Docosahexaenoic acid improves the nitroso-redox balance and reduces VEGF-mediated angiogenic signaling in microvascular endothelial cells.

Purpose: Disturbances to the cellular production of nitric oxide (NO) and superoxide (O(2)(-)) can have deleterious effects on retinal vascular integrity and angiogenic signaling. Dietary agents that could modulate the production of these signaling molecules from their likely enzymatic sources, endothelial nitric oxide synthase (eNOS) and NADPH oxidase, would therefore have a major beneficial effect on retinal vascular disease. The effect of ω-3 polyunsaturated fatty acids (PUFAs) on angiogenic signaling and NO/superoxide production in retinal microvascular endothelial cells (RMECs) was investigated.

Statins have beneficial effects on platelet free radical activity and intracellular distribution of GTPases in hyperlipidaemia.

In addition to lowering cholesterol, statins may alter endothelial release of the vasodilator NO and harmful superoxide free radicals. Statins also reduce cholesterol intermediates including isoprenoids. These are important for post-translational modification of substances including the GTPases Rho and Rac.

A randomised interventional trial of omega-3-polyunsaturated fatty acids on endothelial function and disease activity in systemic lupus erythematosus.

Objective: To determine the clinical effect of dietary supplementation with low-dose omega-3-polyunsaturated fatty acids on disease activity and endothelial function in patients with systemic lupus erythematosus.

Methods: A 24-week randomised double-blind placebo-controlled parallel trial of the effect of 3 g of omega-3-polyunsaturated fatty acids on 60 patients with systemic lupus erythematosus was performed. Serial measurements of disease activity using the revised Systemic Lupus Activity Measure (SLAM-R) and British Isles Lupus Assessment Group index of disease activity for systemic lupus erythematosus (BILAG), endothelial function using flow-mediated dilation (FMD) of the brachial artery, oxidative stress using platelet 8-isoprostanes and analysis of platelet membrane fatty acids were taken at baseline, 12 and 24 weeks.

Microcirculatory hemodynamics and endothelial dysfunction in systemic lupus erythematosus.

Objective: Impaired flow-mediated dilation (FMD) occurs in disease states associated with atherosclerosis, including SLE. The primary hemodynamic determinant of FMD is wall shear stress, which is critically dependent on the forearm microcirculation. We explored the relationship between FMD, diastolic shear stress (DSS), and the forearm microcirculation in 32 patients with SLE and 19 controls.

Effects of dietary omega-3 fatty acid supplementation on endothelium-dependent vasodilation in patients with chronic heart failure.

We investigated the effects of omega-3 fatty acids administration on endothelium-dependent vasodilation in patients > or =65 years old who received treatment for chronic heart failure (CHF). Twenty patients (mean age 73 years; 15 men) with grade II and III CHF who were on maximal medical management were recruited. Patients were randomized in a double-blind, crossover fashion to 6 weeks of omega-3 fatty acid (1.

Increased superoxide production in hypertensive patients with diabetes mellitus: role of nitric oxide synthase.

Background: Hypertension and diabetes are important independent risk factors for increased oxidative stress and increased cardiovascular risk. The combination of hypertension and diabetes results in a dramatic increase in cardiovascular risk. Enhanced oxidative stress in hypertension and diabetes is linked to decreased nitric oxide (NO) bioavailability because of its interaction with vascular superoxide (O(2)(*-)), derived predominantly from NAD(P)H-dependent oxidases.

NAD(P)H-dependent superoxide production in platelets: the role of angiotensin II and protein kinase C.

Objectives: Vascular NAD(P)H oxidase represents a major source for excessive superoxide production in hypertension. Angiotensin II (AngII) can activate NAD(P)H oxidase via the angiotensin II type 1 (AT1) receptor and protein kinase C (PKC). Platelets possess AT1 receptors and all the components of the NAD(P)H oxidase system.

Impaired endothelium-dependent and -independent vasodilation in elderly patients with chronic heart failure.

Background: Impaired endothelium-dependent and independent vasodilator responses in chronic heart failure (CHF) have been well described. Previous studies involved younger patients and omitted medications prior to study.

Aims: We explored if new therapeutic interventions would restore vasodilator responses in typical patients with chronic heart failure.

Functional consequences of endothelial nitric oxide synthase uncoupling in congestive cardiac failure.

Background: Impaired endothelium-mediated vasodilatation (EMVD) in congestive cardiac failure (CCF) has been linked to decreased nitric oxide (NO) bioavailability because of its interaction with vascular superoxide (O2*-), derived predominantly from NAD(P)H-dependent oxidases. When uncoupled from essential cofactors, endothelial nitric oxide synthase (eNOS) produces O2*-. We studied the functional consequences of eNOS uncoupling in relation to EMVD in patients with CCF.

Platelet nitric oxide and superoxide release during the development of nitrate tolerance: effect of supplemental ascorbate.

Background: The therapeutic benefits that accompany the continuous administration of organic nitrates are attenuated by the development of tolerance to the compounds. Altered superoxide production and NO bioavailability have been implicated in contributing to the development of tolerance, an effect that may be ameliorated by the administration of antioxidants.

Methods And Results: We studied the effect of 3 days of continuous transdermal administration of nitroglycerin (NTG) (10 mg/24 hours) on platelet free radical (NO and superoxide anion [O2*-] activity) with and without coadministration of supplemental ascorbate (2.

Pharmacological analysis of established ventricular fibrillation.

1. The effects of anti-arrhythmic drugs on the power spectrum of established ventricular fibrillation induced by endocardial electrical stimulation, have been studied in greyhounds anaesthetized with sodium pentobarbitone (35 mg kg-1, i.v.

The relationship between clinical and biochemical changes following neuroleptic treatment in schizophrenia.

Clinical improvement in psychotic symptoms is not immediate when neuroleptic treatment is commenced. Previous studies have demonstrated the development of biochemical tolerance to the effects of neuroleptics on the dopamine system. This study demonstrates a relationship between this biochemical change and the clinical changes occurring in the patients.

Pharmacokinetics of praziquantel in healthy volunteers and patients with schistosomiasis.

The pharmacokinetics of a novel praziquantel preparation (Distocide) were investigated in Sudanese patients with hepatosplenic schistosomiasis and in healthy volunteers, and compared with those of Biltricide. The results of the first study indicated greater (P less than 0.05) plasma concentrations of Biltricide at 1.

Short-term effects of alcohol on peripheral blood flow, platelet aggregation and noradrenaline output in normal man.

The effects of acute oral administration of alcohol on finger and forearm blood flow, platelet aggregation and plasma noradrenaline were examined over a three-hour period in a group of healthy male volunteers. Finger blood flow was increased at 15, 30 and 60 min and skin temperature was raised at 30 and 60 min. Digital systolic blood pressure was decreased at 15 and 30 min.

The effect of electroconvulsive therapy on CSF amine metabolites in schizophrenic patients.

The effects of a series of six ECT treatments were observed on the CSF concentrations of HVA, MHPG, and 5-HIAA in 12 patients suffering from schizophrenia. Four patients were previously neuroleptic drug-free, and eight had received only oral neuroleptic drugs at the same dose for more than 4 weeks. A significant increase in the concentration of HVA was observed after the first ECT treatment but not after the final treatment.

Recombinant human interferon alpha increases oestrogen receptor expression in human breast cancer cells (ZR-75-1) and sensitizes them to the anti-proliferative effects of tamoxifen.

Exposure of ZR-75-1 human breast cancer cells for 48 h to human recombinant interferon alpha (IFN alpha) resulted in increased expression of oestrogen receptors as measured in a whole cell binding assay. This effect was inversely proportional to dose being significant following treatment with 10-100 IU IFN ml-1 and was only observed at a low initial cell plating density. The extent of the increase in oestrogen receptor levels ranged from 1.

The effect of chronic captopril therapy on adrenergic receptors, plasma noradrenaline and the vascular responses to infused noradrenaline.

Adrenergic receptors (alpha 2, beta 2), plasma noradrenaline, heart rate and the pressor responsiveness to infused noradrenaline were examined in ten healthy male volunteers before and after 2 weeks of placebo or captopril therapy in a double blind cross-over study. No significant differences in these measurements were observed between the captopril and placebo treated groups. The study shows that in sodium replete normotensive subjects, long-term angiotensin converting enzyme inhibition does not lead to changes in adrenoceptor density.

The effects of propranolol and digoxin on the acute vascular responses to frusemide in normal man.

To examine the importance of acute frusemide-induced renin release in the production of the acute peripheral venous and arterial responses to frusemide in man, the effects of two drugs, previously described as inhibitors of acute frusemide-induced renin release, propranolol and digoxin, were examined. Propranolol abolished the acute increases in venous capacitance and blood pressure and attenuated the increases in forearm vascular resistance produced by frusemide. The acute increases in plasma renin activity and plasma aldosterone concentrations were also abolished.

Effect of indoramin, labetalol and alinidine on sympathetic function in normal man.

The effects of single oral doses of indoramin (mean dose 58 mg), abetalol (mean dose 150 mg), alinidine 80 mg and placebo on arterial pressure and heart rate in the supine and standing positions were studied in six normal volunteers. Doses were chosen to give equivalent reductions of arterial pressure in the standing position. Observations were made before and at 2 and 4 h after drug administration.

The dose-response characteristics of the acute non-diuretic peripheral vascular effects of frusemide in normal subjects.

The peripheral venous and arterial effects of frusemide, plasma renin activity and plasma frusemide concentrations were examined during the 15 min period following the i.v. administration of 0, 5, 10, 20, 40 and 80 mg of frusemide in a group of nine salt depleted volunteers.

Differential blockade of alpha-adrenoceptors by indoramin.

The effect of equihypotensive single oral doses of indoramin (mean dose 67 mg), phenoxybenzamine (mean dose 50 mg), hydralazine (mean dose 133 mg) and placebo on arterial pressure and heart rate in the supine and standing position was studied in six normal volunteers. Observations were made before and at 2 and 4 h after drug administration. Plasma noradrenaline (NA) was measured at each time interval in the supine position, and after 4 min of standing.

The effects of captopril on the acute vascular responses to frusemide in man.

To examine the importance of angiotensin II formation in the production of frusemide's acute peripheral venous and arterial responses, the effect of pretreatment with captopril was studied. Captopril abolished the acute increases in venous capacitance and blood pressure and attenuated the increases in forearm vascular resistance produced by intravenous frusemide. The study provides evidence that angiotensin II formation performs an essential role in the production of the acute vascular effects of frusemide in man.

Pharmacokinetics of sotalol during pregnancy.

Sotalol, a beta-adrenoceptor blocking drug, was administered to 6 healthy pregnant volunteers between 32-36 weeks gestation and when at least 6 weeks post-partum. On both occasions, each volunteer was given sotalol 100 mg intravenously and 400 mg orally in randomised order with at least a 1 week washout period between. Plasma samples were analysed for sotalol using a fluorometric method and the pharmacokinetic profiles investigated.

Observation on the efficacy and pharmacokinetics of betaxolol (SL 75212), a cardioselective beta-adrenoceptor blocking drug.

1 Observations were made in five subjects who exercised before and at 2, 3, 6, 8, 24, 33 and 48 h after the oral administration of placebo and 5, 10, 20 and 40 mg betaxolol. 2 The exercise heart rate remained constant at all times after the placebo. All doses of betaxolol significantly reduced the exercise tachycardia at all times.