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Biomedical subjects

N Benjamin

Publications and source records attributed to N Benjamin.

At least 37 records · Page 2Linked to original sources
PubMed1999

Effects of sildenafil citrate on human hemodynamics.

Nitric oxide (NO) induces the formation of intracellular cyclic guanosine monophosphate (cGMP) by guanylate cyclase. Sildenafil, which selectively inhibits phosphodiesterase type 5 (PDE5) found predominantly in the corpora cavernosa of the penis, effectively blocks the degradation of cGMP and enhances erectile function in men with erectile dysfunction. The NO-cGMP pathway also plays an important role in mediating blood pressure. It is, therefore, possible that the therapeutic doses of sildenafil used to treat erectile dysfunction may have clinically significant effects on human hemodynamics. Three studies were undertaken to assess the effects of intravenously, intra-arterially, and orally administered doses of sildenafil on blood pressure, heart rate, cardiac output, and forearm blood flow and venous compliance in healthy men. A fourth study evaluated the hemodynamic effects of intravenous sildenafil in men with stable ischemic heart disease. In healthy men, significant (p <0.01) decreases in supine systolic and diastolic blood pressures were observed with intravenous sildenafil (20, 40, and 80 mg) at the end of the infusion period when plasma levels of sildenafil were highest (mean decreases from baseline of 7.0/6.9 and 9.2/6.7 mm Hg, for the 40- and 80-mg doses, respectively). These changes were transient and not dose related. Modest reductions in systemic vascular resistance also were observed (maximum decrease 16%), although heart rate was not affected by sildenafil administration when compared with placebo. Single oral doses of sildenafil (100, 150, and 200 mg) produced no significant changes in cardiac index from 1-12 hours postdose between placebo- and sildenafil-treated subjects. The approved dosage strengths of sildenafil citrate are 25 mg, 50 mg, and 100 mg. The 80-mg intravenous dose and the 200-mg oral dose of sildenafil produced comparable plasma levels at twice the maximum therapeutic dose (recommended range, 25-100 mg). After brachial artery infusion of sildenafil (up to 300 microg/min), there was a modest vasodilation of resistance arteries and a reversal of norepinephrine-induced preconstriction of forearm veins. These hemodynamic effects were similar to but smaller in magnitude than those of nitrates. In a small pilot study of men with ischemic heart disease, decreases from baseline in pulmonary arterial pressure (-27% at rest and -19% during exercise) and cardiac output (-7% at rest and -11% during exercise) were observed after 40-mg intravenous doses of sildenafil. Sildenafil was well tolerated by subjects and patients in all studies, with headache and other symptoms of vasodilation the most commonly reported adverse effects of treatment. Modest, transient hemodynamic changes were observed in healthy men after single intravenous or oral doses of sildenafil even at supratherapeutic doses. In men with stable ischemic heart disease, sildenafil produced modest effects on hemodynamic parameters at rest and during exercise.

Administration, Oral↗
PubMed1999

Antimicrobial effect of acidified nitrite on cariogenic bacteria.

The antimicrobial agent nitric oxide (NO) is formed in the mouth and its concentration is directly related to salivary nitrite, which in turn is related to dietary nitrate intake. The aim of this study was to determine whether nitrite under acidic conditions will have an inhibitory effect, possibly occurring through NO production, on Streptococcus mutans, Lactobacillus casei and Actinomyces naeslundii. Whereas the growth of S. mutans was inhibited by a more acid pH, the addition of nitrite caused a marked, further dose-dependent reduction in bacterial numbers after 24 h of exposure. Similar effects were observed with A. naeslundii and L. casei. The ability of these bacteria to recover from nitrite exposure was also markedly affected by nitrite concentration. At acidity levels below pH 7, low concentrations of nitrite (0.2 mM) caused effective complete killing of S. mutans, with similar effects on the other organisms tested. These results demonstrate the possibility that nitrite in saliva has an effect on the growth and survival of cariogenic bacteria.

Actinomyces↗
PubMed1999

Molluscum contagiosum effectively treated with a topical acidified nitrite, nitric oxide liberating cream.

A double-blind, group-sequential clinical trial of acidified nitrite was performed to demonstrate the efficacy of this nitric oxide donor in treating molluscum contagiosum. Subjects received either 5% sodium nitrite co-applied with 5% salicylic acid under occlusion, or identical cream with 5% salicylic acid, omitting sodium nitrite. Active and control treatment groups were well matched for the number and duration of lesions and made a similar number of applications. We found a 75% cure rate in the active treatment group and 21% cure with control treatment (P = 0.01). The mean time to cure was 1.83 months. Staining of the skin and irritation were frequent side-effects but did not prevent successful treatment.

Administration, Cutaneous↗
PubMed1999

Nitric oxide synthesis in patients with infective gastroenteritis.

BACKGROUND: There is evidence that endogenous nitrate synthesis is notably increased in patients with infective gastroenteritis. AIMS: To determine whether this is due to nitric oxide (NO) production via the L-arginine/NO pathway. METHODS: Seven male patients with community acquired bacterial gastroenteritis and 15 healthy male volunteers participated in this study. All patients had stool culture positive infective gastroenteritis. A bolus of 200 mg L-[(15)N](2)-arginine was administered intravenously after an overnight fast. Urine was collected for the next 36 hours. Urinary [(15)N:(14)N]nitrate ratio was assessed by dry combustion in an isotope ratio mass spectrometer. RESULTS: Mean 36 hour total urinary nitrate excretion in the gastroenteritis group was 5157 (577) micromol compared with 2594 (234) micromol in the control group (p<0.001). Thirty six hour urinary [(15)N]nitrate excretion was considerably higher in the gastroenteritis group compared with the control group (13782 (1665) versus 1698 (98) etamol; p<0.001). These values represent 1.129 (0.139)% and 0.138 (0.007)% of [(15)N]nitrogen administered (p<0.001), respectively. Corrected 36 hour urinary [(15)N]nitrate excretion for urinary creatinine was also significantly higher in the patient compared with the control group (1934 (221) versus 303 (35) etamol/mmol; p<0.001). CONCLUSION: Results show notably enhanced nitrate synthesis due to increased activity of the L-arginine/NO pathway in patients with infective gastroenteritis.

Adult↗
PubMed1998

Generation of nitric oxide by a nitrite reductase activity of xanthine oxidase: a potential pathway for nitric oxide formation in the absence of nitric oxide synthase activity.

Nitric oxide (NO) synthesis is well-known to result from the oxidation of L-arginine by a family of NO synthases (NOS). However, under hypoxic conditions this mechanism of NO synthesis may be impaired and NO is formed by a NOS independent mechanism. This study was designed to examine the reduction of nitrite to NO by xanthine oxidase (XO) under hypoxia, because the bacterial nitrate/nitrite reductases have structural similarity to XO. We found that both purified and tissue containing XO catalyze the reduction of nitrite to NO, as demonstrated using a chemiluminescent NO meter. This redox reaction requires NADH as an electron donor, and is oxygen independent. The inhibitory profiles suggest that reduction of nitrite takes place at the molybdenum center of XO whilst NADH is oxidized at the FAD center. Heparin binding of XO caused an increase in the catalysis of nitrite reduction. The XO-catalyzed generation of NO may be important in redistribution of blood flow to ischaemic tissue as a supplement to NOS, since both nitrite and NADH have been shown to be elevated in hypoxic tissue.

Anaerobiosis↗
PubMed1998

Xanthine oxidoreductase catalyses the reduction of nitrates and nitrite to nitric oxide under hypoxic conditions.

Xanthine oxidoreductase (XOR) catalyses the reduction of the therapeutic organic nitrate, nitroglycerin (glyceryl trinitrate, GTN), as well as inorganic nitrate and nitrite, to nitric oxide (NO) under hypoxic conditions in the presence of NADH. Generation of nitric oxide is not detectable under normoxic conditions and is inhibited by the molybdenum site-specific inhibitors, oxypurinol and (-)BOF 4272. These enzymic reactions provide a mechanism for generation of NO under hypoxic conditions where nitric oxide synthase does not function, suggesting a vasodilatory role in ischaemia.

Animals↗
PubMed1998

Helicobacter pylori is killed by nitrite under acidic conditions.

BACKGROUND: Due to the expression of urease, Helicobacter pylori is able to establish itself in the human stomach under acidic conditions. A novel host defence mechanism was recently proposed, suggesting that the formation of salivary nitrite in symbiosis with facultative anaerobic bacteria in the oropharynx, is aimed at enhancing the antimicrobial activity of gastric juice. AIMS: To investigate whether the addition of nitrite in physiological concentrations influences the resistance of H pylori to acid. METHODS: H pylori cultured from fresh gastric Biopsy specimens was exposed for 30 minutes to normal saline and to HCl/KCl buffer (0.2M) at pH 2 with urea (5 mM) added. The influence of potassium nitrite (50-1000 mumol/l) on bacterial survival was determined. RESULTS: Addition of nitrite (1 mM) to acidic solutions (pH 2) resulted in complete kill of H pylori within 30 minutes exposure time whereas acid alone allowed the organism to survive (p < 0.001). The antimicrobial effect of nitrite at pH 2 against H pylori was dose dependent and complete kill of organisms occurred at concentrations > or = 500 mumol/l. CONCLUSION: Acidified nitrite has anti-bacterial activity against H pylori. This should prompt further research into the effect of salivary nitrite on the survival of H pylori in the human stomach.

Anti-Bacterial Agents↗
PubMed1998

Evidence for a difference in nitric oxide biosynthesis between healthy women and men.

There is indirect evidence for a gender difference in nitric oxide (NO) synthesis from vascular endothelium. The aim of the present study was to determine NO production more directly in healthy women and men by the measurement of 15N nitrate excreted in urine after the intravenous administration of L-[15N]2-guanidino arginine. Twenty-four healthy volunteers (13 men aged 22 to 40 years and 11 women aged 23 to 42 years) participated in this study. No subjects were receiving any medication. Women were studied between the 7th and 14th days of their menstrual cycles. Arterial blood pressure was measured oscillometrically, and 1.13 micromol L-[15N]2 arginine was administered intravenously after an overnight fast. Urine was collected for the next 36 hours in separate 12-hour periods. Urinary 15N/14N nitrate ratio was assessed by dry combustion in an isotope ratio mass spectrometer. Mean 36-hour urinary 15N nitrate excretion was greater in women than in men (2111+/-139 versus 1682+/-87 etamol; P<0.05). Furthermore, total urinary 15N nitrate excretion was associated inversely with the mean arterial blood pressure in the whole group of subjects (coefficient of correlation, 0.47; P=0.022). The present data show that whole-body production of NO is greater in healthy premenopausal women than in men under ambulatory conditions. The cellular origin of NO measured in this study is unknown, but differences in endothelial production could underlie differences in vascular function between men and women.

Adult↗
PubMed1997

Basal nitric oxide synthesis in essential hypertension.

BACKGROUND: There is indirect evidence that nitric oxide (NO) synthesis in vascular endothelium of patients with hypertension is altered. The aim of this study was to estimate more directly NO production in patients with untreated essential hypertension by measurement of synthesis of inorganic nitrate, which is the end product of NO oxidation in humans. Two separate studies were undertaken in patients with hypertension and appropriate healthy controls. METHODS: In the first study, ten patients and 13 controls were given a diet containing 82 mumoles nitrate per day for 2 days, with urinary and plasma nitrate measurement and 24 h ambulatory blood pressure monitoring on the 2nd day. In the second study, 11 patients and 11 controls were studied in the postabsorptive state; a bolus of 200 mg L[15N]2 arginine was administered intravenously over 10 min. 24 h ambulatory blood pressure monitoring was done and complete urine collections were made for the next 36 h. FINDINGS: In the first study, 24 h urinary nitrate excretion was lower in the hypertensive patients than in the control group (mean 450 [SEM 37] vs 760 mumoles [77] per 24 h; p < 0.001). There was an inverse correlation between average mean daytime ambulatory blood pressure and nitrate excretion (p = 0.007; r2 = -0.73). In the second study, mean 36 h urinary 15N nitrate excretion was significantly lower in the hypertensive than in the control group (1313 [50] vs 2133 [142] pmoles; p < 0.001). There was an inverse correlation also between average mean daytime ambulatory blood pressure and 24 h urinary 15N nitrate excretion expressed per mmole of creatinine (p = 0.002, r2 = -0.59). In addition, total urinary 15N nitrate excretion in the hypertensive group was significantly higher in women than in men (285 [16] vs 198 [14] micrograms 15N nitrate per kg; p = 0.026). INTERPRETATION: These data suggest that whole-body NO production in patients with essential hypertension is diminished under basal conditions. The origin of the NO we measured is not known, and we cannot tell whether the impaired synthesis is primary or secondary to a rise in blood pressure.

Adult↗
PubMed1997

Effect of enalapril and quinapril on forearm vascular ACE in man.

OBJECTIVE: Different ACE inhibitors can be distinguished in vitro by their affinity for converting enzyme in vascular and other tissues. Quinapril appears to be amongst the more effective inhibitors of vascular tissue ACE in vitro. This study assesses the in vivo effect of single oral doses of quinapril and enalapril, in attenuating the vasoconstrictive action of angiotensin I (AI) (which we have previously shown depends on its conversion to angiotensin II (AII) by vascular ACE) in the forearm resistance vessels of man. METHODS: The design was of randomized, open, placebo controlled, two way crossover type, Forearm blood flow (FABF) was measured simultaneously in both forearms by mercury in silastic strain gauge plethysmography. AI infusion were via a fine bore cannula in the left brachial artery with the right arm serving as a control. RESULTS: Mean plasma ACE on placebo was 34.3 U.l-1. Both quinapril and enalapril produced a similar degree of plasma ACE inhibition reducing concentrations to 2.8 U.l-1 and 2.6 U.l-1 respectively. Quinapril caused a significantly greater inhibition of AI induced vasoconstriction with a 30.0% reduction compared with 67.0% and 85.0% for enalapril and placebo respectively. Enalapril attenuated AI induced vasoconstriction to a greater degree than placebo but the difference was not significantly different. CONCLUSION: These results indicate that when quinapril and enalapril are administered as single 20 mg doses, each of which produces the same degree of plasma ACE inhibition and blood pressure reduction- quinapril inhibits vascular ACE to a greater degree than both enalapril and placebo.

Adult↗
PubMed1997

Protection against oral and gastrointestinal diseases: importance of dietary nitrate intake, oral nitrate reduction and enterosalivary nitrate circulation.

Over the last 20 years, dietary nitrate has been implicated in the formation of methemoglobin and carcinogenic nitrosamines in humans. This has led to restrictions of nitrate and nitrite levels in food and drinking water. However, there is no epidemiological evidence for an increased risk of gastric and intestinal cancer in population groups with high dietary vegetable or nitrate intake. A reevaluation of our currently very negative perception of dietary nitrates comes from recent research into the metabolism and enterosalivary circulation of nitrate in mammals. These studies showed that nitrate is converted to nitrite in the oral cavity that then "fuels" an important mammalian resistance mechanism against infectious diseases. Moreover, there is now evidence that the conversion of nitrate into oxides of nitrogen prevents the formation carcinogenic nitrosamines.

Animals↗
PubMed1997

Impaired nitric oxide-mediated vasodilatation and total body nitric oxide production in healthy old age.

1. Basal release of nitric oxide from the vascular endothelium maintains a constant vasodilating tone. Impaired nitric oxide-mediated vasodilatation has been described in hypertension and atheromatous disease. Circulatory diseases account for considerable morbidity and almost half of all deaths in people over the age of 75 years. 2. We have therefore compared nitric oxide-dependent vasorelaxation in 12 healthy elderly subjects with 12 young volunteers matched for blood pressure, cholesterol and glucose, using forearm occlusion venous plethysmography combined with brachial artery infusions of the nitric oxide synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA; 1, 2 and 4 mumol/min) with noradrenaline (60, 120 and 240 pmol/min) as a control vasoconstrictor. We also measured urinary nitrate excretion after a controlled 48 h low nitrate diet as an index of total body nitric oxide production and correlated these changes with forearm blood flow responses to L-NMMA and noradrenaline in both groups. 3. The mean age and blood pressure of the elderly subjects was 76 (range 66-82) years and 132/76 (SEM 4/3) mmHg respectively, while in the young these were 27 (20-35) years and 131/72 (4/3) mmHg respectively. L-NMMA and noradrenaline produced dose-dependent reductions in forearm blood flow in both groups. L-NMMA (4 mumol/min) produced less vasoconstriction in the elderly than in the young (-37.7 +/- 2.6 versus -48.3 +/- 4.2%; P = 0.017). The mean slope of the L-NMMA dose-response curves in the elderly was significantly less than the younger group (-35.2 +/- 3.1 versus -63.7 +/- 10.6; P = 0.041). Noradrenaline, 240 pmol/min, also produced less vasoconstriction in the elderly compared with the young (-22.8 +/- 2.9 versus -35.3 +/- 5.0%; P = 0.029) although the slopes of the dose-response curves did not differ significantly. 4. Urinary nitrate adjusted for creatinine clearance was also significantly higher in the younger group (460.6 +/- 97.7 versus 205.9 +/- 64.8 mumol/day; P = 0.042) and showed a significant correlation with the percentage change in forearm blood flow in response to the maximum dose of L-NMMA (r = 0.5, P = 0.046). 5. We conclude that nitric oxide-mediated vasodilatation in the forearm vascular bed is diminished in old age and this reflects a more generalized reduction in nitric oxide production (as measured by urinary nitrate) in the circulation of older people. The blunted response to noradrenaline points to a more generalized reduction in vascular reactivity in the elderly.

Adult↗
PubMed1997

Nitrate-reducing bacteria on rat tongues.

Nitrite-producing bacteria (NPB) were isolated from tongues of laboratory rats. The most commonly found nitrite-producing organism was Staphylococcus sciuri, followed by Staphylococcus intermedius, Pasteurella spp., and finally Streptococcus spp. Both morphometric quantification of bacteria on tongue sections and enumeration of culturable bacteria (CFU) showed an increase in the density of bacteria towards the posterior tongue. Up to 65% of bacteria were located in the deep clefts on the posterior tongue. The proportion of culturable NPB in the total culturable microbial population increased from 6% (10(5) CFU cm-2) on the anterior tongue to 65% (10(7) CFU cm-2) on the posterior tongue. Different species compositions of NPB were found on different tongue sections with S. intermedius populations decreasing and S. sciuri and Pasteurella populations increasing towards the posterior tongue. Nitrite production was sensitive to oxygen, and significant nitrite production was only detected on the posterior tongue where the majority of bacteria are situated in deep clefts in the tongue surface. This study suggests the importance of bacteria in nitrite production, from nitrate, on the tongue. Nitrite produced on the tongue may subsequently form nitric oxide in the acidic environment of the stomach. Because of the antimicrobial properties of nitric oxide, a key role for nitrate-reducing tongue bacteria in host animal defense against food-borne pathogens in proposed.

Animals↗
PubMed1997

Chemical synthesis of nitric oxide in the stomach from dietary nitrate in humans.

BACKGROUND/AIMS: It has been suggested that dietary nitrate, after concentration in the saliva and reduction to nitrite by tongue surface bacteria, is chemically reduced to nitric oxide (NO) in the acidic conditions of the stomach. This study aimed to quantify this in humans. METHODS: Ten healthy fasting volunteers were studied twice, after oral administration of 2 mmol of potassium nitrate or potassium chloride. Plasma, salivary and gastric nitrate, salivary and gastric nitrite, and gastric headspace NO concentrations were measured over six hours. RESULTS: On the control day the parameters measured varied little from basal values. Gastric nitrate concentration was 105.3 (13) mumol/l (mean (SEM), plasma nitrate concentration was 17.9 (2.4) mumol/l, salivary nitrate concentration 92.6 (31.6) mumol/l, and nitrite concentration 53.9 (22.8) mumol/l. Gastric nitrite concentrations were minimal (< 1 mumol/l). Gastric headspace gas NO concentration was 16.4 (5.8) parts per million (ppm). After nitrate ingestion, gastric nitrate peaked at 20 minutes at 3430 (832) mumol/l, plasma nitrate at 134 (7.2) mumol/l, salivary nitrate at 1516.7 (280.5) mumol/l, and salivary nitrite at 761.5 (187.7) mumol/l after 20-40 minutes. Gastric nitrite concentrations tended to be low, variable, and any rise was non-sustained. Gastric NO concentrations rose considerably from 14.8 (3.1) ppm to 89.4 (28.6) ppm (p < 0.0001) after 60 minutes. All parameters remained increased significantly for the duration of the study. CONCLUSIONS: A very large and sustained increase in chemically derived gastric NO concentrations after an oral nitrate load was shown, which may be important both in host defence against swallowed pathogens and in gastric physiology.

Administration, Oral↗