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The effects of oral arginine on neuroautonomic parameters in healthy subjects.


L-arginine is an essential amino acid that exerts both peripheral and central nervous system effects. Although it has been used as a growth hormone releasing agent, this amino acid also provokes significant blood pressure and heart rate changes in all patients tested. This study assessed the changes induced by the oral administration of this amino acid on the peripheral autonomic nervous system in 52 subjects (26 L-arginine, 26 placebo). The levels of the following circulating neurotransmitters were measured before and after a small oral dose (50 mg) of L-arginine: noradrenaline (NA), adrenaline (Ad), dopamine (DA), plasma serotonin (f-5HT), platelet serotonin (p-5HT), and plasma tryptophane. Systolic blood pressure, diastolic blood pressure, and heart rate were also monitored. L-arginine triggered sustained and progressive increases of NA, DA, f-5HT, p-5HT, and the f-5HT/p-5HT ratio as well as sustained and progressive decrease of Ad. Diastolic blood pressure but not systolic blood pressure showed significant and progressive reductions. Progressive heart rate reductions were also observed. Significant positive correlation was registered between diastolic blood pressure versus NA/DA ratio and significant negative correlation was found between heart rate versus f-5HT/p-5HT ratio. An oral administration of 50 mg of L-arginine was able to provoke parasympathetic over sympathetic and neural-sympathetic over adrenal-sympathetic predominance.

KEY WORDS: arginine, plasma noradrenaline, plasma adrenaline, plasma dopamine, blood serotonin, diastolic blood pressure, neural sympathetic activity


Nitric oxide (NO) is synthesized from the amino acid L-arginine by the enzyme nitric oxide synthase (NOS), and it modulates a wide variety of neural, cardiovascular, endocrinologic, and humoral processes. Cardiovascular autonomic dysfunction and impaired neurohormonal secretion are characteristics often seen in patients with primary autonomic failure and, in addition, are also involved in blood pressure and heart rate disorders. NO, which plays an important role in the balance of the peripheral autonomic nervous system (ANS) by acting at both peripheral and central nervous system (CNS) levels, is likely to be involved in all of the above-mentioned disorders. For instance, abrogation and enhancement of NO activity are associated with sympathetic and parasympathetic predominance, respectively; both ANS imbalances are present in all diseases. In addition, it has been shown that nitrergic pathways are involved in serotonergic and cholinergic mechanisms responsible for vascular physiologic modulations. (1)

According to the above and considering that L-arginine has been used as a coadjuvant therapeutic tool in different types of diseases, the purpose of this study was to investigate the neuroautonomic mechanisms triggered by a small oral dose of L-arginine that was administered to subjects. This research was possible because the neurochemical laboratory at the Instituto de Medicina Experimental, Faculty of Medicine at the Universidad Central de Venezuela has the capability to assess all circulating neurotransmitters, and this is where those parameters were routinely tested before and after the administration of many neuropharmacologic agents, (2-7) as well as during supine-resting plus orthostasis plus exercise and several pharmacologic challenges. (8-17) Up to the present, approximately 30,000 healthy and diseased subjects as well as many experimental mammals have been tested. The protocol included the assessment of noradrenaline (NA), adrenaline (Ad), dopamine (DA), platelet serotonin (p-5HT), plasma serotonin (f-5HT), and plasma tryptophane (trp). In addition, the metabolites of these neurotransmitters were tested according to different types of protocols. The results obtained from an oral dose (50 mg) of L-arginine, which is the dose usually administered to patients in order to excite growth hormone release at nocturnal periods, is presented. However, in this study, the effects of this amino acid were obtained throughout the supine-resting condition during morning periods.


The levels of plasma NA, Ad, DA, f-5HT, p-5HT, and plasma trp were measured before (-30 and 0 minutes) and after (60, 90, and 120 minutes) the oral administration of 50 mg of L-arginine (Ajinomoto Co., Inc., Tokyo, Japan) in 26 subjects (13 men and 13 women). Twenty-six other age- and sex-paired subjects received placebo instead of the drug. Ages ranged from 22 to 29 years (mean [+ or -] standard error was 25.6 [+ or -] 2.2). Platelet aggregation was also measured. All subjects were volunteers recruited from the students of the Faculty of Medicine at the Universidad Central de Venezuela. Written informed consent was obtained from all volunteers, and the procedure was approved by the Ethical Committee of FUNDAIME (Fundacion Instituto de Medicina Experimental). All volunteers were within 10% of ideal body weight, none had any physical or psychiatric illness, and all were nonsmokers. Exclusion criteria included pregnancy, lactation, and alcohol abuse.

Volunteers were recumbent during all procedures. A heparinized venous catheter was inserted into a forearm vein at least 30 minutes before the test. Cold plastic syringes were used to collect blood samples at the times specified above. L-arginine (50-mg capsule) or placebo was orally administered after the second blood sample (0 minutes). Blood samples were obtained for measuring plasma neurotransmitters and platelet aggregation. Blood for measuring plasma neurotransmitters was transferred to plastic tubes, each containing 1 mL of an antioxidant solution (20 mg of ethylenediaminetetraacetic acid [EDTA] plus sodium metabisulfite 10 mg/mL). The tubes were carefully inverted several times and placed on ice until centrifugation. To obtain platelet-rich plasma (PRP), the tubes were centrifuged at 600 rpm at 4[degrees]C for 15 minutes. Two milliliters of PRP was stored at -70[degrees]C until needed for determination of p-5HT levels. The remaining blood was centrifuged again at 7000 rpm. Two aliquots of the supernatant, which was platelet-poor plasma (PPP), was stored at -70[degrees]C until needed for assays of catecholamines and f-5HT. Blood samples for platelet aggregation were processed immediately. A physician was in constant attendance who monitored heart rate and blood pressure and noted any symptoms reported by subjects.

Analytical Assays


Plasma catecholamine and serotonin samples were measured in duplicate, and all determinations were made at the same time. Reverse phase, ion pair high-pressure liquid chromatography with electrochemical detection was used. (18-20)

Reagents and Standards

NA, Ad, DA, serotonin creatinine sulfate, dihydroxybenzylamine, 5-hydroxy-tryptophane, sodium octyl sulfate, dibutylamine K[H.sub.2]P[O.sub.4], citric acid, sodium acetate, and EDTA were obtained from Sigma-Aldrich Co. (St. Louis, MO). Acid-washed aluminum oxide and microfilters were purchased from Bioanalytical Systems Inc. (West Lafayette, IN). Acetonitrile and 2-propanol were obtained from Riedel-de-Haen AG (Frankfurt, Germany). Glass-distilled water was de-ionized and filtered through a Milli-O reagent grade water system (Millipore, Bedford, MA). Solutions and solvent were filtered through a 0.2 [micro]m Millipore filter and were vacuum de-aereated. Standard solutions (1 mmol/L) were prepared in 0.1 mol/L perchloric acid and diluted to the desired concentration.


Liquid chromatography was performed using Waters 515 pumps (Waters Co., Milford, MA) equipped with 7125i Rheodyne valve injector fitted with a 20-ML sample loop for detection of catecholamines, and 50-[micro]L sample loop for p-5HT and f-5HT detection (Rheodyne, Berodine, Berkeley, CA). For catecholamine assays, a 15 cm x 4 mm ID Discovery (Supelco, Sigma-Aldrich Co.) analytical column packed with C18 3[micro]m particles was used, fitted with a precolumn filter 0.2 [micro]m (Sigma-Aldrich Co.).

The detection system was a Waters 460 Electrochemical Detector (Waters Co.). A potential of 0.70 volts was applied to the working electrode (glassy carbon) versus the silver-silver chloride reference electrode. The chromatograms were registered and quantified using Millennium software (Waters Assoc., Milford, MA).

Catecholamine Assay

These were performed by extraction onto 20 mg of acid washed alumina followed by their elution with 200 [micro]L of 0.2 mol/L perchloric acid using Bioanalytical Systems microfilters. The instrument was calibrated with standard plasma. After incubation with acid-washed aluminum oxide, a plasma-pool free of catecholamines was obtained. This was processed similarly to plasma samples, but 20 [micro]L of standard solution containing NA, Ad, and DA (50 ng/mL each) was added to 1 mL of the plasma pool to obtain the standard plasma. Both standard plasma and sample plasma were supplemented with 20 [micro]L of internal standard solution (dihydroxy-benzylamine 100 ng/mL). The mobile phase was composed of K[H.sub.2]P[O.sub.4] 50 mmol/L, EDTA 25.16 nmol/L, sodium octyl sulfate 2.37 mmol/L, di-N-butylamine 100 [micro]L/L, and acetonitrile 2.5% (v/v) with pH adjusted to 5.2.

Catecholamine determinations were performed after injection of 50 [micro]L of processed plasma. Correction for dilution was performed. Concentrations were expressed in pg/mL. The sensitivity of this method is as follows: NA was 3.2 pg/mL, Ad was 4.2 pg/mL, and DA was 2.5 pg/mL. The intea-assay coefficients of variation were 2.3%, 3.6%, and 2.3% for NA, Ad, and DA, respectively. The inter-assay coefficients of variation were 2.6%, 3.9%, and 3.8%, respectively.

Serotonin Assay

After sonication of PRP to disrupt any intact platelets (Ultrasonic Liquid Processor, model 385, Heat Systems Ultrasonic, Inc., Farmingdale, NY), both PRP and PPP were processed in the same way: 200 [micro]L of 3.4 M of perchloric acid as deproteinizing agent and 10 [micro]L of 5-OH-trp solution (80 [micro]g/mL) as internal standard, were added to 1 mL of plasma, vortexed, and centrifuged at 10,000 rpm x 15 minutes at 4[degrees]C. The clear supernatant was filtered through a 0.22-[micro]m membrane (Millipore) and injected in high-pressure liquid chromatography. Calibration runs were generated by spiking blank plasma containing 50 [micro]L of serotonin solution (10 [micro]g/mL) and 10 [micro]L of 5-OH-trp solution (80 [micro]g/mL). This standard plasma was processed in the same manner as the samples. PRP serotonin (p-5HT) and PPP serotonin (f-5HT) levels were determined after injection of 100 [micro]L of the deproteinized sample onto a 30 cm x 4.0 mm ID Discovery column filled with C18 5[micro]m. The mobile phase was composed of citric acid 20 mmol, sodium acetate 50 mmol, sodium octyl sulfate 6.45 nmol, dibutylamine 100 [micro]l/L, and propanol 3.5% (v/v). Ph was adjusted to 4.9; flow rate was adjusted to 0.70 mL/min. The sensitivity of this method for plasma serotonin was 0.18 ng/mL; intra-assay coefficients of variation were 2.8% for PRP serotonin and 3.1 % for PPP serotonin. Inter-assay coefficients of variation were 3.5% and 5.2%, respectively. Correction factor for dilution was used. Concentrations are expressed in ng/mL. Platelet serotonin value (p-5HT) = PRP serotonin value (total circulating serotonin) minus PPP serotonin value (f-5HT).

Platelet Aggregation

Blood was collected with citrate-phosphate dextrose (1:9 v/v) as the anticoagulant. Blood was subsequently centrifuged at 120 g for 10 minutes to prepare PRE Aggregation studies were carried out according to Born's method, (21) and aggregation was induced by adenosine 5'diphosphate (Fluka, Sigma-Aldrich Co.) and collagen at final concentrations of 4 [micro]mol/L and 4 m[micro]g/mL, respectively. Maximal aggregation, expressed as the percentage of maximal light transmission, was measured.

Statistical Analyses

Results were expressed as mean [+ or -] SE. Multivariate analyses of variance with repeated measurements, paired t-test, and correlation coefficients (exploratory factor analysis) were employed in interpreting the data yielded by this investigation. Differences were considered significant at P [less than or equal to] 0.05. Stat-100 General Statistics Package (Biosoft, Great Shelford, Cambridge, UK) was used for statistical analyses.



NA was significantly and progressively increased at all periods following L-arginine administration. Maximal increases in plasma NA occurred at the 120-minute period (Figure 1).


DA also showed significant and progressive increases. Maximal increase occurred at the 120-minute period (Figure 2).


Ad showed slight and progressive decrease (significant at the 120-minute period) (Figure 1).


p-5HT showed slight but sustained and significant increases throughout all post-arginine periods (Figure 3).f-5HT showed great and progressive increases until it reached maximal rise at the 120-minute period. These rises overwhelmed the p-5HT increases in such a way that the f-5HHT/p-5HT ratio showed progressive and significant augmentation (Figure 3).


Both the NA increase and the Ad decreases resulted in a progressive NA/Ad ratio rise which reached maximal values at the 120-minute period (Figure 2).

Blood Pressure

The significant and progressive reduction of the diastolic blood pressure (DBP) but not the systolic blood pressure (SBP) resulted in a progressive and significant rise of differential blood pressure (SBP-DBP) (Figure 4).


Heart Rate

This parameter showed significant and progressive reductions (Figure 4), which paralleled DBP decreases.


Significant positive correlations were found between NA/DA ratio versus DBP values: r=0.53, 0.61, 0.68; P<0.05, P<0.02, P<0.01 at 60-, 90-, and 120-minute periods, respectively, whereas significant negative correlations were registered when tested NA/Ad ratio versus f-5HT/p-5HT ratio: r=-0.51, -0.69, -0.73; P<0.05, P<0.01, P<0.005. In addition, heart rate decreases correlated negatively with f-5HT/p-5HT ratio: r=-0.56, -0.71, -0.77; P<0.05, P<0.01, P<0.005 at 60-,90-, and 120-minute periods, respectively. Significant positive correlations were found when DBP was compared with NA values: r=0.47, 0.59, 0.67; P<0.05, P<0.02, P<0.01, as well as significant negative correlations when DBP was compared with DA values: -0.46,-0.53,-0.56; P<0.05, P<0.05, P<0.02 at 60-, 90-, and 120-minute periods, respectively.


The results obtained from this study show that a small dose (50 mg) of oral L-arginine was enough to induce significant changes in the levels of circulating neurotransmitters, DBP, and heart rate in healthy subjects. These physiologic changes were paralleled by feelings of well-being and mental brightness, which might be attributed to the enhancement of neural sympathetic activity, as revealed by the rise of the NA but not Ad plasma levels, together with the increase of parasympathetic tone, as revealed by the neurophysiologic, neurochemical, and clinical parameters.

Although a bulk of research work has been devoted to the effects of L-arginine on mammals, most if not all of these reports are based on the administration of high doses (oral or parenteral) of this amino acid, which obviously provoke complex responses that are hard to understand and associate with their intimate underlying physiologic mechanisms. In addition, most research dealing with the effects triggered by this amino acid was performed to show singular effects obtained from lineal experiment design; however, those experimental findings allowed a better understanding of the results of this study.

L-arginine is a NO releasing agent whose inhibition is associated with arterial hypertension and the enhancement of sympathetic activity. (22) These effects are paralleled by deficits of NO at the hypothalamic paraventricular nucleus (PVN) (23) In addition, it has also been reported that angiotensin is involved in the hypertensive mechanisms associated with the inhibition of NO. (24) The CNS-mediated sympatho-inhibition triggered by NO would involve NOS (neuron-mediated) mechanisms including CNS serotonergic (5-HT) nuclei. (25) At the same time, other research work shows that the NO synthesis inhibition triggers adrenal sympathetic hyperactivity plus neural sympathetic inhibition; this is the opposite of the ANS profile that was reported in this study. (26) Other experimental findings show that DBP was reduced by L-arginine (30 mg/kg IV) because it facilitates NO synthesis at the CNS level. (27)

Other findings show that the inhibition of CNS-NO synthesis triggers hypertension because it increases adrenal sympathetic activity. (28) These findings support the results of this study, which show that L-arginine annuls adrenal sympathetic activity. Many other research studies report that CNS mechanisms are involved in the L-arginine-NO sympathetic modulatory role. With respect to this, it has been shown that the glutamic acid N-methyl d-aspartate receptor mediates mechanisms that are responsible for the adrenal sympathetic hyperactivity associated with NO-synthesis inhibition. This phenomenon includes the PVN hypothalamic nucleus (29) and the dorsomedial and rostral ventrolateral medulla (30) as well as the medullary nucleus of the solitary tract (NTS). (31) These findings are supported by others that show that NO synthesis in the brain inhibits the Ad release from the adrenal glands. (32) All these findings are consistent with the results of this study which show the reduction of Ad plus the increase of the NA/Ad ratio after oral L-arginine administration. Kimber et al (33) reported that L-arginine increased DBP in patients affected by postural and postprandial hypotension, which is due to a deficit of neural sympathetic activity. Conversely, Prados and colleagues" associated the deficiency of L-arginine with the age of spontaneously hypertensive rats, which could be linked to the inefficient production of NO. Similar postulation is presented by Augustyniak et al (35) who suggested the inclusion of NO-excitatory mechanisms in order to attempt new therapeutic strategies for patients with hypertension. Furthermore, findings by Kvetnansky and colleagues (36) reinforce the above postulation with the demonstration that the blockade of NO synthesis with N-nitro-L-arginine (L-NAME) triggers adrenal sympathetic activation and arterial hypertension, as reflected by the reduction of the NA/Ad ratio, the opposite catecholaminergic profile to that registered in the present study after the administration of oral L-arginine.

The findings by Claxton and Brands (37) are in agreement with all of the above. Their work shows that the NO-synthesis inhibition with L-NAME is responsible for the hypertension triggered by glucose infusion associated with the suppression of the neural sympathetic activity plus the enhancement of adrenal sympathetic drive.

Other findings by Giugliano et al (38) show that L-NAME administration in humans induces vasodilation and platelet aggregation, which is associated with Ad release. The aforementioned research studies support the findings of this study by showing that L-arginine administration enhances parasympathetic activity. The latter should be associated to the overproduction of NO at the CNS level. With respect to this, the excitation of the NTS parasympathetic medullary nucleus plus the inhibition of the C1-Ad rostral ventrolateral medullary nuclei through the L-arginine-NO pathway has been found to play a key role into this mechanism. (39) In addition, other research reports that L-arginine uptake is stimulated by acetylcholine in vivo and in vitro. (40)

The fact that L-arginine lowers DBP despite the increase of neural sympathetic activity (NA + DA), as seen in this study, is explained not only because the inhibition of the adrenal glands provoked by the drug but also by the reduction of the NA/DA ratio. This is because the direct vasodilator effect was triggered by NO at the vascular area, at which level NO was able to deactivate the vasoconstrictor effect of NA. (41) Thus, stimulation of the endogenous NO pathway would enhance parasympathetic activity against the influences of NA-sympathetic effect, as shown by Chowdhary et al (42) in humans. The information mentioned above has been summarized by Lepori and colleagues, (43) and is consistent with the postulation that acetylcholinergic mechanisms play an important hitherto unrecognized role in offsetting the hypertension and cardiac sympathetic activation caused by NOS inhibition in humans.

Decreased parasympathetic activity and impaired NO synthesis would characterize several cardiovascular disease states, including hypertension. With respect to this, the findings by Prior et al (44) show that short-term oral supplementation with L-arginine produced marked and sustained elevation of acetylcholine and vasodilation are in agreement with the above-mentioned research. Finally, Elayan and colleagues (45) report that the inhibition of L-arginine synthesis with L-NAME enhances adrenal sympathetic activity, which is the opposite phenomenon seen in the present study.

Other additional studies reinforce these results. For instance, acetylcholine enhances the uptake of L-arginine both in vitro and in vivo. (40) This is consistent with the findings of the present study that show the lowering of DBP and heart rate by L-arginine.

The NA/Ad ratio increase triggered by the small dose of oral L-arginine registered in this study supports the postulation that neural but not adrenal sympathetic activity was enhanced by the drug. The fact that adrenal glands secrete 80% of Ad whereas sympathetic nerves release 80% to 90% of NA plus 10% to 20% of DA are consistent with all the above. The close positive correlations shown between the 2 latter parameters but not with Ad reinforce the postulation. NA versus DA: r=0.63, 0.69, 0.65; P<0.01 in all cases.

The dissociation between both adrenal and neural sympathetic activities triggered by L-arginine would explain why the DBP but not the SBP dropped throughout the present trial. With respect to this, it should be remembered that a DA pool exists at sympathetic nerves which is released before NA and modulates its release by acting at presynaptic DA-2 receptors. (46,47) This postulation is supported by the close DA versus DBP negative correlations registered in this study: r=-0.46, -0.53, -0.56; P<0.05, P<0.05, P<0.02 at 60-, 90-, and 120-minute periods, respectively. These significant negative correlations become positive when DBP values were plotted against NA/DA ratio: r=0.53, 0.61, 0.68; P<0.05, P<0.02, P<0.01 at 60-, 90-, and 120-minute periods, respectively.

Two mechanisms might explain the reduction of heart rate provoked by L-arginine in the subjects in the present study: a) the reduction of the adrenal sympathetic activity and b) the enhancement of parasympathetic activity. The significant positive Ad versus heart rate and negative heart rate versus the f-5HT/p-5HT ratio fit well with the authors' postulation. In effect, it has been shown that f-5HT competes with circulating acetylcholine for the platelet uptake, (48) thus the increase of the f-5HT/p-5HT is registered during parasympathetic enhancements. This phenomenon is consistent with the fact that atropine provokes an abrupt reduction of the f-5HT/p-5HT ratio in both normal and hyper-parasympathetic syndromes (Bezold-Jarisch reflex). (49-55)

The above hyperparasympathetic activity is explained because plasma serotonin excites the medullary area postrema located outside the blood brain barrier and activates parasympathetic mechanisms that increase the release of serotonin from the enterochromaffin cells, associated with the blood pressure and heart rate decreases. (51,56-59) The increase of circulating serotonin triggered by this mechanism provokes additional activation of the medullary vagal complex, which in turn induces further release of serotonin from the intestinal source. The above mechanism is consistent with the close negative correlations registered between the f-5HT/p-5HT ratio versus heart rate (r=-0.56, -0.71, -0.77, P<0.05, P<0.01, P<0.005 at 60-,90-, and 120-minute periods, respectively).

In summary, the results from the present study show that the administration of 50 mg of oral L-arginine triggered the inhibition of adrenal sympathetic activity plus the enhancement of the parasympathetic system. The increase of the NA/Ad ratio registered in this oral L-arginine trial fit well with the postulation of a neural over adrenal predominance triggered by the drug. This neural sympathetic predominance avoids neither the decreased in DBP nor in heart rate reported in this study. The intrinsic neural (DA-mediated) plus the extrinsic parasympathetic (NO-mediated) mechanisms might explain the above ANS changes, respectively. These results afford enough experimental findings that justify the use of L-arginine in the treatment of hypertension syndromes and other cardiovascular disorders.


(1.) Zucker IH, Schultz HD, Li YF, et al. The origin of sympathetic outflow in heart failure: the roles of angiotensin II and nitric oxide. Prog Biophys Mol Biol. 2004;84:217-232.

(2.) Lechin F, van der Dijs B, Jakubowicz D, et al. Effects of clonidine on blood pressure, noradrenaline, cortisol, growth hormone and prolactin plasma levels in low and high intestinal tone subjects. Neuroendocrinology. 1985;40:253-261.

(3.) Lechin F, van der Dijs B, Jakubowicz D, et al. Effects of clonidine on blood pressure, noradrenaline, cortisol, growth hormone, and prolactin plasma levels in high and low intestinal tone depressed patients. Neuroendocrinology. 1985;41:156-162.

(4.) Lechin F, van der Dijs B, Lechin A, et al. Doxepin therapy for postprandial symptomatic hypoglycemic patients neurochemical, hormonal and metabolic disturbances. Clin Sci. 1991;80:373-384.

(5.) Lechin F, van der Dijs B, Jara H, et al. Effects of buspirone on plasma neurotransmitters in healthy subjects. J Neural Transm. 1998;105:561-573.

(6.) Lechin F, van der Dijs B, Hernandez G, et al. Effects of sibutramine on circulating neurotransmitters in healthy subjects. Neurotoxicology. 2006;27:184-191.

(7.) Lechin F, van der Dijs B, Hernandez G, et al. Acute effects of tianeptine on circulating neurotransmitters and cardiovascular parameters. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:214-222.

(8.) Lechin F, van der Dijs B, Lechin ME, et al. Plasma neurotransmitters, blood pressure and heart rate during supine-resting, orthostasis, and moderate exercise conditions in two types of hypertensive patients. Res Comm Biol Psychol Psychiatry. 1997;22:111-145.

(9.) Lechin F, van der Dijs B, Orozco B, et al. Plasma neurotransmitters, blood pressure and heart during supine-resting, orthostasis and moderate exercise in severely ill patients: A model of failing to cope with stress. Psychother Psychosom. 1996;65:129-136.

(10.) Lechin F, van der Dijs B, Orozco B, et al. Plasma neurotransmitters, blood pressure and heart rate during supine-resting, orthostasis and moderate exercise conditions in major depressed patients. Biol Psychiat. 1995;38:166-173.

(11.) Lechin F, van der Dijs B, Orozco B, et al. Plasma neurotransmitters, blood pressure and heart rate during supine-resting, orthostasis and moderate exercise in dysthymic depressed patients. Biol Psychiat. 1995;37:884-891.

(12.) Lechin AE, Varon J, van der Dijs B, et al. Plasma neurotransmitters, blood pressure and heart rate during rest and exercise. Am J Respir Crit Care Med. 1994;149:A482. Abstract.

(13.) Lechin F, van der Dijs B, Lechin M, et al. Plasma neurotransmitters throughout an oral glucose tolerance test in essential hypertension. Clin Exp Hypertens. 1993;15:209-240.

(14.) Lechin F, van der Dijs B, Lechin M, et al. Effects of an oral glucose load on plasma neurotransmitters in humans: involvement of REM sleep? Neuropsychobiology. 1992;26:4-11.

(15.) Lechin F, van der Dijs B, Rada I, et al. Plasma neurotransmitters and cortisol in duodenal ulcer patients: role of stress. Dig Dis Sci. 1990;35:1313-1319.

(16.) Lechin E Adrenergic-serotonergic influences on gallbladder motility and irritable bowel syndrome. Am J Physiol. 1992;262:G375-G376.

(17.) Lechin F, van der Dijs B, Pardey-Maldonado B, et al. Circulating neurotransmitter profiles during the different wake-sleep stages in normal subjects. Psychoneuroendocrinology. 2004;29:669-685.

(18.) Davies CL, Molyneux SG. Routine determination of plasma catecholamines using reversed phase ion pair high performance liquid chromatography with electrochemical detection. J Chromatogr. 1982;231:41-51.

(19.) Picard M, Olichon D, Gombert J. Determination of serotonin in plasma by liquid chromatography with electrochemical detection. J Chromatogr. 1985;341:445-451.

(20.) Eisenhofer G, Goldstein DS, Stull R. Simultaneous liquid chromatographic determination of 3,4-dihydroxyphenylglycol, catecholamines, and 3,4-dihydroxy-phenylalanine in plasma and their responses to inhibition of monoamine oxidase. Clin Chem. 1986;32:2030-2033.

(21.) Born GVR. Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature. 1962;194:927-929.

(20.) Li X, Yuasa S, Hitomi H, et al. Mechanism mediating hypertension induced by chronic inhibition of nitric oxide synthesis. Nippon Jinzo Gakkai Shi. 1997;39:718-727.

(23.) Zhang K, Mayhan WG, Patel KP Nitric oxide within the paraventricular nucleus mediates changes in renal sympathetic nerve activity. Am J Physiol. 1997;273:R864-R872.

(24.) Tandai-Hiruma M, Horiuchi J, Sakamoto H, et al. Brain neuronal nitric oxide synthase neuron-mediated sympathoinhibition is enhanced in hypertensive Dahl rats. J Hypertens. 2005;23:825-834.

(25.) Li YF, Wang W, Mayhan WG, et al. Angiotensin-mediated increase in renal sympathetic nerve discharge within the PVN: role of nitric oxide. Am J Physiol Regul Integr Comp Physiol. 2006;290:R1035-R1043.

(26.) Lindqvist M. Melcher A, Hjemdahl P. Hemodynamic and sympathoadrenal responses to mental stress during nitric oxide synthesis inhibition. Am J Physiol Heart Circ Physiol. 2004;287:H2309-H2315.

(27.) Tjen-A-Looi SC, Phan NT, Longhurst JC. Nitric oxide modulates sympathoexcitatory cardiac-cardiovascular reflexes elicited by bradykinin. Am J Physiol Heart Circ Physiol. 2001;281:H2010-H2017.

(28.) Matsumura K, Abe J Tsuchihashi T, et al. Central nitric oxide attenuates the baroreceptor reflex in conscious rabbits. Am J Physiol. 1998;274:R1142-R1149.

(29.) Li YF, Mayhan WG, Patel KP NMDA-mediated increase in renal sympathetic nerve discharge within the PVN: role of nitric oxide. Am J Physiol Heart Circ Physiol. 2001;281:H2328-H2336.20.

(30.) Chen SY, Mao SP, Chai CY Role of nitric oxide on pressor mechanisms within the dorsomedial and rostral ventrolateral medulla in anaesthetized cats. Clin Exp Pharmacol Physiol. 2001;28:155-163.

(31.) Matsuo I, Hirooka Y, Hironaga K, et al. Glutamate release via NO production evoked by NMDA in the NTS enhances hypotension and bradycardia in vivo. Am J Physiol Regul Integr Comp Physiol. 2001;280:R1285-1291.

(32.) Song DK, Im YB, Jung JS, et al. Central injection of nitric oxide synthase inhibitors increases peripheral interleukin-6 and serum amyloid A: involvement of adrenaline from adrenal medulla. Br J Pharmacol. 2000;130:41-48.

(33.) Kimber J, Watson L, Mathias CJ. Cardiovascular and neurohormonal responses to i.v. L-arginine in two groups with primary autonomic failure. J Neurol. 2001;248:1036-1041.

(34.) Prados P, Matsunaga H, Mori T, et al. Changes of plasma L-arginine levels in spontaneously hypertensive rats under induced hypotension. Biomed Chromatogr. 1999;13:27-32.

(35.) Augustyniak RA, Thomas GD, Victor RG, et al. Nitric oxide pathway as new drug targets for refractory hypertension. Curr Pharm Des. 2005;11:3307-3315.

(36.) Kvetnansky R, Pacak K, Tokarev D, et al. Chronic blockade of nitric oxide synthesis elevates plasma levels of catecholamines and their metabolites at rest and during stress in rats. Neurochem Res. 1997;22:995-1001.

(37.) Claxton CR, Brands MW Nitric oxide opposes glucose-induced hypertension by suppressing sympathetic activity. Hypertension. 2003;41:274-278.

(38.) Giugliano D, Martella R, Verrazzo G, et al. The vascular effects of L-arginine in humans. The role of endogenous insulin. J Clin Invest. 1997;1;99:433-438.

(39.) Hirooka Y, Kishi T, Sakai K, et al. Effect of overproduction of nitric oxide in the brain stem on the cardiovascular response in con scious rats. J Cardiovasc Pharmacol. 2003;41(suppl 1):S119-S126.

(40.) Parnell MM, Chin-Dusting JP, Starr J, et al. In vivo and in vitro evidence for ACh-stimulated L-arginine uptake. Am J Physiol Heart Circ Physiol. 2004;287:H395-H400.

(41.) Kolo LL, Westfall TC, Macarthur H. Nitric oxide decreases the biological activity of norepinephrine resulting in altered vascular tone in the rat mesenteric arterial bed. Am J Physiol Heart Circ Physiol. 2004;286:H296-H303.

(42.) Chowdhary S, Marsh AM, Coote JH, et al. Nitric oxide and cardiac muscarinic control in humans. Hypertension. 2004;43:1023-1028.

(43.) Lepori M, Sartori C, Duplain H, et al. Interaction between cholinergic and nitrergic vasodilation: a novel mechanism of blood pressure control. Cardiovasc Res. 2001;51:767-772.

(44.) Prior DL, Jennings GLR, Chin-Dusting JP Transient improvement of acetylcholine responses after short-term oral L-arginine in forearms of human heart failure. J Cardiovasc Pharmacol. 2000;36:31-37.

(45.) Elayan HH, Kennedy BP, Ziegler MG. Selective peripheral regulation of noradrenaline and adrenaline release by nitric oxide. Clin Exp Pharmacol Physiol. 2002;29:589-594.

(46.) Mannelli M, Pupilli C, Fabbri G, et al. Endogenous dopamine (DA) and DA2 receptors: a mechanism limiting excessive sympathetic-adrenal discharge in humans. J Clin Endocr Metab. 1988;66:626-631.

(47.) Mercuro G, Gessa G, Rivano CA, et al. Evidence for a dopaminergic control of sympathoadrenal catecholamines release. Am J Cardiol. 1988;62:827-828.

(48.) Born GV, Gillson RE. Studies on the uptake of 5-hydroxy-tryptamine by blood platelets. J Physiol. 1959;146:472-491.

(49.) Sawchenko PE, Swanson LW, Grzanna R, et al. Colocalization of neuropeptide Y immunoreactivity in brainstem catecholamin ergic neurons that project to the paraventricular nucleus of the hypothalamus. J Comp Neurol. 1985;241:138-153.

(50.) Miller AD, Nonaka S. Mechanisms of vomiting induced by the serotonin-3 receptor agonists in the cat: effect of vagotomy, splanchnicectomy or area postrema lesion. J Pharmacol Exp Ther. 1992;260:509-517.

(51.) Callera JC, Bonagamba LGH, Sevoz C, et al. Cardiovascular effects of microinjection of low doses of serotonin into the NTS of unanesthetized rats. Am J Physiol. 1997;272:R1135-R1142.

(52.) Ireland SJ, Tyers MB. Pharmacological characterization of 5-hydroxy-tryptamine-induced depolarization of the rat isolated vagus nerve. Br J Pharmacy. 1987;90:229-238.

(53.) McCann M, Hermann GE, Rogers RC. Nucleus raphe obscurus (nRO) influence vagal control of gastric motility in rats. Brain Res. 1989;486:181-184.

(54.) Lechin F, van der Dijs B, Orozco B, et al. Plasma neurotransmitters, blood pressure and heart rate during supine-resting, orthostasis and moderate exercise stress test in healthy humans before and after parasympathetic blockade with atropine. Res Comm Biol Psychol Psychiatry. 1996;21:55-72.

(55.) Lechin F, van der Dijs B. Blood pressure and autonomic system assessment throughout the sleep cycle in normal adults. Sleep. 2005;28:645-646.

(56.) Larsson PT, Hjemdhal P, Olsson G, et al. Altered platelet function during mental stress and adrenaline infusion in humans: evidence for an increase aggregability in vivo as measured by filtragometry. Clin Sci. 1989;76:369-376.

(57.) Schworer H, Racke K, Kilbinger H. Cholinergic modulation of the release of 5-hydroxytryptamine from the guinea pig ileum. Naunyn Schmiedebergs Arch Pharmacol. 1987;336:127-132.

(58.) Gronstad KO, Zinner MJ, Dahlstrom A. Vagal release of serotonin into gut lumen and portal circulation via separate control mechanisms. J Surg Res. 1987;43:205-210.

(59.) Ahlman H, Bhargava HN, Dahlstrom A, et al. On the presence of serotonin in the gut lumen and possible release mechanisms. Acta Physiol Scand. 1981;112:263-269.

Fuad Lechin, MD, PhD * ([dagger]) ([double dagger]) ([section]) Bertha van der Dijs, MD ([dagger]) ([double dagger]) ([section]) Scarlet Baez, MD ([dagger]) ([double dagger]) Gerardo Hernandez, MD * ([double dagger]) ([section]) Beatriz Orozco, MD ([double dagger]) ([section]) Simon Rodriguez, MD ([double dagger]) ([section])

Departments of * Neurophysiology, ([dagger]) Neurochemistry, ([double dagger]) Neuropharmacology, and ([section]) Neuroimmunology, Instituto de Medicina Experimental, Faculty of Medicine, Universidad Central de Venezuela, Caracas, Venezuela
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Author:Lechin, Fuad; van der Dijs, Bertha; Baez, Scarlet; Hernandez, Gerardo; Orozco, Beatriz; Rodriguez, S
Publication:Journal of Applied Research
Date:Sep 1, 2006
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