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Biomedical subjects

N Benjamin

Publications and source records attributed to N Benjamin.

At least 55 records · Page 3Linked to original sources
PubMed1997

Measurement of NO synthesis in humans by L-[15N2]arginine: application to the response to vaccination.

Induction of nitric oxide (NO) synthesis is a key element of the inflammatory response in humans. We describe a sensitive gas isotope ratio mass spectrometric (GIRMS) method for measuring urinary [15N]nitrate production during intravenous infusion of L-[guanidino-15N2]arginine and its application to investigate the effects of a controlled inflammatory stimulus, typhoid vaccination, on NO synthesis in humans. Intravenous infusion of L-[15N2]arginine at 5-12 mumol.kg-1.h-1 for 24 h in three subjects was used to determine arginine and nitrate pool kinetics. Eight subjects received primed constant infusion of 2.5 mumol.kg-1.h-1 of L-[15N2]arginine for 12 h once before and again after typhoid vaccination. NO synthesis was calculated from 15N enrichment of plasma arginine and urinary nitrate, measured by gas chromatography mass spectrometry and GIRMS, respectively, and total urinary nitrate excretion. Baseline NO synthesis was 298 +/- 44 nmol.h-1.kg lean body mass-1, representing 0.41% of arginine flux. After vaccination, NO synthesis (267 +/- 77 nmol.h-1.kg-1) was not increased (P = 0.18), despite demonstration of an acute phase response. Typhoid vaccination is not accompanied by accelerated NO synthesis.

Adult↗
PubMed1997

Physiological role of nitric oxide in regulation of renal function in humans.

The physiological role of endogenous nitric oxide in regulation of renal function in humans is unclear. Eight healthy men received an inhibitor of nitric oxide synthase, N(G)-monomethyl-L-arginine (L-NMMA, 3 mg/kg), and saline placebo intravenously on two occasions. L-NMMA significantly increased mean arterial pressure (+7%) and total peripheral resistance (+36%). However, because renal plasma flow did not decrease significantly, the increase in renal vascular resistance (+21%) was significantly less than the increase in total peripheral resistance. Glomerular filtration rate (-19%), filtration fraction (-10%), urine flow rate (-18%), sodium (-28%), and free water excretion (-25%) all decreased significantly. Fractional distal, but not proximal, sodium reabsorption increased. L-NMMA also significantly decreased plasma nitrate and urinary excretion of nitrate and dopamine. There were no significant changes in plasma renin activity, plasma endothelin, and aldosterone or in platelet number and ex vivo aggregation. L-NMMA had a plasma half-life of 75 min. Basal generation of nitric oxide appears to contribute less to vascular tone in the kidney than systemically but may alter afferent arteriolar tone. Decreased fractional sodium excretion supports an important physiological role for nitric oxide in inhibition of tubular sodium reabsorption, possibly mediated by the renal dopaminergic system.

Adenosine Diphosphate↗
PubMed1997

Effect of the non peptide angiotensin II antagonist, GR117289C on the vasoconstrictor actions of angiotensin II in the human forearm.

AIMS: GR117289C is a non peptide, selective angiotensin (AT1) receptor antagonist. The purpose of this study was to determine whether this agent, given orally, could attenuate the vasoconstrictor effects of angiotensin II(AII) infused locally into the forearm circulation in man. METHODS: Eight healthy male subjects were studied on four occasions in a randomized, double-blind, placebo controlled, crossover study. Five hours (approximate time of peak dynamic effect) following dosing with GR117289C (300 mg, 100 mg, 10 mg or placebo), A II was infused in incremental doses (0, 0.1, 0.4, 1.6, 6.2, 25 and 100 pmol min-1) into the left brachial artery, each for 10 min. Forearm blood flow was measured using venous occlusion plethysmography. RESULTS: GR117289C inhibits the vasoconstrictor effects of A II in a dose dependent manner. The active treatment: placebo ratios of forearm blood flow in the infused arm during the highest dose of AII (100 pmol min-1) were: GR117289C 10 mg, 1.12 (95% C.I. 0.81-1.55; P = 0.478), 100 mg, 1.43 (95% C.I. 1.01-2.01; P = 0.042) and 300 mg, 1.62 (95% C.I. 1.17-2.24; P = 0.006). There was no significant difference in blood pressure between each of the treatment groups and placebo. CONCLUSIONS: GR117289C is a pharmacologically active, oral A II antagonist in healthy men.

Administration, Oral↗
PubMed1996

Elevated nitric oxide production in rheumatoid arthritis. Detection using the fasting urinary nitrate:creatinine ratio.

OBJECTIVE: To develop a simple method for assessing endogenous nitric oxide (NO) production applicable to routine clinical practice in rheumatology. METHODS: NO production was assessed in patients with rheumatoid arthritis (RA) as serum nitrate levels and as the urinary nitrate:creatinine ratio in morning samples of urine following an overnight fast. The influence of dietary intake of nitrate on these measurements was investigated in healthy volunteers. The clinical value of the urinary nitrate:creatinine ratio was validated in patients with infectious gastroenteritis, in whom its production is known to be increased. RESULTS: Urinary nitrate:creatinine ratios were significantly elevated in patients with RA (average 3-fold elevation over controls; P < 0.005) or infectious gastroenteritis (average 10-fold elevation, P < 0.001). Serum nitrate was significantly elevated only in patients with infectious gastroenteritis (P < 0.001). Dietary intake of nitrate had no significant influence on the fasting morning urinary nitrate:creatinine ratio in the healthy volunteers, showing that this parameter is a useful indicator of endogenous NO production.

Adult↗
PubMed1996

Nitric oxide is generated on the skin surface by reduction of sweat nitrate.

Nitric oxide (NO) is known to be synthesized by mammalian cells from L-arginine by a group of NO synthase enzymes. We now show that NO is generated from human skin and propose a different mechanism of production. Whereas enzymatic NO synthesis is inhibited by monomethyl L-arginine, this arginine analog, when infused into the brachial artery at concentrations sufficient to inhibit endothelial NO synthase activity, has little effect on hand skin NO production. Hand skin NO production is increased by topical acidification of the skin surface and greatly increased by the addition of nitrite solutions. We propose that NO generation from skin derives from sweat nitrite (the concentration of which was found to average 3.4 microM in six subjects) due to chemical reduction consequent to the acidic nature of sweat. Sweat contains nitrate in appreciable amounts, and skin commensal bacteria can synthesize nitrate reductase enzyme. Patients on long-term tetracycline antibiotics showed significantly reduced skin NO synthesis, although topical antiseptic and antibiotics had little effect on NO generation in the short-term. We propose that NO generation from skin is dependent on bacterial nitrate reduction to nitrite and subsequent reduction by acidification. We speculate that this has a physiologic role in the inhibition of infection by pathogenic fungi and other susceptible microorganisms and may affect cutaneous T-cell function, keratinocyte differentiation, and skin blood flow.

Administration, Topical↗
PubMed1996

Antimicrobial effect of acidified nitrite on gut pathogens: importance of dietary nitrate in host defense.

Dietary intake of nitrate generates salivary nitrite, which is acidified in the stomach, leading to a number of reactive intermediates of nitrogen, among which are the potentially carcinogenic N-nitrosamines. Acidified nitrite, however, also has antimicrobial activity which coincides with the formation of nitric oxide. The present study examines the antimicrobial effect in vitro of acidified nitrite on Salmonella enteritidis, Salmonella typhimurium, Yersinia enterocolitica, Shigella sonnei, and Escherichia coli O157. First-order regression plots showed a linear inverse relationship of log-transformed proton and nitrite concentrations with MICs and MBCs after 30 min, 2 h, and 24 h of exposure (P < 0.001 for all antibacterial activities). Susceptibility to the acidified nitrate solutions ranked as follows: Y. enterocolitica > S. enteritidis > S. typhimurium = Shigella sonnei > E. coli O157 (P < 0.05). Addition of SCN-, but not that of CI-, increased the antibacterial activity (paired t testing, P < 0.001). Generation of salivary nitrite from dietary nitrate may provide significant protection against gut pathogens in humans.

Diet↗
PubMed1996

Plasma nitrate concentration in infective gastroenteritis and inflammatory bowel disease.

BACKGROUND: In subjects on a low nitrate diet, plasma nitrate concentration and urinary nitrate excretion are thought to reflect endogenous nitric oxide (NO) production, and have been reported to increase during infective and inflammatory bowel disease. AIMS: To compare the extent of NO production in patients with infective versus non-infective forms of bowel dysfunction. SUBJECTS: Four groups: 20 healthy, volunteer clerical and laboratory staff, 12 patients with irritable bowel syndrome, 19 patients with inflammatory bowel disease, and 20 patients with infective gastroenteritis. METHODS: The plasma nitrate concentration was determined with a copper coated cadmium column and spectrophotometry. Mean and median plasma nitrate concentrations were calculated and compared within the four groups. Mann-Whitney distribution free rank testing was used to compare the median values. RESULTS: Median plasma nitrate concentrations in the four groups were: controls 32.7 mumol/l; irritable bowel syndrome 35.5 mumol/l; inflammatory bowel disease 35.1 mumol/l; and gastroenteritis 117.9 mumol/l (p < 0.001 gastroenteritis v all other groups). CONCLUSIONS: Plasma nitrate concentration could serve as a discriminant between infective and inflammatory or functional bowel disease in patients presenting with diarrhoea. It is not clear why there is considerable difference in endogenous nitrate synthesis in these two conditions, which are both characterised by severe gut inflammation.

Adolescent↗
PubMed1996

Variation of phenotype in patients with glucocorticoid remediable aldosteronism.

Glucocorticoid remediable aldosteronism (GRA), an autosomal dominant cause of primary aldosteronism, has been described as resulting in severe hypertension with premature death from stroke. We describe two new large pedigrees which include subjects who have the abnormal chimaeric gene strongly linked to GRA. The majority of affected members, who have only mild hypertension and normal biochemistry, are clinically indistinguishable from patients with essential hypertension. It is therefore likely that this condition is underdiagnosed.

Adult↗
PubMed1996

Prostacyclin biosynthesis in essential hypertension before and during treatment.

Protacyclin biosynthesis was investigated in 133 untreated newly diagnosed patients with uncomplicated essential hypertension. Urinary excretion of 6-oxo-prostaglandin F1 alpha and of 2,3-dinor-6-oxo-prostaglandin F1 alpha, stable breakdown products of prostacyclin, was measured following a 1 month run-in period. To determine whether lowering blood pressure (BP) influenced prostacyclin biosynthesis, 106 consenting patients with diastolic pressure 90-120 mm Hg were allocated randomly to treatment with bendrofluazide, metoprolol, quinapril or amlodipine in an open parallel group design. Dose was increased to reduce diastolic arterial pressure to <90 mm Hg. Terazosin was added if this target BP was not achieved, and its dose increased if necessary. Urinary excretion rates of prostaglandins were measured after 1 year in patients in whom the target diastolic pressure was achieved. Mean arterial pressure varied from 106-168 mm Hg in untreated patients and excretion of both prostacyclin-derived products varied from <5 to >350 ng/g creatinine. Arterial pressure and prostaglandin excretion were not significantly correlated. In 57 patients in whom target pressure was achieved, BP before treatment was 166 +/- 2/100 +/- 1 at baseline and 144 +/- 2/86 +/- 1 mm Hg at 1 year. Excretion rates of each prostacyclin-derived product were similar before treatment and at 1 year, with no significant differences between the drugs. These findings do not support the hypothesis that deficient prostacyclin biosynthesis contributes to the pathogenesis of essential hypertension, or that increased prostacyclin biosynthesis plays a part in the response to treatment with antihypertensive medication.

6-Ketoprostaglandin F1 alpha↗
PubMed1995

Angiotensin II. Adrenergic sympathetic constrictor action in humans.

BACKGROUND: Angiotensin II (Ang II) facilitates adrenergic neurotransmission in normotensive and hypertensive subjects, whereas angiotensin-converting enzyme inhibitors have been shown to depress circulating catecholamine concentrations in some studies. We investigated the effect of local intra-arterial infusion of Ang II into the brachial artery of healthy volunteers during blockade of postsynaptic alpha-receptors with phentolamine. The response was compared with that seen with Ang II infused during nitroprusside administration at a dose designed to give a dilator response similar to that with phentolamine. METHODS AND RESULTS: Ang II (6.25, 25, and 100 pmol/min) was infused alone and then together with sodium nitroprusside (4 micrograms/min) and phentolamine (40 micrograms/min) in eight healthy volunteers. Forearm blood flow was measured by strain-gauge plethysmography. The percentage reduction in forearm blood flow produced by Ang II 100 pmol/min in the phentolamine-predilated vascular bed was significantly lower than that seen in the sodium nitroprusside-predilated forearm bed (28.1 +/- 2.9% versus 52.9 +/- 4.2%; P = .006). Comparison of the rate of change of blood flow in response to quadrupling doses of Ang II during blockade of alpha-receptors with phentolamine and during nitroprusside administration was calculated from the mean slope of the regression line of log-transformed blood flow versus dose of Ang II. The mean slope during nitroprusside administration (-0.16 +/- 0.025) was significantly greater than that during blockade with phentolamine (-0.098 +/- 0.020) (P = .046). CONCLUSIONS: We conclude that a significant part of the vasoconstrictive action of exogenous Ang II on forearm resistance vessels in humans is sympathetically mediated.

Adult↗
PubMed1995

Nitric oxide: a cytokine-induced regulator of bone resorption.

Nitric oxide (NO) has been reported to inhibit osteoclastic bone resorption, yet potent stimulators of bone resorption, such as interleukin-1 (IL-1) and tumor necrosis factor (TNF), are known to stimulate NO production. This paradox prompted us to reinvestigate the relationship between NO production and bone resorption in mouse calvarial organ cultures. Control cultures and those stimulated with calciotropic hormones and individual cytokines produced little NO, and under these conditions the NO synthase inhibitor, L-NG-monomethyl arginine (LMMA), had no significant effect on bone resorption. Cytokine combinations were much more potent stimulators of NO production than individual cytokines. Dramatic stimulation of NO production and inhibition of bone resorption resulted when gamma-interferon (IFN) was combined with IL-1 or TNF and these effects were reversed by LMMA. IFN had no effect on bone resorption and little effect on NO production when used alone or in combination with calciotropic hormones, however, suggesting that IFN selectively inhibits cytokine-induced bone resorption by generating large amounts of NO. IL-1 and TNF acted together to stimulate NO production but to a lesser degree than when combined with IFN. LMMA inhibited bone resorption induced by IL-1 and TNF, suggesting that lower concentrations of NO stimulate bone resorption. Experiments with the pharmacological NO donor S-nitroso-acetyl-penicillamine (SNAP) supported this view in showing generalized suppression of bone resorption at high SNAP concentrations, but potentiation of IL-1 induced bone resorption at lower SNAP concentrations. We conclude that cytokines are potent inducers of NO in bone and that cytokine-induced NO production has biphasic effects on bone resorption.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Plasma nitrate concentration and urinary nitrate excretion in patients with gastroenteritis.

The concentration of nitrate (the stable oxidation product of nitric oxide) in plasma and its excretion in urine was measured in 20 patients with a diagnosis of gastroenteritis. On day 1 of the illness plasma nitrate concentration was significantly elevated compared with a healthy control population (92.7 +/- 17.0 mumol/l vs. 33.1 +/- 1.6 mumol/l; P < 0.001) and continued to be elevated on days 2 and 3. Urinary nitrate excretion was also elevated. The plasma nitrate concentration correlated with disease severity as assessed by stool frequency and plasma urea concentration. Plasma nitrate concentration may be a sensitive and clinically useful indicator of severity of gastroenteritis.

Adult↗
PubMed1995

Chemical generation of nitric oxide in the mouth from the enterosalivary circulation of dietary nitrate.

High concentrations of nitrite present in saliva (derived from dietary nitrate) may, upon acidification, generate nitrogen oxides in the stomach in sufficient amounts to provide protection from swallowed pathogens. We now show that, in the rat, reduction of nitrate to nitrite is confined to a specialized area on the posterior surface of the tongue, which is heavily colonized by bacteria, and that nitrate reduction is absent in germ-free rats. We also show that in humans increased salivary nitrite production resulting from nitrate intake enhances oral nitric oxide production. We propose that the salivary generation of nitrite is accomplished by a symbiotic relationship involving nitrate-reducing bacteria on the tongue surface, which is designed to provide host defence against microbial pathogens in the mouth and lower gut. These results provide further evidence for beneficial effects of dietary nitrate.

Adult↗
PubMed1995

The effect of amoxycillin on salivary nitrite concentrations: an important mechanism of adverse reactions?

Broad spectrum antibiotics are known to predispose towards oral candidiasis and gastroenteritis. Oral nitrite synthesis by commensal bacteria may be important in protecting the mouth and lower intestine from pathogenic organisms, including Candida albicans. The effect of 2 days administration of the broad spectrum antibiotic amoxycillin on salivary nitrite concentration, following a 200 mg potassium nitrate oral load, was studied in 10 healthy volunteers. The Cmax fell by 40% and the AUC was reduced by 1227 microM h (43%, 95% CI 273, 2181, P < 0.006) in the antibiotic treated group when compared with control. These findings suggest that destruction of nitrate reductase containing bacteria in the mouth by antibiotics may explain an increased incidence of infection with Candida and other pathogens.

Adult↗
PubMed1995

Plasma nitrate concentrations in neutropenic and non-neutropenic patients with suspected septicaemia.

Nitric oxide (NO) is an important physiological mediator of vascular tone and is thought to be involved in the pathogenesis of septic shock. Plasma nitrate is the stable end product of NO oxidation and in part reflects endogenous NO production. We measured plasma nitrate levels in 47 episodes of suspected septicaemia in 43 in-patients (16 male and 27 female, age 15-63 years). Nitrate concentrations were significantly higher (P < 0.01) compared to healthy controls. Further analysis revealed that significantly elevated levels occurred only in the septic patients who had normal or elevated numbers of neutrophils in the peripheral blood and were hypotensive on presentation. Failure of plasma nitrate concentrations to rise significantly in patients with neutropenia suggests that this cell type may be important in the activation of the arginine-NO system in severe sepsis in man.

Adolescent↗
PubMed1995

Measuring forearm blood flow and interpreting the responses to drugs and mediators.

Venous occlusion plethysmography has been widely used to study forearm blood flow. The principle of the technique is straightforward: the rate of swelling of the forearm during occlusion of venous return is used to assess the rate of arterial inflow. Provided that perfusion pressure (arterial blood pressure) remains constant, changes in flow reflect changes in smooth muscle tone in small arteries and arterioles. Local infusion into the brachial artery allows assessment of the direct effect of drugs on vascular tone and has been used to probe the roles of endogenous mediators. The technique is at its most powerful when dose-response relationships to different drugs or mediators within a single study are being compared but can also be used for comparison of responses to drugs between healthy control subjects and patient populations. However, when responses between groups are being compared, it is important to take into account the starting conditions of baseline blood flow and pressure. This article describes venous occlusion plethysmography, discusses the presentation and analysis of data (dose of drug or concentration? forearm blood flow or resistance?), and highlights certain potential problems and limitations of the technique as a means of studying disease states.

Blood Pressure↗