl ester (l-NAME; 4 mg kg −1 ), and for 120 min following the infusion (i.e. 180 min total). Skin SNA and arterial blood pressure (BP) were continuously measured. BP was increased from baseline at the end of the l-NAME infusion ( 14 ± 2 mmHg; P < 0.05) and remained significantly elevated for the remainder of the experiment ( 18 ± 3 mmHg; P < 0.05). Similarly, systemic NOS inhibition produced time-dependent increases in skin SNA, such that skin SNA was elevated at the end of the l-NAME infusion (total activity, 200 ± 22% baseline; P = 0.08) and was further increased at the end of the study protocol (total activity, 350 ± 41% baseline; P < 0.05). Importantly, skin SNA remained unchanged during time and hypertensive (phenylephrine) control experiments. These findings indicate that pharmacological inhibition of NOS causes sympathetic activation and support a role of nitric oxide in central sympathetic control in humans.
PLOS ONE, 2015
Nitric oxide (NO) seems to contribute to vascular homeostasis regulating neurotransmission. This work aimed at assessing the influence of NO from different sources and respective intracellular pathways on sympathetic neurotransmission, in two vascular beds. Electrically-evoked [ 3 H]-noradrenaline release was assessed in rat mesenteric and tail arteries in the presence of NO donors or endothelial/neuronal nitric oxide synthase (NOS) inhibitors. The influence of NO on adenosine-mediated effects was also studied using selective antagonists for adenosine receptors subtypes. Location of neuronal NOS (nNOS) was investigated by immunohistochemistry (with specific antibodies for nNOS and for Schwann cells) and Confocal Microscopy. Results indicated that: 1) in mesenteric arteries, noradrenaline release was reduced by NO donors and it was increased by nNOS inhibitors; the effect of NO donors was only abolished by the adenosine A 1 receptors antagonist; 2) in tail arteries, noradrenaline release was increased by NO donors and it was reduced by eNOS inhibitors; adenosine receptors antagonists were devoid of effect; 3) confocal microscopy showed nNOS staining in adventitial cells, some co-localized with Schwann cells. nNOS staining and its co-localization with Schwann cells were significantly lower in tail compared to mesenteric arteries. In conclusion, in mesenteric arteries, nNOS, mainly located in Schwann cells, seems to be the main source of NO influencing perivascular sympathetic neurotransmission with an inhibitory effect, mediated by adenosine A 1 receptors activation. Instead, in tail arteries endothelial NO seems to play a more relevant role and has a facilitatory effect, independent of adenosine receptors activation.