Urinary Excretion Of 5-HIAA Research Articles

Chromogranin A, a Marker of the Therapeutic Success of Resection of Neuroendocrine Liver Metastases: Preliminary Report

Recent publications indicate that life may be prolonged by surgical debulking of neuroendocrine tumors. A minimum 90% reduction of liver metastases has been suggested to alleviate symptoms of the carcinoid. We have used the tumor marker chromogranin A (CgA) to assess hepatic resection in patients with neuroendocrine metastatic tumor disease. Since 1998, seven patients (3 men) of median age 73 years (range 64-84 years) with carcinoid primary tumors in the ileum who had solitary (n = 2) or multiple (n = 5) liver metastases underwent hepatic resections. Two patients had synchronous small intestinal and liver resections; the rest had deferred hepatic resections after intestinal resection. Hormonal manifestations in the form of loose stools or diarrhea or flushing were observed in five patients, and five had abdominal symptoms from partial obstruction of the small bowel. The resection was deemed radical in five patients. Two patients with non-radical resection needed postoperative octreotide treatment, and symptoms were alleviated or improved in the others. All seven patients are alive with an observation period from 6 to 64 months (median 36 months). Median CgA (normal < 30 ng/ml) was 292 ng/ml (range 79-14,000 ng/ml) before liver surgery. Postoperatively, CgA became normal in three of the radically resected patients, whereas in two others, it decreased to a lowest median level of 79 ng/ml (range 52-105 ng/ml). In two palliatively resected patients, one had a near normalization to 65 ng/ml, and the last patient had a reduction from 14,000 to 2400 ng/ml following debulking surgery. A similar postoperative reduction was noted for 24 hr urinary 5-HIAA excretion. Postoperative octreotide scintigraphy suggested residual hepatic or extrahepatic tumors in three of the patients thought radically resected, whereas two had no clear sign of disease corresponding to a normal CgA value. The CgA values, however, reflected the extent of positive scintigraphy findings. Serum CgA levels monitored the extent and short-term course of the disease and corresponded well with scintigraphy findings and 5-HIAA excretion, but prolonged follow-up in more patients may be necessary before decisive conclusions are allowed to be drawn.

Patients With Carcinoid Syndrome Exhibit Symptoms of Aggressive Impulse Dysregulation

Objective: Carcinoid tumors can produce excessive amounts of biogenic amines, notably serotonin. We assessed psychiatric symptoms in carcinoid patients and peripheral metabolism of tryptophan, the precursor of serotonin. Methods: Twenty consecutive patients with carcinoid syndrome underwent a structured psychiatric interview applying DSM-IV (Diagnostical Statistical Manual) criteria. Tumor activity was measured by determination of 24-hour urine excretion of 5-hydroxyindoleacetic acid (5-HIAA) and platelet serotonin levels. Plasma tryptophan levels were measured and compared with sex- and age-matched references. Results: Fifteen patients (75%) fulfilled diagnostic DSM-IV criteria for a disorder of impulse control. Tryptophan plasma levels were lower in patients compared with controls (p = .031) and were correlated negatively with urinary 5-HIAA excretion (p = .001). Conclusions: Impulse control disorders are prevalent in patients with carcinoid syndrome. The serotonin production by the tumor possibly decreases the tryptophan pool in the cerebrospinal fluid, which is the essential substrate for the production of brain serotonin as a pivotal neurotransmitter.

Patients With Carcinoid Syndrome Exhibit Symptoms of Aggressive Impulse Dysregulation

Carcinoid tumors can produce excessive amounts of biogenic amines, notably serotonin. We assessed psychiatric symptoms in carcinoid patients and peripheral metabolism of tryptophan, the precursor of serotonin. Twenty consecutive patients with carcinoid syndrome underwent a structured psychiatric interview applying DSM-IV (Diagnostical Statistical Manual) criteria. Tumor activity was measured by determination of 24-hour urine excretion of 5-hydroxyindoleacetic acid (5-HIAA) and platelet serotonin levels. Plasma tryptophan levels were measured and compared with sex- and age-matched references. Fifteen patients (75%) fulfilled diagnostic DSM-IV criteria for a disorder of impulse control. Tryptophan plasma levels were lower in patients compared with controls (p =.031) and were correlated negatively with urinary 5-HIAA excretion (p =.001). Impulse control disorders are prevalent in patients with carcinoid syndrome. The serotonin production by the tumor possibly decreases the tryptophan pool in the cerebrospinal fluid, which is the essential substrate for the production of brain serotonin as a pivotal neurotransmitter.

Reserpine methonitrate, a novel quaternary analogue of reserpine augments urinary excretion of VMA and 5-HIAA without affecting HVA in rats

BackgroundReserpine, an alkaloid from Rauwolfia serpentina was widely used for its antihypertensive action in the past. In later years, its use has been reduced because of precipitation of depression and extra pyramidal symptoms due to its central action. In the present investigation, reserpine methonitrate (RMN), a novel quaternary analogue of reserpine was synthesised and evaluated biochemically for its central and peripheral amine depleting actions in rats while its influence on the blood pressure was measured in anaesthetized rats in comparison with reserpineResultsReserpine treatment (5 mg/kg) produced a significant increase in the urinary excretion of VMA, 5-HIAA and HVA while RMN at doses of equal to and double the equimolar doses of reserpine (5 and 10 mg/kg) produced significant increase in VMA and 5-HIAA excretion without producing any effect on HVA excretion compared to control animals. Reserpine in the dose range of 0.5 to15 μg/kg produced significant reduction in blood pressure compared to control. RMN was also found to produce significant decrease in blood pressure at doses of 10, 25 and 50 μg/kg body weight in comparison to control. The results indicated peripheral depletion of biogenic amines by RMN without affecting the central stores of the amines.ConclusionsThe present study clearly indicated that the quaternization of reserpine restricts its transfer across the blood-brain barrier and could be the reason for its selective peripheral action. It is also clear that the hypotensive actions of RMN could be due to peripheral depletion of catecholamines.

Anti-emetic efficacy of oral granisetron in the total control of late-onset emesis induced by cyclophosphamide-containing chemotherapy

IntroductionEffectiveness of 5-HT3 receptor antagonists in preventing cyclophosphamide-induced emesis suggests that it is mediated by serotonin release. Since urinary 5-hydroxyindoleacetic acid (5-HIAA) is not significantly increased, the mechanism of emesis induction remains poorly understood, and the usefulness of these drugs in late-onset emesis prevention remains controversial.Material and methodsIn this randomised, double-blind, and placebo-controlled trial, 139 chemotherapy-naïve breast cancer patients received intravenous chemotherapy combinations containing cyclophosphamide at doses ≥500 mg/m2. Total antiemetic control was the primary efficacy parameter. On day 0 all patients received intravenous granisetron (3 mg) prior to chemotherapy. On day 1 patients were randomly assigned either to oral granisetron (1 mg bid) or to placebo, for a 2-day course. Patients remained hospitalised during the study period. Rescue therapy (up to 2 doses of i.v. granisetron 3 mg) was promptly administered should there be a second episode of vomiting. Twenty-four hour urine samples were collected on days −1 to +2, for analysis of 5-HIAA excretion.ResultsRelative to the control group, significantly more patients in the oral granisetron group experienced total control of emesis on day 1 (67% versus 49%; p=0.04), on day 2 (76% versus 52%; p<0.01), and on days 1–2 (60% versus 42%; p=0.04). Excretion of 5-HIAA was significantly increased on day 0, day 1 and day 2 compared to levels on day −1 (p<0.01 for all paired comparisons). The type of chemotherapy administered and the patient's history of vomiting were the variables influencing the total control of emesis.ConclusionsOral granisetron provided high rates of effective and safe control of late-onset emesis induced by cyclophosphamide-based chemotherapy. Urinary excretion of 5-HIAA was significantly increased during the entire emesis period.

Liquid Chromatographic–Tandem Mass Spectrometric Method for the Determination of 5-Hydroxyindole-3-acetic Acid in Urine

5-Hydroxyindole-3-acetic acid (5-HIAA), the primary metabolite of the neurotransmitter serotonin, is one of the biochemical markers measured in urine by different methods [colorimetric, fluorometric, HPLC, gas chromatography, and immunoassay (1)(2)] in the identification and surveillance of intestinal carcinoid syndrome (3). Usually, 1–3% of dietary tryptophan is metabolized to serotonin. However, as much as 60% of tryptophan is converted to serotonin in patients with the intestinal carcinoid syndrome. Modestly increased urinary 5-HIAA has been seen in Whipple disease, celiac disease, tropical sprue, and some noncarcinoid pancreatic islet tumors. Diet is also a factor affecting urinary excretion of 5-HIAA (4)(5). Our laboratory is actively involved in the conversion to tandem mass spectrometry (MS/MS) of assays currently based on other chromatographic technologies to improve quality and to reduce turnaround time, supply costs, and personnel needs in a high-volume testing environment (6)(7)(8)(9)(10). We directed our efforts toward developing a liquid chromatography (LC)-MS/MS method to replace an interference-prone HPLC procedure currently used for the routine determination of urinary 5-HIAA (2). We purchased 5-HIAA from Sigma. HIAA-d6 was custom-synthesized by Cambridge Isotope Laboratories (Andover, MA). Working solutions of 5-HIAA (0.5–150 mg/L) were prepared in acetic acid (10 mL/L) from an aqueous stock solution (1 g/L). A working solution of HIAA-d6 (10 mg/L) was prepared in acetic acid (10 mL/L) from a methanol stock solution (1 g/L). Bond-Elut® C18 solid-phase extraction (SPE) cartridges were obtained from Varian Inc. All other chemicals and solvents were of the highest purity available from commercial sources and were used without further purification. We mixed 0.5 mL of urine …

Profiling of Tryptophan-related Plasma Indoles in Patients with Carcinoid Tumors by Automated, On-Line, Solid-Phase Extraction and HPLC with Fluorescence Detection

Profiling of the plasma indoles tryptophan, 5-hydroxytryptophan (5-HTP), serotonin, and 5-hydroxyindoleacetic acid (5-HIAA) is useful in the diagnosis and follow-up of patients with carcinoid tumors. We describe an automated method for the profiling of these indoles in protein-containing matrices as well as the plasma indole concentrations in healthy controls and patients with carcinoid tumors. Plasma, cerebrospinal fluid, and tissue homogenates were prepurified by automated on-line solid-phase extraction (SPE) in Hysphere Resin SH SPE cartridges containing strong hydrophobic polystyrene resin. Analytes were eluted from the SPE cartridge by column switching. Subsequent separation and detection were performed by reversed-phase HPLC combined with fluorometric detection in a total cycle time of 20 min. We obtained samples from 14 healthy controls and 17 patients with metastasized midgut carcinoid tumors for plasma indole analysis. In the patient group, urinary excretion of 5-HIAA and serotonin was compared with concentrations of plasma indoles. Within- and between-series CVs for indoles in platelet-rich plasma were 0.6-6.2% and 3.7-12%, respectively. Results for platelet-rich plasma serotonin compared favorably with those obtained by single-component analysis. Plasma 5-HIAA, but not 5-HTP was detectable in 8 of 17 patients with carcinoid tumors. In the patient group, platelet-rich plasma total tryptophan correlated negatively with platelet-rich plasma serotonin (P = 0.021; r = -0.56), urinary 5-HIAA (P = 0.003; r = -0.68), and urinary serotonin (P <0.0001; r = -0.80). The present chromatographic approach reduces analytical variation and time needed for analysis and gives more detailed information about metabolic deviations in indole metabolism than do manual, single-component analyses.

Cardiac disease and midgut carcinoid syndrome

Abstract Background Valvular heart disease is a well known complication of the midgut carcinoid syndrome but its impact on survival and effects of modern tumour treatment remain to be analysed. Methods In a prospective study cardiac abnormalities and clinical outcome were analysed in 64 consecutive patients with high urinary excretion of the serotonin metabolite 5-HIAA and carcinoid tumours with liver metastases (mean(s.d.) follow-up 119(7) months). A tumour reduction programme by radical surgery alone (including hemihepatectomy) or with hepatic artery embolization following primary surgery (in bilobar liver disease) was offered to all patients. At entry into the study, patients underwent Doppler echocardiography, exercise electrocardiography, Holter monitoring and urinary 5-HIAA determination. Results At follow-up, patients were grouped according to clinical outcome. Twenty-four patients were alive, 11 after radical surgery alone (group 1) and 13 after embolization plus octreotide (group 2). Forty patients had died during follow-up (group 3), three with radical surgery (unrelated disease) and 27 patients with embolization plus octreotide. Ten deceased patients had medical therapy alone after primary surgery owing to complicating diseases. The mean 5-HIAA levels before treatment were lower in group 1 (185 mol per 24 h) than in group 2 (956 (mol per 24 h) or group 3 (566 (mol per 24 h). Tricuspid valve structural abnormalities (TSA) were found in 13, 38 and 33 per cent, and holosystolic tricuspid regurgitation (TR) in 36, 54 and 60 per cent of patients in groups 1, 2 and 3 respectively. No patient had pulmonary stenosis, but 9 per cent (group 1), 15 per cent (group 2) and 13 per cent (group 3) had holodiastolic pulmonary regurgitation. A novel index (TSA–TR) of TSA (0–4) and TR (0–4) was formed. Patients with TSA–TR (3 had significantly (P = 0·025) higher 5-HIAA levels than patients with an index (1. Patients with 5-HIAA levels above 500 (mol per 24 h demonstrated a significantly (P = 0·04) higher late-to-early peak ratio (A/E) of diastolic tricuspid Doppler flow than patients with 5-HIAA levels less than 500 (mol per 24 h. Of the six patients who suffered cardiac death, five died from ischaemic heart disease or sudden death and one from advanced right heart failure. Conclusion Tricuspid abnormalities were common findings in patients with the midgut carcinoid syndrome and severe findings were related to high urinary excretion of 5-HIAA. The highest initial hormone levels were seen in one of the surviving groups. Sudden or ischaemic heart death was more common than death from right-sided heart failure.

Peripheral markers of serotonergic and noradrenergic function in post-pubertal, caucasian males with autistic disorder.

Some studies have suggested that disorders in the peripheral and central metabolism of serotonin (5-HT) and noradrenaline may play a role in the pathophysiology of autistic disorder. This study examines serotonergic and noradrenergic markers in a study group of 13 male, post-pubertal, caucasian autistic patients (age 12-18 y; I.Q. > 55) and 13 matched volunteers. [3H]-paroxetine binding Kd values were significantly higher in patients with autism than in healthy volunteers. Plasma concentrations of tryptophan, the precursor of 5-HT, were significantly lower in autistic patients than in healthy volunteers. There were no significant differences between autistic and normal children in the serum concentrations of 5-HT, or the 24-hr urinary excretion of 5-hydroxy-indoleacetic acid (5-HIAA), adrenaline, noradrenaline, and dopamine. There were no significant differences in [3H]-rauwolscine binding Bmax or Kd values, or in the serum concentrations of tyrosine, the precursor of noradrenaline, between both study groups. There were highly significant positive correlations between age and 24-hr urinary excretion of 5-HIAA and serum tryptophan. The results suggest that: 1) serotonergic disturbances, such as defects in the 5-HT transporter system and lowered plasma tryptophan, may play a role in the pathophysiology of autism; 2) autism is not associated with alterations in the noradrenergic system; and 3) the metabolism of serotonin in humans undergoes significant changes between the ages of 12 and 18 years.

Urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion before and during cisplatin chemotherapy in patients with intrathoracic malignancy

Background : Nausea and vomiting associated with chemotherapy are common side effects which remain difficult to control. Acute phase nausea and vomiting (0-24 hours after induction of chemotherapy) parallels plasma serotonin release, which explains the effectiveness of receptor antagonists. Serotonin released from gastrointestinal enterochromaffin cells may mediate chemotherapy-induced emesis. In this study, we analyzed urinary excretion of 5-HIAA, the main metabolite of serotonin. Methods : Eight men and four women were studied in their cisplatin chemotherapy cycle. Urinary 5-hydroxyindoleaoetic aicd (HIAA) levels were determined before and during a 24-hour period under ondansetron prophylaxis. Results : Urinary 5-HIAA excretion for a 24-hour period was increased in all patients after induction of cisplatin (P=0.002). Conclusion : Cisplatin chemotherapy is associated with serotonin release in the acute phase. Our finding may provide evidence for a relationship between emesis and serotonin following cisplatin chemotherapy.

Reduced Urinary Excretion of Dopamine and Metabolites in Chronic Renal Parenchymal Disease

Background: Chronic renal parenchymal diseases are accompanied by a progressive loss of tubular units endowed with the ability to synthesise dopamine from L-3,4-dihydroxyphenylalanine (L-DOPA), and preliminary evidence has suggested that the urinary excretion of free dopamine may be reduced in these disorders. However, it is well recognised now that under in vitro conditions, dopamine newly synthesised in tubular epithelial cells undergoes extensive deamination to 3,4-dihydroxyphenylacetic acid (DOPAC) by monoamine oxidase (MAO); a small amount of the amine is converted to homovanillic acid by both MAO and catechol-O-methyltransferase (COMT) and a minor amount is methylated to 3-methoxytyramine. Aims: The present study aimed at examining the relationship between renal function and daily urinary levels of L-DOPA, free dopamine and its main metabolites, DOPAC and homovanillic acid (HVA) in patients (n = 28) with chronic renal parenchymal disease, in conditions of controlled sodium, potassium and phosphate intake. The levels of 5-hydroxyindolacetic acid (5-HIAA) were also evaluated in the same cohort of patients. Results: The patients were divided in two groups according to creatinine clearance (group 1, 39±6 ml/min/1.73 m², n = 14; group 2, 139±6 ml/min/1.73 m², n = 14). In patients of group 1, the urinary levels of L-DOPA, dopamine and DOPAC (in nmol/24 h) were significantly lower (60% reduction) than in patients of group 2 (L-DOPA, 134±36 vs. 308±51; dopamine, 759± 175 vs. 1,936± 117; DOPAC 2,595±340 vs. 7,938±833). Also, the urinary excretion of HVA in patients group 1 was significantly lower (40% reduction) than in patients of group 2 (17,434±2,455 vs. 27,179±2,271 nmol/24 h). By contrast, no significant difference was observed in daily urinary excretion of 5-HIAA between the two groups of patients (group 1, 27,280±3,721 nmol/day; group 2, 28,851±2,854 nmol/day). A positive linear relationship was found in these 28 patients between the creatinine clearance and the daily urinary excretion of L-DOPA (r = 0.64, p < 0.001), free dopamine (r = 0.83; p < 0.0001), DOPAC (r = 0.86; p < 0.0001) and HVA (r = 0.65; p < 0.002), but not with that of 5-HIAA (r = 0.14; ns). The U_{dopamine/L-DOPA} and U_{DOPAC/dopamine} ratios were found to be similar in both groups of patients, whereas the U_HVA/DOPAC ratios in patients of group 1 were found greater than in group 2 (p < 0.05). Conclusion: Patients suffering from chronic parenchymal disease with a compromised renal function present with a reduced activity of their renal dopaminergic system which correlates well with the degree of deterioration of renal function. The reduced urinary dopamine output in renal insufficiency is not attributable to enhanced metabolism of renal dopamine. We suggest that the urinary levels of DOPAC may represent a useful parameter for the assessment of renal dopamine synthesis.

Serotonin metabolite excretion after postmenopausal estradiol therapy.

Serotonin, known for its beneficial action on mood and well-being, is also involved in cardiovascular functions. Thus the current work was undertaken to study the effect of hormone replacement therapy on serotonin turnover in postmenopausal women. Eighteen women received estradiol transdermally and 17 women estradiol valerate orally for 4 weeks. The serotonin metabolite 5-hydroxyindole acetic acid (5-HIAA) was determined in the urine before, and after 2 and 4 weeks' estradiol treatment. With both administration routes estradiol produced a significant increase in urinary 5-HIAA excretion, greatest with transdermal estradiol after 28 days of treatment. The enhancement of serotonin turnover may contribute not only to an improvement of mood and well-being but also to a cardioprotective effect of estradiol observed after hormone substitution in postmenopausal women.

Effect of cisplatin on the disposition of endogenous serotonin and its main metabolite, 5-hydroxyindole-3-acetic acid, in rats and dogs.

Emesis after the administration of cisplatin is a severe complication, and its treatment is an important problem clinically. Cisplatin forces the release of serotonin (5-HT) from enterochromaffin cells in the mucosa, and emesis occurs by the stimulation of 5-HT3 receptors. In this study, we established a simple and simultaneous method of determining 5-HT and its main metabolite, 5-hydroxyindole-3-acetic acid (5-HIAA), in plasma and urine by high performance liquid chromatography with electrochemical detection (HPLC-ECD), and determined the disposition of endogenous 5-HT and 5-HIAA after the administration of cisplatin in rats and dogs. In rats, we found no change in the plasma concentration of 5-HIAA after cisplatin administration, while a distinct increase was shown in the plasma concentration of 5-HT, but it was not significantly different from that of the control rats. The urinary excretion of 5-HIAA was also not different between the two groups. In dogs, we observed intense vomiting in all cisplatin treated dogs. However, we could not detect any change in the 5-HIAA or 5-HT level in the dog plasma. Furthermore, no significant difference in the urinary excretion of 5-HIAA was observed between the cisplatin group and the controls. From these results, the plasma concentration of 5-HT and the urinary excretion of 5-HIAA may not be suitable markers for the evaluation of emesis induced by anticancer drugs in dogs.

Acidic Catecholamine Metabolites and 5-Hydroxyindoleacetic Acid in Urine: The Influence of Diet

Concentrations of vanillylmandelic acid (VMA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), vanillic acid (VA) and 5-hydroxyindoleacetic acid (5-HIAA) in urine from healthy subjects were determined by a high-performance liquid chromatography system with a mixed-mode (C18/anion-exchange) column and an 8-channel electrochemical detector, in order to study the influence of diet, diurnal variation and age. The urinary excretion of 5-HIAA increased significantly after eating banana, pineapple, tomato, kiwi fruit and walnut. An increase in the urinary excretion of DOPAC and HVA after eating banana and that of VA after taking vanilla was also noted. The urinary excretion of VMA was not significantly influenced by any of the foods examined. The urinary excretion of 5-HIAA in the first-morning urine increased beyond the upper limit of the reference value when banana was taken at 2000 h the previous day. The excretion of all metabolites in the second-morning urine in the fasting state was within respective reference ranges. Diurnal variation of the excretion of VMA, DOPAC, HVA and 5-HIAA in urine was relatively small, but that of VA was large. The concentrations (mmol/mol creatinine) of VMA, DOPAC, HVA, 5-HIAA and VA in the first-morning urine from healthy subjects increased from 7 days after birth to 1 year and then decreased to adult levels at 13 years of age.

Serotonin mechanisms in chemotherapy-induced emesis in cancer patients.

Emesis is a common side effect of chemotherapeutic drugs. Cisplatin, nitrogen mustard and dacarbazine induce increases in urinary 5-hydroxyindoleacetic acid (5-HIAA) in parallel with the development of the period of emesis which is sensitive to 5-HT3 receptor antagonists ('acute emesis'). It is suggested that these cytotoxics release serotonin from enterochromaffin cells, which then acts on 5-HT3 receptors to trigger the emetic response. Cyclophosphamide, on the other hand, induces a modest emetic response, partly sensitive to 5-HT3 receptor antagonists, but not associated with increases in urinary 5-HIAA. It is suggested that cyclophosphamide-induced emesis is not mediated by the release of serotonin from enterochromaffin cells. Although after high-dose cisplatin most emesis is sensitive to 5-HT3 receptor antagonists, patients often present a milder, although more prolonged form of emesis which is mostly resistant to 5-HT3 receptor antagonists (also known as 'delayed emesis'). This form of emesis is not associated with increases in urinary 5-HIAA (not due to serotonin released from the enterochromaffin cells). Treatment with p-chlorophenylalanine (a serotonin synthesis inhibitor) inhibited cisplatin-induced emesis and cisplatin-induced increases in urinary 5-HIAA excretion. In summary, these results indicate that in human patients, serotonin plays a fundamental role in chemotherapy-induced emesis. Serotonin released from enterochromaffin cells seems to mediate emesis sensitive to 5-HT3 receptor antagonists induced by cisplatin, dacarbazine and nitrogen mustard. Emesis sensitive to 5-HT3 receptor antagonists associated with cyclophosphamide treatment, is not mediated by the release of serotonin from enterochromaffin cells by the cytotoxic. Therefore, cyclophosphamide could induce serotonin release either from enteric serotonin nerves or from the CNS. Cisplatin-induced emesis resistant to 5-HT3 receptor antagonists ('delayed emesis') is not mediated by serotonin released from enterochromaffin cells.

Assessment of renal dopaminergic system activity in the nitric oxide‐deprived hypertensive rat model

1. The present paper reports changes in the urinary excretion of dopamine, 5-hydroxytryptamine and amine metabolites in nitric oxide deprived hypertensive rats during long-term administration of NG-nitro-L-arginine methyl ester (L-NAME). Aromatic L-amino acid decarboxylase (AAAD) activity in renal tissues and the ability of newly-formed dopamine to leave the cellular compartment where the synthesis of the amine has occurred were also determined. 2. Twenty four hours after exposure to L-NAME, both systolic (SBP) and diastolic (DBP) blood pressure were increased by 20 mmHg; heart rate was slightly decreased. During the next 13 days both SBP and DBP increased progressively reaching 170 +/- 3 and 116 +/- 3 mmHg, respectively. 3. Baseline urinary excretion of L-DOPA, dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT) and homovanillic acid (HVA) during the 4 day period of stabilization averaged 4.4 +/- 0.5, 13.8 +/- 0.3, 37.4 +/- 0.8, 180.0 +/- 2.7 and 206.1 +/- 6.7 nmol day-1, respectively. The urinary excretion of L-DOPA, dopamine and DOPAC, but not that of 3-MT and HVA, were increased from day 6-8 of L-NAME administration onwards (L-DOPA, up to 13.4 +/- 2.1; dopamine, up to 23.0 +/- 1.6; DOPAC, up to 62.8 +/- 3.7 nmol day-1). Baseline daily urinary excretion of 5-hydroxytryptamine and 5-hydroxyindolacetic acid (5-HIAA) averaged 73.5 +/- 1.1 and 241.7 +/- 5.4 nmol day-1, respectively. During the first week of L-NAME administration, the urinary excretion of both 5-hydroxytryptamine and 5-HIAA did not change significantly; however, as was found with dopamine and DOPAC, changes in the urinary excretion of 5-hydroxytryptamine were evident during the second week of L-NAME administration. 4. In experiments performed on homogenates of isolated renal tubules, the decarboxylation of L-DOPA to dopamine was dependent on the concentration of L-DOPA used (10 to 5000 microM) and saturable at 1000 microM. AAAD activity as determined in homogenates (Vmax, in nmol mg-1 protein h-1; Km in microM) was significantly (P < 0.01) higher in rats given L-NAME for 14 days (Vmax = 25 +/- 2; Km = 72 +/- 10) than in control rats (Vmax = 14 +/- 1; Km = 63 +/- 7), rats given L-NAME for 7 days (Vmax = 15 +/- 1; Km = 69 +/- 5) and rats given L-NAME plus L-arginine (Vmax = 13 +/- 1; Km = 60 +/- 3) for 14 days. 5. A considerable amount of the total dopamine formed from added L-DOPA in kidney slices escaped into the incubation medium. The application of the Michaelis-Menten equation to the net transport of newly-formed dopamine allowed the identification of a saturable (carrier-mediated transfer) and a non-saturable component (diffusion). No significant differences in the diffusional rate of transfer(0.14 +/- 0.02 micro mol-1) were observed between the four experimental groups. However, the saturable outward transfer of dopamine (Vmax, in micromol mg-1 protein h-1; Km in microM) was higher in control animals(Vmax= 2.3 +/- 0.2; Km = 568 +/- 67) than that in rats treated with L-NAME for 14 days (Vmax = 0.8 +/- 0.02;Km = 241 +/- 21), but similar to that observed in rats receiving L-NAME plus L-arginine (Vmax= 2.4+/- 0.2; Km= 618 +/- 61); the saturable dopamine outward rate of transfer in rats given L-NAME for 7days (Vmax = 3.9 +/- 0.2; Km = 1006 +/- 32) was higher than in controls.6. In conclusion, the present studies show that the hypertensive response resulting from the long-term administration of L-NAME is accompanied by an increased urinary excretion of dopamine and 5-hydroxytryptamine, which appears to follow an enhanced activity of renal AAAD. The observation that the increased AAAD activity can be reversed by the administration of L-arginine to L-NAME treated rats favours the view that the adaptational response which results in an enhanced AAAD activity probably involves a decrease in the generation of nitric oxide.

Cardiac manifestations in mid-gut carcinoid disease.

The extent of heart disease and its relationship to the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), was studied with M-mode, 2D and Doppler echocardiography in 42 consecutive patients, 30 females and 12 males, median age 63 (range 23-75) years with histologically verified mid-gut tumour, liver metastases and 24-h urinary 5-HIAA excretion above 47 mumol.24 h-1. All patients had normal left ventricular ejection fractions, median 65% (interquartile range (IQR) 54-74%). Moderate to severe tricuspid regurgitation (TR) was diagnosed in 22 patients (59%); mitral or aortic regurgitation was found in nine (24%) and six (16%) patients, respectively. The mitral flow peak early (E) on late (A) velocity ratio was significantly decreased compared to age-matched normal subjects. The group of patients with 5-HIAA excretion exceeding 1000 mumol.24h-1 contained significantly more patients with severe TR than those with a lower excretion. The decrease in the E/A ratio may indicate reduced left ventricular compliance, possibly secondary to fibrous changes similar to those seen intra-abdominally and in the right side of the heart. As serotonin is degraded in the lung circulation, other mediators such as tachykinins and cytokines (PDGF) may be involved.

ＣＤＤＰおう吐に対する抗セロトニン薬の効果

The efficacy of ondansetron, an antagonist of serotonin 5HT3-receptor, was compared with that of metoclopramide, an antagonist of dopamin D2-receptors, in the contorol of nausea and vomiting induced by cisplatin treatment in 30 patients with head and neck cancers. Nausea and vomiting were significantly in those treated with ondansetron less than in those receiving metoclopramide. It was concluded that ondansetron is an effective agent for the control of cisplatin-induced nausea and vomiting. The urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA), the main metabolite of serotonin, was significantly increased in the patients who received cisplatin chemotherapy. There was a significant positive correlation between the degree of nausea induced by cisplatin and the urinary excretion of 5-HIAA, suggesting that the release of serotonin induced by cisplatin causes emesis.

Effects of inhibition of serotonin synthesis on 5-hydroxyindoleacetic acid excretion, in healthy subjects.

The urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA), the main metabolite of serotonin, reflects the content and turnover of gastrointestinal (GI) serotonin. Employing longitudinal measurements of 5-HIAA, the authors investigated in healthy subjects (n = 43) how manipulations of serotonin synthesis affect GI serotonin. Under conditions of serotonin-free diets, the intersubject and intrasubject variability (coefficient of variation) for 5-HIAA excretion averaged 33% and 14%, respectively. Dietary tryptophan restrictions to 50% of minimal daily requirements (which is equivalent to a 10-fold reduction in baseline tryptophan intake) decreased by half the urinary excretion of 5-HIAA, irrespective of the caloric content of diet. Restoration to the regular tryptophan intake produced a rapid normalization of the 5-HIAA excretion. Neutral amino acids are known to compete with the intestinal transport absorption mechanisms of tryptophan. Administration of neutral amino acids (1.8 g, by mouth, three times a day, before each meal) or of carbidopa (50 mg, by mouth, three times a day for 3 days) to a normal tryptophan diet failed to alter significantly the 5-HIAA excretion. Further, neutral amino acids failed to enhance the reduction in 5-HIAA produced by the low-tryptophan diet. The failure of these treatments to reduce 5-HIAA excretion could be due to large capacity transport and decarboxylation systems for tryptophan. Other possibilities are discussed. In summary, dietary tryptophan is essential for the maintenance of GI serotonin. Reductions or increases in dietary tryptophan are the easiest and most effective method to alter GI serotonin.(ABSTRACT TRUNCATED AT 250 WORDS)

Chromogranin A and pancreastatin-like immunoreactivity in human carcinoid disease

Objective: To evaluate chromogranin A (CgA) and pancreastatin-like immunoreactivity (PST-LI) as tumor markers in human carcinoid disease, compared with urinary excretion of 5-hydroxyindole acetic acid (5-HIAA), and to evaluate their role as indicators of survival. Patients and methods: Urinary 5-HIAA excretion was determined by a spectrophotometric method, while serum CgA and PST-LI were determined by radioimmunoassay methods in 38 patients with midgut, 10 with foregut and one with hindgut carcinoids. Results: In midgut carcinoid patients levels of 5-HIAA, CgA and PST-LI were raised by 76, 82 and 76%, respectively. The median CgA level in midgut carcinoid patients was significantly higher than in the controls (193 compared with 12ng/ml; P<0.01). In the midgut carcinoid patients, the median CgA value was significantly higher in women who died (1990 ng/ml) than in those who survived (46ng/ml; P<0.01), and significantly higher than in men, either survivors or non-survivors. The median PST-LI value was significantly higher in midgut carcinoid patients than in the control group (2282 compared with 33 pg/ml; P< 0.01). In women, the median PST-LI level was significantly higher in non-survivors than in survivors (9088 compared with 1337 pg/ml; P<0.01), and significantly higher than in male survivors and non-survivors. In foregut carcinoid patients, levels of CgA, PST-LI and 5-HIAA were increased in nine, eight and one patient, respectively. The median CgA and PST-LI levels in the foregut group were similar to the midgut group. Conclusion: CgA and PST-LI are useful markers in the diagnosis of both midgut and foregut carcinoids. They are as good as, or more sensitive than, 5-HIAA.