Effects of L-Carnitine on Oxidant/Antioxidant Status in Acetic Acid-Induced Colitis

Recently, the role of oxidative stress in the pathogenesis of ulcerative colitis has been investigated. This study was designed to evaluate the possible beneficial effects of L-carnitine on tissue injury and oxidative stress in acetic acid-induced colitis in rats. Acetic acid administration induced severe damage macroscopically and histopathologically in colon and significantly increased the levels of malondialdehyde and myeloperoxidase in colonic tissue. Supplementation of L-carnitine to acetic acid-treated rats did not prove to induce any improvements in macroscopic scores, while L-carnitine administration improved histopathologic scores and significantly decreased malondialdehyde and myeloperoxidase levels in treatment groups. Acetic acid administration significantly decreased reduced glutathione, superoxide dismutase, and catalase levels in colonic homogenate. Supplementation of L-carnitine prevented the depletion of reduced glutathione levels but significantly increased superoxide dismutase levels. On the other hand, no significant change in catalase activity was observed. In conclusion, these results may reflect that L-carnitine could be beneficial as a complementary agent in treatment of ulcerative colitis.     

Effects of doxorubicin-containing chemotherapy and a combination with l-carnitine on oxidative metabolism in patients with non-Hodgkin lymphoma

Purpose: Chemotherapy regimens based on anthracycline (doxorubicin) are well established in lymphoma therapy. The purpose of this study was to examine the effects of l-carnitine with a view to reducing cytotoxic side-effects. Methods: 20 patients were scheduled to receive 3 g l-carnitine before each chemotherapy cycle, followed by 1 g l-carnitine/day during the following 21 days, while 20 patients received a placebo (randomized controlled trial). The plasma lipid profile and relative mRNA levels of key enzymes of oxidative metabolism (carnitine acyltransferases) were measured at three points of time. In addition to the clinical parameters we used the mRNA of white blood cells to evaluate the toxic effects on cardiomyocytes. Results: In the present study no cardiotoxicity of anthracycline therapy was detected. Carnitine treated patients showed a rise in plasma carnitine which led to an increase of relative mRNA levels from CPT1A (liver isoform of carnitine palmitoyltransferase) and OCTN2 (carnitine transporter). Following chemotherapy, an activation of carnitine acyltransferases was associated with a stimulation of OCTN2 in both groups. Conclusion: Biochemical and molecular analyses indicated a stimulation of oxidative metabolism in white blood cells through carnitine uptake.     

Chromosome abnormalities in peripheral lymphocytes from patients with progressive systemic sclerosis

Summary Chromosomal abnormalities in cultured peripheral lymphocytes from 14 progressive systemic sclerosis (PSS) patients and 15 normal subjects were examined. No increase was observed in the frequency of chromosome aberrations in PSS patients who had not received any medical treatment. Those who had received medication showed an increased frequency of dicentrics (0.3%) although the frequency was not significantly higher than that for normal subjects. It is not clear, however, whether the increase was due to the hypersensitivity of PSS patients to agents used for therapeutic purposes.     

Elevated levels of soluble fibrin in patients with venous thromboembolism

The fibrin-related markers (FRMs), including soluble fibrin (SF), d-dimer and fibrin and fibrinogen degradation products (FDP) are considered to be useful for the diagnosis of thrombosis; however, evidence for the diagnosis of thrombosis by SF is still not well established. The present study was designed to evaluate the usefulness of SF in the diagnosis of venous thromboembolism (VTE). The plasma concentrations of FRMs were measured in 551 in-patients suspected to have a VTE. The plasma levels of SF, d-dimer and FDP were significantly higher in patients with VTE than patients without VTE and those were significantly higher in patients without VTE than in healthy volunteers. In a receiver operating characteristic analysis for the diagnosis of VTE, the area under the curve was 0.950 for SF, 0.933 for FDP and 0.805 for d-dimer. The appropriate cut-off values for the diagnosis were as follows SF 5.9 μg/ml, FDP 2.1 μg/ml and d-dimer 4.8 μg/ml. To obtain a 100% negative predictive value for the diagnosis of VTE, the SF was less than 5.2 μg/ml, FDP was less than 1.3 μg/ml, and d-dimer was less than 0.5 μg/ml. Our findings suggest that the SF assay is useful for the diagnosis and exclusion of VTE.     

Protective effect of nitric oxide on development of acute pancreatitis in rats

Nitric oxide (NO) has been implicated to regulate pancreatic circulation, promote capillary integrity, and inhibit leukocyte adhesion. We investigated the role of NO in the development of pancreatitis. Nitro-l-arginine, an inhibitor of NO synthase, in total dose of 35 mg/kg body wt was infused in the rats with edematous pancreatitis induced by two intraperitoneal injections of cerulein (20 g/kg).l-Arginine (125 or 250 mg/kg), a NO donor was intravenously administered twice in the rats with hemorrhagic pancreatitis induced by waterimmersion stress plus two intraperitoneal injections of cerulein (40 g/kg). The degree of pancreas edema, serum amylase levels, and histologic alterations were investigated. Nitro-l-arginine exacerbated cerulein-induced pancreatitis and caused a decrease in pancreatic blood flow.l-Arginine ameliorated the severity of hemorrhagic pancreatitis dose dependently and improved the pancreatic blood flow. These findings suggest that NO could confer protection against the development of hemorrhagic pancreatitis, probably through improvement of the pancreatic microcirculation.This study was supported by the research fund of the Research Committee on Intractable Diseases of the Pancreas of the Japanese Ministry of Health and Welfare, and by a Grant-in-Aid for General Scientific Research from the Ministry of Education, Science and Culture, Japan.     

Effects of l-Acetylcarnitine on Cirrhotic Patients with Hepatic Coma: Randomized Double-Blind, Placebo-Controlled Trial

Multiple therapeutic modalities have been used to treat hepatic encephalopathy. l-Acetylcarnitine (LAC) is a physiologically active substance that improves both the energetic and the neurotransmission profiles. LAC is able to cross the hematoencephalic barrier and reach the cerebral regions, where the acetylic group may be utilized. The aim of this work was to evaluate the efficacy of LAC in the treatment of hepatic coma in cirrhotic patients. Twenty-four suitably selected patients were enrolled in the study and, following randomization, received either LAC (n=13) or placebo (n=11). Statistically significant differences in neurological findings, as evaluated by the Glasgow Scale, as well as in ammonia serum levels and BUN were found following LAC treatment. In the placebo group we observed two cases of improved neurological findings as well as one case of improved EEG grading. In the other group we observed an improvement of neurological findings and of EEG grade in 10 and 8 subjects, respectively. Noteworthily, seven (54%) patients went from grade 4 down to grade 3, and one from grade 4 down to grade 1. The improvement in the neurological picture was evident at between 1 and 4 hr after the end of treatment, remaining until 24 hr after. No side effects were observed in our study series. Our study demonstrates that LAC administration improved neurological and biohumoral symptoms in selective cirrhotic patients with hepatic coma.     

Effects of the polyacetate esters of nutrient and nonnutrient monosaccharides on45Calcium efflux and insulin release from perifused rat pancreatic islets

Summary Conclusion The polyacetate esters of selected nonnutrient monosaccharides represent potential tools for either stimulation of insulin release in noninsulin-dependent diabetes or inhibition of insulin secretion in hyperinsulinemic syndromes. Background The polyacetate esters of several monosaccharides were recently shown to display greater nutritional value or biological efficiency than the corresponding unesterified carbohydrates. Methods The effects of seven polyacetate esters of monosaccharides, all tested at a 1.7-mM concentration on both⁴⁵Ca efflux and insulin release were investigated in prelabeled rat pancreatic islets perifused in the presence of 10.0 mM succinic acid dimethyl ester. Results Both α-D-glucose penta-acetate and, to a lesser extent, β-L-glucose penta-acetate stimulated insulin release. Inversely, α-D-galactose penta-acetate, but not β-D-galactose penta-acetate inhibited insulin secretion evoked by succinic acid dimethyl ester. Esters of carbohydrates which are inhibitors ofD-glucose metabolism, such asD-mannoheptulose hexa-acetate and the two anomers of 2-deoxy-D-glucose tetra-acetate. Only also enhanced insulin output, with a preference for the α-anomer of 2-deoxy-D-glucose tetra-acetate. Only those esters with positive insulinotropic action augmented⁴⁵Ca efflux from the prelabeled islets.     

Effect of <Emphasis Type="SmallCaps">L</Emphasis>-carnitine on the physical fitness of thalassemic patients

Poor physical fitness is a common problem among thalassemic patients. l-Carnitine plays an essential role in fatty acid β-oxidation, a process especially important in the organs that preferentially use fatty acid as a source of energy such as the myocardium and the skeletal muscles. The main objective of this study is to assess the effect of the administration of oral l-carnitine on exercise tolerance and physical fitness in patients with thalassemia major. Thirty patients followed up at the New Cairo University Children Hospital were included in this study. Clinical, laboratory, and cardiopulmonary exercise testing were performed before and after 6 months of oral l-carnitine therapy (50 mg/kg/day). The oxygen consumption, cardiac output, and oxygen pulse at maximal exercise significantly increased after l-carnitine therapy (p<0.001, p=0.002 and p<0.001, respectively). However, there was no significant change in minute ventilation and ventilatory equivalent of carbon dioxide (p=0.07 and p=0.06, respectively). A weak but positive correlation between the age of the patients and the degree of improvement in exercise parameters was noted. There was also significant increase in the blood transfusion intervals after l-carnitine administration (p=0.008). However, there was no significant change in hemoglobin concentration (p=0.4). l-Carnitine seems to be a safe and effective adjunctive therapeutic approach in thalassemic patients. It improves their cardiac performance and physical fitness. The younger the patients are, the higher is the degree of improvement in their exercise parameters.     

More Than 13 Years of Hypereosinophila Associated With Clonal CD3−CD4+ Lymphocytosis Of TH2/TH0 Type

A 65-year-old Japanese woman was referred to our hospital because of hypereosinophilia lasting for more than 10 years, and skin ulceration, especially on the hands. Closer examination revealed the clonal proliferation of CD3-CD4+T-lymphocytes. The patient had generalized pruritus without severe end-organ involvement and high serum levels of IgE. A diagnosis of monoclonal CD3-CD4+ T-lymphocyte-associated idiopathic hypereosinophilic syndrome (HES) was made based on these findings. This case showed that this newly recognized entity of HES is not restricted to Western countries. The abnormal T-cell clone was not merely TH2 type but was clearly TH2/TH0 type. Although this disease is considered prelymphoma, this patient did not develop lymphoma during more than 13 years of follow-up. Therefore, in some patients, clonal CD3-CD4+ lymphocyte-associated HES may take a more indolent course. In this subgroup, the control of clinical manifestations seems very important. In the present case, treatment with hydroxyurea quite dramatically improved the intractable skin manifestations, although the treatment lessened only the number of peripheral eosinophils and not the number of clonal CD3-CD4+ T-lymphocytes.     

D-Xylose hydrogen breath tests compared to absorption kinetics in human patients with and without malabsorption

Thed-xylose breath H₂ test may be useful in characterizing intestinal absorptive function. Our aim was to determine whether breath H₂ followingd-xylose administration reflects the extent to which thed-xylose is absorbed by comparing it to a kinetic model ofd-xylose absorption. Twenty-five subjects were studied. They ingested 15 gd-xylose on the first day and 25 gd-xylose on the third day. On the second day they received 10 g intravenousd-xylose along with 15 g oral lactulose. Multiple serum and urine samples were obtained ford-xylose content to calculate its rate constants and extent of absorption by multicompartmental analysis. Breath H₂ determinations were obtained every 15 min for 3 hr following the 15 gd-xylose and lactulose ingestion. Peak breath H₂ concentration correlated with extent of absorption (r=–0.787,P<0.001),K ₀, the rate constant for nonabsorptive loss (r=0.744,P<0.001), and 5-hr urine content (r=–0.705,P<0.001). Area under the breath H₂ curve also correlated with these parameters: extent of absorption (r=–0.770,P<0.001),K ₀ (r=0.662,P<0.001), 5-hr urine content (r=–0.629,P<0.012). Peakd-xylose breath H₂ to peak lactulose breath H₂ showed no correlation with extent of absorption. The extent of absorption was higher with the 15-g dose than the 25-g dose in all patients tested (P<0.01). This was the result of decreased nonabsorptive loss (lowerK ₀), as the rate constant for absorption,K _a , was not statistically different (P>0.05). Peakd-xylose breath H₂ can be used as an inverse estimate ofd-xylose absorption. Lactulose breath H₂ cannot be used as a standard for comparison ford-xylose. The three compartment kinetic model ford-xylose absorption with passive absorption of this carbohydrate is supported by similar rate constants for absorption for the twod-xylose doses used.d-xylose at 15 g may be a more appropriate dose than 25 g for H₂ breath testing as it does not lead to increased nonabsorptive losses.Supported in part by grant RR0048, National Institutes of Health, National Center for Research Resources.     

Clinical applicability of shortenedd-Xylose breath test for diagnosis of intestinal malabsorption

Urinary and/or plasmaticd-xylose tests are broadly used in clinical practice for the diagnosis of intestinal malabsorption. A 5-hr hydrogen breath test (H₂ BT) has also proven useful. Our goal was to determine whether a shorter, hence more efficient, 3-hr test would perform as well as the 5-hr test. We studied 33 patients with proven malabsorption, 44 patients with irritable bowel syndrome (IBS), and 27 healthy subjects. Each individual ingested 25 g ofd-xylose, and alveolar breath samples were obtained thereafter at 30 min intervals for 5 hr. Breath samples were analyzed for H₂ by gas chromatography. Individual peak delta changes and area under the curve (AUC) were calculated. Simultaneously, the 5-hr cumulative urinary excretion ofd-xylose was measured by colorimetry. Results of 5-hr tests were compared with those of the first 3 hrs. In the malabsorption group, the 5-hr test showed a markedly enhanced production of H₂ relative to healthy controls (delta: 60.7±6.4 vs 7.7±1.5 and AUC: 8465.0±985.4 vs 393.2±232.6,P<0.001 for both) and a reduced urinary excretion ofd-xylose (2.8±0.3 g/5 hr vs 6.3±0.2,P<0.001). Results in IBS patients did not differ from those in healthy controls. Three-hour analysis also reflected an enhanced production of H₂ in the malabsorption group (delta: 45.4±6.4 and AUC: 3700.0±545.6,P<0.001 vs healthy controls). Correlation between 3-hr and 5-hr tests was significant in healthy controls (r=0.9), IBS (r=0.9), and malabsorption (r=0.8). The sensitivity of the 3-hr test was lower than of the 5-hr test (0.72 vs 0.91). The loss of sensitivity of the 3-hr test was attributed to a delayed appearance of the delta peak in the malabsorption group. In conclusion, the H₂ breath test withd-xylose is a useful test for the diagnosis of the intestinal malabsorption, but requires a 5-hr monitoring period to be reliable.     

Lack of HLA-antigen association in Greek rheumatoid arthritis patients

Summary One hundred and eighteen unrelated Greek patients with classic rheumatoid arthritis (RA) were tissue-type for HLA-A, -B, -DR antigens and the frequency was compared to that of healthy controls. Greek RA patients regardless of sex, anatomical severity, seropositivity and age at disease onset are not associated with any of the HLA alloantigens tested. Only an increased prevalence, not statistically significant, was observed of the HLA-DF_-5 antigen in the Ro(SSA) positive RA group.     

Myocardial oxidative stress and antioxidants in hypertension as a result of nitric oxide synthase inhibition

Rats were made hypertensive by the administration of the nitric oxide synthase inhibitor nitro-L-arginine (LNA, 2.74 mmol/L) in drinking water for 7 d. Hearts from hemodynamically assessed animals were analyzed for lipid peroxidation (LPO), ψ-glutamylcysteine-synthetase (ψ-GCS), glutathione disulfide reductase (GR), glutathione peroxidase (GSHPx), catalase (CAT), superoxide dismutase (SOD), and total radical trapping potential (TRAP) activities. LNA treatment increased the mean arterial blood pressure by 46% and the heart rate by 22% without changing plasma renin activity. LNA treatment resulted in a 30% increase in LPO. ψ-GCS was reduced by 48% and GR by 36% in the cardiac tissue of hypertensive rats as compared to controls. The activity of nonselenium GSHPx was reduced by 27%, and selenium-dependent GSHPx activity in the heart was not affected by LNA treatment. In hypertensive rats, SOD activity was increased by 16%, and CAT was decreased by 46%. TRAP was lower (27%) in the myocardium of hypertensive rats than in that of controls. These data suggest that LNA-induced hypertension is associated with increased myocardial oxidative stress.     

Malabsorption and deficiency of vitamin B12 in HIV-infected patients with chronic diarrhea

Deficiency of vitamin B₁₂ is commonly reported in HIV-infected patients. We measured vitamin B₁₂ levels in 36 HIV-infected patients with chronic diarrhea (>3 stools/day for six weeks or more). Eight patients had an identifiable cause of diarrhea. Vitamin B₁₂ levels were low in 39%. Sixteen of these patients were selected to undergo further testing, eight patients with low levels of vitamin B₁₂ and eight with normal B₁₂ levels. These 16 patients had both a stage II Schilling test and measurement of multiple serumd-xylose concentrations performed after both oral and intravenous doses ofd-xylose. Integrated areas under the curves (AUC) ford-xylose concentration versus time were calculated for intravenous and oral doses, andd-xylose bioavailability was determined. Stage II Schilling tests were abnormal in 11 patients, (69%).d-Xylose bioavailability correlated closely with vitamin B₁₂ absorption (r=0.648,P<0.01). Comparisons of mean values for CD4 count, serum albumin, Karnovsky score, six-month weight loss, 1-hr serumd-xylose levels and MCV failed to reveal a significant difference between those with and without abnormal serum vitamin B₁₂ levels. These data indicate that below-normal levels of vitamin B₁₂ are highly prevalent in HIV-infected patients with chronic diarrhea. Malabsorption of vitamin B₁₂ occurs in the setting of an enteropathic process effecting both the proximal and distal small bowel. Since no risk factors for vitamin B₁₂ deficiency could be identified, screening for vitamin B₁₂ deficiency in HIV-infected patients with chronic diarrhea is strongly recommended.Supported in part by grant RR00048 National Institutes of Health, National Center for Research Resources.     

<Emphasis Type="SmallCaps">L</Emphasis>-Carnitine inhibits protein glycation <Emphasis Type="Italic">in vitro</Emphasis> and <Emphasis Type="Italic">in vivo</Emphasis>: evidence for a role in diabetic management

Glycation-initiated changes in tissue proteins are suggested to play an important role in the development of diabetes-related pathological changes. The purpose of this study was to examine the anti-glycating effect of L-carnitine (CA) in vivo in the high-fructose diet-fed rat and to determine the potential of CA to inhibit in vitro glycation. Additionally the glucose-disposal efficiency of CA in the rat diaphragm was investigated. High-fructose diet (60 g/100 g diet)-fed rats were treated with CA (300 mg/kg/day i.p.) for 60 days. The effect of CA on glucose, fructose and fructosamine in plasma, methyl glyoxal and glycated haemoglobin in whole blood and skin and tail tendon collagen glycation were determined. The inhibitory effect of CA on the glycation of bovine serum albumin in vitro was compared with that of aminoguanidine (AG), a known antiglycation agent. Glucose utilisation induced by insulin in the control rat diaphragm was monitored in the presence and absence of CA. High-fructose feeding induced hyperglycaemia and glycation of haemoglobin and skin and tail tendon collagen. In CA-administered fructose-fed rats glycation was significantly reduced. In vitro glycation and accumulation of advanced glycation end products were mitigated by CA. CA was more effective than AG in inhibiting glycation in vitro. CA also enhanced the utilisation of glucose in the rat diaphragm. The findings of the study reveal that CA not only has antiglycation effect but also enhances glucose disposal in the rat diaphragm. These findings provide evidence for the therapeutic utility of CA in diabetes and associated complications.     

Hepatic encephalopathy following transjugular intrahepatic portosystemic shunt (TIPS): Management with <Emphasis Type="SmallCaps">l</Emphasis>-ornithine-<Emphasis Type="SmallCaps">l</Emphasis>-aspartate and stent reduction

Hepatic encephalopathy (HE) is a common problem after insertion of a trans-jugular intrahepatic portosystemic shunt (TIPS), which may be difficult to manage. We present a case of severe post-TIPS HE unresponsive to high doses of l-ornithine-l-aspartate (LOLA) despite reduction of venous ammonia levels in a dose-dependent fashion. Ultimately, high-grade HE was successfully treated by a reduction stent and the patient subsequently underwent successful liver transplantation.     

Gastric emptying of solids but not liquids is decreased in rats with chronic renal failure

Severe gastric complications occur in uremic patients, yet few studies have addressed the effect of chronic renal failure (RF) on gastric physiology. In the present study, we investigated: (1) the effect of RF on gastric emptying of liquids and solids in awake rats, (2) the motor function in the gastric corpus, and (3) the role of nitric oxide in any alterations in gastric motor function in uremic rats. RF was induced by partial kidney infarction. RF had no effect on gastric emptying of liquids but significantly inhibited gastric emptying of solids by 68%.N-Nitro-l-arginine, an inhibitor of nitric oxide (NO) synthesis, had no effect on the reduced gastric emptying of solids in RF rats. RF rats showed an altered pattern of gastric motility compared to sham-operated rats. These data suggest that RF induced an inhibition of gastric emptying of solids, but not liquids. However, NO does not seem to play a role in this inhibition.This work was supported by NIH grant DDK 41004 (H.E.R.) and the CURE/UCLA Digestive Disease Core Center DDK 41031 (Animal and Gastrointestinal Blood Flow Cores). E.Q. was the recipient of a Fogarty International Fellowship Award (NIH 1 FO5 TWO4443-01) and a grant from the Conserja de Education, Cultura y Deportes of the Canary Islands Autonomous Government. J.B. was supported by a grant from Fondacio La Caixa, Spain.     

Inhibition of liver metastasis in mice by blocking hepatocyte lectins with arabinogalactan infusions and d-galactose

Summary According to our hypothesis, organ-specific lectins (e.g., the d-galactose-specific hepatic binding protein) play an important role in the organ location of metastatic malignant cells. The rapid clearance and uptake by the liver of tritiated -acid-(asialo)glycoprotein from the circulation of Balb/c mice was markedly delayed after preinjection of d-galactose or arabinogalactan. The preinjection (1h) and regular application (for 3 days after tumor cell inoculation in Balb/c mice) of the receptor blocking agents d-galactose and arabinogalactan prevented the settling of sarcoma L-1 tumor in the liver completely, but did not influence the settling in the lung. Other galactans, dextrans, and phosphate-buffered saline showed no effect. Therefore, when lectins were blocked with competitive-specific glycoconjugates, colonization was prevented.     

Treatment of Chronic Anal Fissure by Application of l-Arginine Gel: A Phase II Study in 15 Patients

PURPOSE Local application of exogenous nitric oxide donors, such as isosorbide dinitrate and glyceryl trinitrate, promotes fissure healing by reducing anal resting pressure and improving anodermal blood flow. The major drawback of these nitric oxide donors is headache. The overall incidence of this side effect is approximately 40 percent. Recently we have shown in healthy volunteers that l-arginine, being an intrinsic precursor of nitric oxide, reduces anal resting pressure without headache as a side effect. The aim of the pres-ent study was to evaluate the effect of l-arginine on anal resting pressure, anodermal blood flow, and fissure healing in patients with chronic anal fissure.METHODS Fifteen patients with a chronic anal fissure were included in the present study. Before entering the study 10 patients were unsuccessfully treated by local application of isosorbide dinitrate. Six of these patients experienced severe headache during treatment with isosorbide dinitrate. All patients were treated for at least 12 weeks by local application of a gel containing l-arginine 400 mg/ml five times a day. In patients with a persistent fissure, treatment was continued until 18 weeks. Anal manometry and laser Doppler flowmetry of the anoderm were performed before treatment, 20 minutes after local application of the first dose, and after 12 weeks of treatment. A visual analog scale was used to assess fissure-related pain and headache.RESULTS One patient dropped out after one day of treatment, and one was excluded because of violation of the study protocol. After 12 weeks of treatment complete fissure healing was observed in 3 of 13 (23 percent) patients, and after 18 weeks the healing rate was 8 of 13 (62 percent) patients. None of the 13 patients experienced typical nitric oxide-induced headache. The pressure recordings showed a significant reduction of maximum anal resting pressure (mean ± SD): pretreatment 89 ± 17 mmHg; 20 minutes after application of the first dose 67 ± 17 mmHg; 12 weeks after treatment 74 ± 14 mmHg (P < 0.005). Recordings of anodermal blood flow showed a significant increase in flow: pretreatment 0.36 ± 0.25 volts; 20 minutes after application of the first dose 0.59 ± 0.27; 12 weeks after treatment 0.64 ± 0.33 (P < 0.005).CONCLUSIONS Local application of l-arginine promotes fissure healing without headache as a side effect, and l-arginine is effective even in patients not responding to isosorbide dinitrate treatment.Norgine Research Ltd. Northwood, United Kingdom, financially supported the study.Reprints are not available.Read at the annual meeting of The American Society of Colon and Rectal Surgeons, Chicago, Illinois, June 3 to 8, 2002.     

Insulin secretion in rats with chronic nitric oxide synthase blockade

Summary Nitric oxide, which is produced from l-arginine by a nitric oxide-synthase enzyme, has been shown to be a ubiquitous messenger molecule. Recently, it has been suggested that nitric oxide might influence insulin secretion by activating the soluble guanylate cyclase and generating cyclic guanosine monophosphate (cGMP). We have investigated the role of the nitric oxide pathway in insulin secretion by evaluating the insulin response to several secretagogues in rats in which nitric oxide-synthase was chronically inhibited by oral administration of the l-arginine analogue, N^G-nitro-l-arginine methyl ester (l-NAME). Blood pressure and aortic wall cGMP content were used as indices of nitric oxide-synthase blockade. Insulin secretion was evaluated after an intravenous bolus of d-glucose, l-arginine or d-arginine. Chronic l-NAME administration induced a 30% increase in blood pressure and a seven-fold drop in arterial cGMP content. Body weight, fasting plasma glucose and insulin were not influenced by l-NAME administration. First-phase insulin secretion (1+3 min) in response to glucose was not significantly different in l-NAME and control rats. The areas under the insulin curve were similar in both groups. Insulin secretion in response to d-arginine or l-arginine in l-NAME-treated and control rats were also similar. In conclusion, chronic nitric oxide-synthase blockade increases blood pressure and decreases aortic cGMP content, but does not alter insulin secretion in response to several secretagogues. Chronic oral administration of l-NAME in the rat provides an adequate animal model for studying the l-arginine nitric oxide-pathway.Abbreviations NO Nitric oxide - cGMP guanosine 3: 5 cyclic monophosphate - l-NMMA N^G-monomethyl-l-arginine - l-NAME N^G-nitro-l-arginine-methyl-ester - NOD mice non obese diabetic mice