Blood Pressure in Healthy Humans Is Regulated by Neuronal NO Synthase

Background Nitric oxide (NO), a recognized cell messenger for activating soluble guanylate cyclase, is produced by the enzyme NO synthase in a wide variety of tissues, including vascular endothelium and the central nervous system. The authors previously reported the possible involvement of the NO pathway in the anesthetic state by showing that a specific NO synthase inhibitor, nitroG-L-arginine methyl ester (L-NAME), dose dependently and reversibly decreases the minimum alveolar concentration (MAC) for halothane anesthesia. The availability of a structurally distinct inhibitor selective for the neuronal isoform of NO synthase, 7-nitro indazole (7-NI), allowed for the possibility of dissociating the central nervous system effects of neuronal NO synthase inhibition from the cardiovascular effects of endothelial NO synthase inhibition. Methods The effect of two structurally distinct inhibitors of NO synthase, L-NAME and 7-NI, on the MAC of isoflurane was investigated in Sprague-Dawley rats while concurrently monitoring the animals' arterial blood pressure and heart rate. L-NAME (1 to 30 mg/kg given intravenously, dissolved in 0.9% saline) and 7-NI (20 to 1,000 mg/kg given intraperitoneally, dissolved in arachis oil) were administered after determining control MAC and 30 min before determining MAC in the presence of NO synthase inhibitor. Results L-NAME and 7-NI caused a dose-dependent decrease from isoflurane control MAC (maximal effect: 35.5 +/- 2.5% and 43.0 +/- 1.7%, respectively) with a ceiling effect observed for both NO synthase inhibitors (above 10 mg/kg and 120 mg/kg, respectively). L-NAME administration significantly increased systolic and diastolic blood pressures (maximal effect: 39.9 +/- 2.2% and 64.3 +/- 4.0%, respectively), which were not accompanied by any changes in heart rate. 7-NI administration resulted in no changes in blood pressure and a small but clinically insignificant decrease in heart rate. Conclusions Inhibition of the NO synthase pathway decreased the MAC for isoflurane, which suggests that inhibition of the NO pathway decreases the level of consciousness and augments sedation, analgesia, and anesthesia. The MAC reduction by two structurally distinct NO synthase inhibitors supports that this is a specific effect on NO synthase. Furthermore, the action of the neuronal NO synthase inhibitor 7-NI supports an effect selective for neuronal NO synthase and also avoids the hypertensive response of generalized NO synthase inhibitors.

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Synergistic effect of the secondary somatosensory cortex stimulation and neuronal NO synthase inhibition on formalin-induced nociception and spinal c-fos expression in the rat

The Japanese Journal of Pharmacology ◽

10.1016/s0021-5198(19)48107-9 ◽

2000 ◽

Vol 82 ◽

pp. 161

Author(s):

Naoyuki Kawao ◽

Atsufumi Kawabata ◽

Hiroko Yoshimura ◽

Wakana Umeda ◽

Ryotaro Kuroda

Keyword(s):

Synergistic Effect ◽

Somatosensory Cortex ◽

No Synthase ◽

Neuronal No Synthase ◽

Secondary Somatosensory Cortex ◽

Fos Expression

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Systemic and regional hemodynamics after nitric oxide synthase inhibition: role of a neurogenic mechanism

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1994.267.1.r84 ◽

1994 ◽

Vol 267 (1) ◽

pp. R84-R88 ◽

Cited By ~ 2

Author(s):

M. Huang ◽

M. L. Leblanc ◽

R. L. Hester

Keyword(s):

Nitric Oxide ◽

Blood Pressure ◽

Cardiac Output ◽

No Synthase ◽

Before And After ◽

Regional Hemodynamics ◽

Autonomic Blockade ◽

Infusion Of Norepinephrine ◽

Oxide Synthase

The study tested the hypothesis that the increase in blood pressure and decrease in cardiac output after nitric oxide (NO) synthase inhibition with N omega-nitro-L-arginine methyl ester (L-NAME) was partially mediated by a neurogenic mechanism. Rats were anesthetized with Inactin (thiobutabarbital), and a control blood pressure was measured for 30 min. Cardiac output and tissue flows were measured with radioactive microspheres. All measurements of pressure and flows were made before and after NO synthase inhibition (20 mg/kg L-NAME) in a group of control animals and in a second group of animals in which the autonomic nervous system was blocked by 20 mg/kg hexamethonium. In this group of animals, an intravenous infusion of norepinephrine (20-140 ng/min) was used to maintain normal blood pressure. L-NAME treatment resulted in a significant increase in mean arterial pressure in both groups. L-NAME treatment decreased cardiac output approximately 50% in both the intact and autonomic blocked animals (P < 0.05). Autonomic blockade alone had no effect on tissue flows. L-NAME treatment caused a significant decrease in renal, hepatic artery, stomach, intestinal, and testicular blood flow in both groups. These results demonstrate that the increase in blood pressure and decreases in cardiac output and tissue flows after L-NAME treatment are not dependent on a neurogenic mechanism.

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Expression of neuronal no synthase in the human gastrointestinal tract

Gastroenterology ◽

10.1016/0016-5085(95)26803-0 ◽

1995 ◽

Vol 108 (4) ◽

pp. A623

Author(s):

M. John ◽

B. Schätzmüller ◽

A. Schmitt-Graeff ◽

C. Ransco ◽

H. Buhr ◽

...

Keyword(s):

Gastrointestinal Tract ◽

No Synthase ◽

Human Gastrointestinal Tract ◽

Neuronal No Synthase

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Chronic intermittent hypoxia in humans during 28 nights results in blood pressure elevation and increased muscle sympathetic nerve activity

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00253.2009 ◽

2010 ◽

Vol 299 (3) ◽

pp. H925-H931 ◽

Cited By ~ 73

Author(s):

G. S. Gilmartin ◽

M. Lynch ◽

R. Tamisier ◽

J. W. Weiss

Keyword(s):

Blood Pressure ◽

Sympathetic Nerve ◽

Intermittent Hypoxia ◽

Sympathetic Nerve Activity ◽

Muscle Sympathetic Nerve Activity ◽

Chronic Intermittent Hypoxia ◽

Sympathetic Activation ◽

Nerve Activity ◽

Blood Pressure Elevation ◽

Healthy Humans

Chronic intermittent hypoxia (CIH) is thought to be responsible for the cardiovascular disease associated with obstructive sleep apnea (OSA). Increased sympathetic activation, altered vascular function, and inflammation are all putative mechanisms. We recently reported (Tamisier R, Gilmartin GS, Launois SH, Pepin JL, Nespoulet H, Thomas RJ, Levy P, Weiss JW. J Appl Physiol 107: 17–24, 2009) a new model of CIH in healthy humans that is associated with both increases in blood pressure and augmented peripheral chemosensitivity. We tested the hypothesis that exposure to CIH would also result in augmented muscle sympathetic nerve activity (MSNA) and altered vascular reactivity contributing to blood pressure elevation. We therefore exposed healthy subjects between the ages of 20 and 34 yr ( n = 7) to 9 h of nocturnal intermittent hypoxia for 28 consecutive nights. Cardiovascular and hemodynamic variables were recorded at three time points; MSNA was collected before and after exposure. Diastolic blood pressure (71 ± 1.3 vs. 74 ± 1.7 mmHg, P < 0.01), MSNA [9.94 ± 2.0 to 14.63 ± 1.5 bursts/min ( P < 0.05); 16.89 ± 3.2 to 26.97 ± 3.3 bursts/100 heartbeats (hb) ( P = 0.01)], and forearm vascular resistance (FVR) (35.3 ± 5.8 vs. 55.3 ± 6.5 mmHg·ml−1·min·100 g tissue, P = 0.01) all increased significantly after 4 wk of exposure. Forearm blood flow response following ischemia of 15 min (reactive hyperemia) fell below baseline values after 4 wk, following an initial increase after 2 wk of exposure. From these results we conclude that the increased blood pressure following prolonged exposure to CIH in healthy humans is associated with sympathetic activation and augmented FVR.

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Inducible NO synthase II and neuronal NO synthase I are constitutively expressed in different structures of guinea pig skeletal muscle: implications for contractile function

The FASEB Journal ◽

10.1096/fasebj.10.14.9002553 ◽

1996 ◽

Vol 10 (14) ◽

pp. 1614-1620 ◽

Cited By ~ 102

Author(s):

Ingolf Gath ◽

Ellen I. Closs ◽

Ute Gödtel‐Armbrust ◽

Sandra Schmitt ◽

Masaki Nakane ◽

...

Keyword(s):

Skeletal Muscle ◽

Guinea Pig ◽

Contractile Function ◽

No Synthase ◽

Neuronal No Synthase ◽

Inducible No Synthase

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Short-term intermittent hypoxia enhances sympathetic responses to continuous hypoxia in humans

Journal of Applied Physiology ◽

10.1152/japplphysiol.00036.2007 ◽

2007 ◽

Vol 103 (3) ◽

pp. 835-842 ◽

Cited By ~ 28

Author(s):

Urs A. Leuenberger ◽

Cynthia S. Hogeman ◽

Sadeq Quraishi ◽

Latoya Linton-Frazier ◽

Kristen S. Gray

Keyword(s):

Blood Pressure ◽

Sleep Apnea ◽

Sympathetic Activity ◽

Intermittent Hypoxia ◽

Muscle Sympathetic Nerve Activity ◽

Acute Hypoxia ◽

Short Term ◽

Healthy Humans ◽

Obstructive Sleep ◽

Normal Humans

Short-term intermittent hypoxia leads to sustained sympathetic activation and a small increase in blood pressure in healthy humans. Because obstructive sleep apnea, a condition associated with intermittent hypoxia, is accompanied by elevated sympathetic activity and enhanced sympathetic chemoreflex responses to acute hypoxia, we sought to determine whether intermittent hypoxia also enhances chemoreflex activity in healthy humans. To this end, we measured the responses of muscle sympathetic nerve activity (MSNA, peroneal microneurography) to arterial chemoreflex stimulation and deactivation before and following exposure to a paradigm of repetitive hypoxic apnea (20 s/min for 30 min; O2 saturation nadir 81.4 ± 0.9%). Compared with baseline, repetitive hypoxic apnea increased MSNA from 113 ± 11 to 159 ± 21 units/min ( P = 0.001) and mean blood pressure from 92.1 ± 2.9 to 95.5 ± 2.9 mmHg ( P = 0.01; n = 19). Furthermore, compared with before, following intermittent hypoxia the MSNA (units/min) responses to acute hypoxia [fraction of inspired O2 (FiO2) 0.1, for 5 min] were enhanced (pre- vs. post-intermittent hypoxia: +16 ± 4 vs. +49 ± 10%; P = 0.02; n = 11), whereas the responses to hyperoxia (FiO2 0.5, for 5 min) were not changed significantly ( P = NS; n = 8). Thus 30 min of intermittent hypoxia is capable of increasing sympathetic activity and sensitizing the sympathetic reflex responses to hypoxia in normal humans. Enhanced sympathetic chemoreflex activity induced by intermittent hypoxia may contribute to altered neurocirculatory control and adverse cardiovascular consequences in sleep apnea.

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Contribution of captopril thiol group to the prevention of spontaneous hypertension

Physiological Research ◽

10.33549/physiolres.931396 ◽

2007 ◽

pp. S41-S48

Author(s):

O Pecháňová

Keyword(s):

Oxidative Stress ◽

Blood Pressure ◽

Ace Inhibitors ◽

Thiol Group ◽

No Synthase ◽

Spontaneous Hypertension ◽

Cgmp Level ◽

Control Group ◽

No Production ◽

Enalapril Group

We aimed to compare the effect of angiotensin converting enzyme (ACE) inhibitors captopril (containing thiol group) and enalapril (without thiol group) on the development of spontaneous hypertension and to analyze mechanisms of their actions, particularly effects on oxidative stress and NO production. Six-week-old SHR were divided into three groups: control, group receiving captopril (50 mg/kg/day) or enalapril (50 mg/kg/day) for 6 weeks. At the end of experiment, systolic blood pressure (SBP) increased by 41 % in controls. Both captopril and enalapril prevented blood pressure increase, however, SBP in the captopril group (121+/-5 mmHg) was significantly lower than that in the enalapril group (140+/-5 mmHg). Concentration of conjugated dienes in the aorta was significantly lower in the captopril group compared to the enalapril group. Captopril and enalapril increased NO synthase activity in the heart and aorta to the similar level. Neither captopril nor enalapril was, however, able to increase the expression of eNOS. Both ACE inhibitors increased the level of cGMP. However, cGMP level was significantly higher in the aorta of captopril group. We conclude that captopril, beside inhibition of ACE, prevented hypertension by increasing NO synthase activity and by simultaneous decrease of oxidative stress which resulted in increase of cGMP concentration.

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