PubMed Health⌕ Search

Biomedical subjects

N Benjamin

Publications and source records attributed to N Benjamin.

At least 73 records · Page 4Linked to original sources
PubMed1994

Preserved endothelium-dependent vasodilatation in patients with essential hypertension.

BACKGROUND: Previous studies suggest that vascular endothelial function may be impaired in essential hypertension. Although muscarinic agonists dilate blood vessels by releasing an endothelium-derived relaxing factor closely related to nitric oxide, nitroprusside dilates vessels by a mechanism that is independent of the endothelium. The finding of an impaired response to muscarinic agonists but a normal response to nitroprusside in patients with hypertension has suggested that endothelial function is abnormal in hypertension. METHODS: We reassessed this issue by measuring forearm blood flow by plethysmography during the infusion of vasodilators into the brachial arteries of 95 subjects: 37 normotensive controls (mean [+/- SE] arterial blood pressure, 92 +/- 1 mm Hg) and 58 patients with essential hypertension (mean arterial blood pressure, 121 +/- 1 mm Hg). RESULTS: In an initial study, vascular responses to the vasodilators carbachol and nitroprusside were similar in normotensive controls (n = 19) and hypertensive patients (n = 17). We wondered whether this might be attributable to the use of previously untreated patients or to the choice of carbachol as the muscarinic agonist. However, we found that the vasodilator responses to nitroprusside, acetylcholine, carbachol, and isoproterenol were also similar in separate groups of normotensive controls (n = 18) and hypertensive subjects, whether the subjects had never been treated for hypertension (n = 24) or had had therapy withheld for two weeks (n = 17). The 95 percent confidence intervals for the difference between the controls and hypertensive patients in the ratio of endothelium-dependent vasodilatation induced by acetylcholine or carbachol to endothelium-independent vasodilatation induced by nitroprusside were -14 to +23 percent for acetylcholine and -13 to +12 percent for carbachol. CONCLUSIONS: In contrast to previous studies, our findings suggest that selective impairment of the responsiveness of the forearm vasculature to muscarinic agonists is not universal in patients with essential hypertension.

Acetylcholine↗
PubMed1994

Angiotensin converting enzyme inhibition does not affect response to exogenous angiotensin II in the forearm of mild-moderate hypertensive patients.

It has been proposed that the suppression of endogenous levels of angiotensin II by angiotensin converting enzyme inhibition, may result in up-regulation of vascular AT1 receptors. This study evaluated the effects of orally administered enalapril on angiotensin II induced vasoconstriction in the human forearm of patients with mild-moderate hypertension. Patients received in random order, enalapril (20 mg) or matched placebo daily for 2 weeks. Forearm blood flow response to increasing doses of angiotensin II was measured using venous occlusion plethysmography at the beginning of the study and at the end of each 2 week treatment period. Treatment with enalapril significantly reduced plasma angiotensin II levels and supine blood pressure compared to placebo. The percentage reductions in forearm blood flow in the infused arm, in response to the maximum dose of angiotensin II (50 pmol.min-1) were 53.2% at baseline, 51.4% on placebo and 59.5% on enalapril. The differences were not significantly different. This study demonstrates that suppression of plasma angiotensin II does not enhance the response to exogenous intra-arterial angiotensin II in the human forearm of mild-moderately hypertensive patients.

Administration, Oral↗
PubMed1994

Angiotensin converting enzyme inhibition does not affect the response to exogenous angiotensin II in the human forearm.

Suppression of endogenous levels of angiotensin II by angiotensin converting enzyme inhibition, may result in up-regulation of vascular AT1 receptors. We have evaluated the effects of orally administered enalapril on angiotensin II induced vasoconstriction in the human forearm. Subjects received in random order, enalapril (20 mg) or matched placebo daily for 2 weeks. Forearm blood flow response to increasing doses of angiotensin II was measured using venous occlusion plethysmography at the beginning of the study and at the end of each 2 week treatment period. Treatment with enalapril significantly reduced plasma angiotensin II levels and supine blood pressure compared with placebo. The percentage reductions in forearm blood flow in the infused arm, in response to the maximum dose of angiotensin II (50,000 fmol min-1) were 48.1 +/- 3.6% at baseline, 57.5 +/- 3.6% on placebo and 54.5 +/- 4.2% on enalapril. The differences were not significantly different. This demonstrates that suppression of plasma angiotensin II for a 14 day period does not enhance the response to exogenous intra-arterial angiotensin II in the human forearm of healthy salt replete subjects.

Administration, Oral↗
PubMed1994

Lack of tolerance in forearm blood vessels in man to glyceryl trinitrate.

1. Nitrate tolerance is a clinical problem. The cause is not known but it has been suggested that tolerance to organic nitrates occurs within the blood vessels to reduce sensitivity to the drug. We have determined the sensitivity of human forearm resistance vessels and veins to glyceryl trinitrate (GTN) at the beginning and end of a 7 day period of GTN administration in healthy volunteers using a clinically relevant dose of transdermal drug. 2. Eight healthy volunteers completed the study which entailed measurement of change in forearm venous compliance and change in forearm blood flow following intraarterial infusions of two doses of glyceryl trinitrate (0.5 and 2.0 micrograms min-1) before, after 2 h and after 7 days of transdermal GTN administration using one 10 mg patch each 24 h. 3. Changes in venous compliance and blood flow were measured by venous occlusion plethysmography using a basal infusion of noradrenaline (1 microgram min-1) to increase venous tone. 4. Noradrenaline produced the expected decrease in forearm blood flow and venous compliance. The effect of locally infused GTN on venous compliance and forearm blood flow was similar on the three study days. In particular there was no significant difference in the response to GTN following 7 days transdermal administration compared with that after 2 h. 5. We conclude from this study that local vascular tolerance to GTN is unlikely to explain the clinical problem of nitrate tolerance, and that other mechanisms such as neurohumoral activation may be important.

Administration, Cutaneous↗
PubMed1994

Human osteoblast-like cells produce nitric oxide and express inducible nitric oxide synthase.

Nitric oxide (NO) is a short-lived free radical that plays an important regulatory role in several biological processes. Cytokines such as interleukin-1, tumor necrosis factor, and interferon-gamma have been shown to stimulate NO production in many cells types. Although these cytokines are known to have potent effects on bone remodeling and osteoblast function, the role of NO as an effector molecule in bone has been little studied. Here we investigate the effects of cytokines and calciotropic hormones on NO production by human osteoblast-like cells (hOB) and the role of NO as a modulator of osteoblast growth. Unstimulated hOB produced little NO, as reflected by measurement of nitrite concentrations in hOB-conditioned medium. NO production was not significantly altered by PTH and 1,25-dihydroxyvitamin D or human recombinant interleukin-1 beta (10 U/ml), tumor necrosis factor-alpha (25 ng/ml), and interferon-gamma (100 U/ml) individually. Combinations of all three cytokines at these concentrations, however, dramatically increased both NO generation and cGMP production. The stimulatory effect of cytokines on NO production began 12 h after exposure and was inhibited by cycloheximide, actinomycin-D, dexamethasone, and the competitive inhibitor of NO synthase L-NG-monomethylarginine. Reverse transcription/polymerase chain reaction analysis of hOB RNA, followed by direct sequencing of the amplified products, showed that hOB express the inducible, rather than the endothelial or neuronal, forms of NO synthase. Cytokine-induced increases in NO production were associated with a marked inhibition of [3H]thymidine uptake to less than 10% of that observed in control cultures. Abrogation of NO synthesis with L-NG-monomethylarginine under these conditions significantly increased [3H]thymidine uptake to approximately 20% of the control value, suggesting that NO may partly be responsible for the inhibition of osteoblast proliferation induced by these cytokines. Our data indicate that proinflammatory cytokines induce NO production in osteoblast-like cells and show and that this mediator plays a role in regulating cell growth. These findings may have important implications for the pathogenesis and management of bone loss in diseases associated with cytokine activation, such as rheumatoid arthritis.

Amino Acid Oxidoreductases↗
PubMed1994

Rat retinal pigment epithelial cells express an inducible form of nitric oxide synthase and produce nitric oxide in response to inflammatory cytokines and activated T cells.

In this report we show that rat retinal pigment epithelial (RPE) cells express an inducible form of nitric oxide synthase (iNOS) and secrete high levels of nitric oxide (NO.) when co-cultured with activated lymphocytes. We have previously shown that cultured rat RPE cells suppress syngeneic lymphocyte proliferation, an effect attributed to prostaglandin E2 (PGE2) secretion by the RPE cells. However supernatants from such co-cultures were also found to contain high levels of nitrite (NO2-), the stable end-product of NO. synthesis. RPE cell secretion of NO. was stimulated by the cytokines interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha), an effect enhanced by endotoxin [lipopolysaccharide (LPS)], reduced by the competitive inhibitor of L-arginine metabolism, NG-monomethyl-L-arginine (L-NMMA) and inhibited by cycloheximide. These effects were dose dependent. Using reverse transcription (RT)/PCR a product of 1398 bp was amplified which showed sequence identity with iNOS cloned from rat vascular smooth muscle. Northern blot analysis of total RNA extracted from rat RPE before and after cytokine stimulation showed induction of a 4.5 kb (kilobase) transcript which hybridized with a 1398 bp (base pair) polymerase chain reaction (PCR)-generated cDNA probe derived from the sequence of rat RPE cell iNOS. These results indicate RPE cells express an inducible form of nitric oxide synthase (NOS) and that high levels of NO. may be produced locally in the eye by the RPE in the presence of activated lymphocytes. Given the cytostatic and cytotoxic properties of this molecule, NO. may play an important role as an inducible mediator of immunosuppressive mechanisms within the microenvironment of the eye at the site of lymphocyte activation.

Amino Acid Oxidoreductases↗
PubMed1994

The effect of antihypertensive therapy on responsiveness to local intra-arterial NG-monomethyl-L-arginine in patients with essential hypertension.

OBJECTIVE: The nitric oxide (NO) system is abnormal in essential hypertension and the response of the forearm vascular bed to local intra-arterial infusions of NG-monomethyl-L-arginine (L-NMMA) is diminished in patients with untreated essential hypertension. Animal data suggest that treatment of hypertension may restore normal NO-mediated responses. We have prospectively examined the effect of standard antihypertensive therapy on the responsiveness to local intra-arterial infusions of L-NMMA in 18 newly diagnosed hypertensive patients. DESIGN: This was a double-blind, randomized, parallel-group study. Patients were randomized to treatment with 10 mg enalapril daily, 5 mg amlodipine daily or matched placebo for 6 weeks (with dose titration after 2 weeks if necessary). METHODS: Forearm blood flow during direct infusion into the brachial artery of L-NMMA (1, 2 and 4 mumol/min) was measured using venous occlusion plethysmography at the beginning and end of the 6-week treatment period. RESULTS: Both enalapril and amlodipine reduced blood pressure significantly compared with placebo. After 6 weeks of antihypertensive therapy, forearm blood flow (+/- SEM) in response to the maximum dose of L-NMMA (4 mumol/min) was reduced by 54.8 (6.9)% (P = 0.012), 58.9 (7.0)% (P = 0.016) and 33.1 (3.0)% (P = 0.17) in the enalapril, amlodipine and placebo groups, respectively. There was no significant difference between enalapril and amlodipine treatment groups. CONCLUSIONS: The forearm arterial responsiveness to L-NMMA in newly diagnosed patients with essential hypertension returns to normal with normalization of blood pressure by antihypertensive drugs with different modes of action. It remains to be determined whether this phenomenon is a consequence of the change in pressure per se or a result of the action of either drug by a common or separate mechanism.

Amlodipine↗
PubMed1993

Induction of nitric oxide synthase in human mesangial cells.

Synthesis of nitric oxide (NO) has been implicated in the development of glomerulonephritis in animal models of the disease. Rat mesangial cells can be stimulated to express an inducible form of NO synthase (NOS) in vitro. Little is known however, about the pathway of induction in human mesangial cells. Here, we report that human mesangial cells require multiple cytokines, unlike rat mesangial cells which require only single stimulants, to produce NO. Our experiments suggest that both interleukin-1 beta (IL-1 beta) and interferon gamma (IFN-gamma) must be present together to elicit a response whilst tumour necrosis factor alpha (TNF-alpha) augments this. The production of nitrite, a stable end product of NO metabolism, was inhibited by NG-monomethyl-L-arginine (L-NMMA), L-nitro-arginine-methyl-ester (L-NAME), cycloheximide and the glucocorticoid dexamethasone.

Amino Acid Oxidoreductases↗
PubMed1993

Evidence for altered platelet nitric oxide synthesis in essential hypertension.

OBJECTIVES: To determine whether platelet aggregation to collagen was abnormal in patients with essential hypertension and whether nitric oxide donors and inhibitors of nitric oxide synthesis affect platelet aggregation differently in hypertensives compared with healthy controls. DESIGN: Platelet aggregation assays were conducted ex vivo from both hypertensive and normal subjects simultaneously. METHODS: Platelet aggregation in response to collagen was measured in platelet-rich plasma from 16 patients with untreated essential hypertension and 16 healthy volunteers matched for age, sex and smoking habits. The effect of sodium nitroprusside (a nitric oxide donor) and NG-monomethyl-L-arginine (L-NMMA), a specific nitric oxide synthase inhibitor, was studied. RESULTS: In healthy controls L-NMMA caused a marked increase in platelet aggregation, whereas in hypertensive patients a small inhibition of aggregation was seen. This was significantly different from the response seen in normal controls. No difference was seen in the aggregatory response to collagen between hypertensive patients and healthy controls. Sodium nitroprusside caused inhibition of aggregation in hypertensive patients and in controls, but there was no significant difference in the degree of inhibition between the two groups. CONCLUSIONS: We conclude that in platelets from hypertensive patients there is a markedly reduced sensitivity to L-NMMA, which could be explained by a reduction in nitric oxide synthesis.

Adult↗
PubMed1992

The effect of endothelium-derived nitric oxide on ex vivo whole blood platelet aggregation in man.

The effects of changes in endogenous endothelium-derived nitric oxide (NO) on forearm blood flow and ex vivo platelet aggregation have been studied in 7 healthy volunteers. Measurements were made of forearm blood flow and ex vivo collagen-stimulated platelet aggregation during unilateral brachial artery infusions of saline, acetylcholine (ACh), NG monomethyl-L-arginine (L-NMMA), and prostacyclin (PGI2). The uninfused arm acted as a control. Forearm blood flow was increased by ACh, an agent which stimulates NO release, and decreased by L-NMMA, an agent which stereospecifically inhibits NO synthesis. Collagen-stimulated platelet aggregation measured ex vivo in whole blood draining the infused arm was unaltered by either ACh or L-NMMA. Conversely, PGI2, an agent which acts independently of NO, caused an increase in forearm blood flow which was accompanied by significant inhibition of platelet aggregation. The results suggest that release of endothelium-derived NO in quantities sufficient to cause substantial changes in blood vessel tone does not lead to changes in platelet aggregation in the blood flowing through the vessels. It is, however, still possible that endothelium-derived NO modulates platelet activity at the level of the endothelium.

Acetylcholine↗
PubMed1991

Vascular responsiveness and cation exchange in insulin-dependent diabetes.

1. We measured forearm blood flow during brachial artery infusions of vasoconstrictors (angiotensin II and noradrenaline) and vasodilators (sodium nitroprusside and carbachol) in 16 healthy control subjects and in 18 patients with uncomplicated insulin-dependent diabetes mellitus. Erythrocyte Na+/Li+ countertransport and platelet Na+/H+ antiport activities were also measured. 2. The mean basal forearm vascular resistance was 22% lower in diabetic patients than in control subjects. The effects of each infusion on forearm vascular resistance were similar in diabetic patients and control subjects. 3. Erythrocyte Na+/Li+ countertransport activities were similar in diabetic patients and control subjects. Platelet Na+/H+ exchange (Vmax) was approximately 40% greater in diabetic patients than in control subjects, whereas the Km for Na+ was similar. 4. In diabetic patients, but not in control subjects, the responses to sodium nitroprusside and carbachol correlated inversely with Na+/Li+ countertransport in erythrocytes (rs = -0.76, P less than 0.001, and rs = -0.66, P less than 0.005, respectively), but not with Na+/H+ exchange in platelets.

Adult↗
PubMed1991

Sensitivity to angiotensin II of forearm resistance vessels in pregnancy.

Resistance vessel sensitivity to angiotensin II in vivo was studied in 13 primigravid normotensive women (16-24 weeks gestation), and in 10 non-pregnant control women. Angiotensin II was infused into the brachial artery at doses of 10, 100, 1,000 and 10,000 fmol min-1 and forearm blood flow measured by plethysmography. Reduction in forearm blood flow at all concentrations of angiotensin II was significantly greater in non-pregnant than in pregnant women. The dose-response relationships, plotted semi-logarithmically, were similar in shape in each group but sensitivity to angiotensin II was reduced in pregnant subjects compared with non-pregnant women. This is most simply explained by an effect of pregnancy on the sensitivity to angiotensin II of vascular smooth muscle in forearm resistance vessels.

Adult↗
PubMed1991

Reduction of LDL cholesterol by pravastatin does not influence platelet activation in patients with mild hypercholesterolaemia at risk of coronary heart disease.

The effect of pravastatin on low density lipoprotein (LDL) cholesterol and platelet activation was studied in 16 patients with mild hypercholesterolaemia who had two or more additional cardiovascular risk factors. Patients were treated with either pravastatin (20-40 mg day-1) or placebo for 1 year. Plasma LDL and urinary excretion of 2,3-dinor-thromboxane B2 (an index of platelet activation in vivo) were determined at 0, 3, 6 and 12 months. There was a significant reduction in LDL at 6 and 12 months (2P less than 0.05) but this was not associated with any significant change in thromboxane metabolite excretion.

Aged↗
PubMed1991

Human vascular smooth muscle cells inhibit platelet aggregation when incubated with glyceryl trinitrate: evidence for generation of nitric oxide.

1. The effect on platelet aggregation of glyceryl trinitrate in the presence of cultured vascular smooth muscle cells was determined turbidometrically. U46619 (a thromboxane mimetic) was used as agonist and experiments were performed in the presence of aspirin. Inorganic nitrite production from glyceryl trinitrate by vascular smooth muscle cells was also measured, to provide an indirect index of nitric oxide synthesis. 2. The combination of vascular smooth muscle cells together with glyceryl trinitrate, at concentrations that had little effect individually, profoundly inhibited platelet aggregation. 3. The inhibitory effect on platelet aggregation of vascular smooth muscle cells together with glyceryl trinitrate was markedly attenuated by haemoglobin, an inhibitor of nitric oxide. 4. These results show that vascular smooth muscle cells inhibit platelet aggregation when exposed to glycerol trinitrate and suggest that this is due to generation of nitric oxide from glyceryl trinitrate by vascular smooth muscle.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗