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Background: Patients with chronic cardiac failure (CCF) have abnormal vascular responses. Bradykinin (BK) is thought to contribute to the vasodilator effects of ACE inhibitors, but the effect of BK itself in patients with CCF has not been examined. Methods: We studied the responses to infused BK at 10, 30 and 100 pmol min−1 in patients with CCF (n-10) and controls (n-10). The slope of the dose-response curve was used for comparisons between the groups. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. Results: Following BK, vasodilatation was observed in both groups as the slopes were positive in all, but the difference between the groups was not significant (P-0.77). The study was repeated with the co-administration of 4 μmol min−1 of NG-monomethyl l-arginine (l-NMMA). The vasodilator response to BK was reduced in both groups, and the effect was somewhat greater in the patient group (P-0.23). The vasodilator response to the endothelium-independent vasodilator sodium nitroprusside was slightly less in the patient group (P-0.08). The patients only then underwent repeat infusion of BK before and after a single oral dose of captopril 12.5 mg or placebo. Following captopril, the vasodilator response to BK was unchanged when compared to placebo (difference between slopes, P-0.53). Conclusions: BK produces dose-dependent vasodilatation in both patients with CCF and controls; there was no difference in the responses, which were antagonised by l-NMMA and therefore in part NO (endothelium)-dependent. The responses were also unchanged after administration of an ACE inhibitor (captopril).

BACKGROUND—Raised homocysteine is a risk factor for vascular disease. Homocysteine is formed from methionine, and dietary manipulation of homocysteine in primates and humans with oral methionine is associated with endothelial dysfunction. A cause-effect relation has not been clearly established. AIM—To study the effect of oral methionine and then oral homocysteine on endothelial function. METHODS—22 healthy adults were recruited for two randomised crossover studies, each containing 11 subjects. Endothelial function was determined by measuring forearm blood flow in response to intra-arterial infusion of acetylcholine (endothelium dependent) and sodium nitroprusside (endothelium independent). Subjects received methionine or placebo (study 1), or homocysteine or placebo (study 2). Methionine and homocysteine were determined at baseline and t = 4 hours. Endothelial function was determined at four hours. The responses to the vasoactive substances are expressed as the area under the curve of change in forearm blood flow from baseline. RESULTS—Study 1: plasma methionine and homocysteine concentrations increased significantly versus placebo. The increases were associated with a reduction of endothelium dependent responses (mean (95% confidence interval), arbitrary units), from 48.8 (95% CI 36.4 to 61.2) to 29.9 (95% CI 18.0 to 41.1), p

The haemodynamic hypothesis for the pathogenesis of diabetic microangiopathy argues that an initial increase in microvascular blood flow leads to microvascular sclerosis and disturbed autoregulation. Endothelin-1 (ET-1) is an endothelium-derived vasoconstrictor peptide that contributes to basal vascular tone. Impairment of the vasoconstrictor response to ET-1 could result in hyperperfusion and subsequent microvascular damage. The purpose of this study was to determine whether vascular responses to ET-1 are impaired in patients with non-insulin-dependent diabetes mellitus (type 2 diabetes). Ten patients with type 2 diabetes and nine control subjects underwent brachial artery cannulation. Forearm blood flow was measured using strain-gauge venous occlusion plethysmography. ET-1 in three doses of 5, 10, and 20 pmol/min and 0.9% saline placebo was infused in a balanced double-blind randomised manner. Vascular smooth muscle function also was assessed using sodium nitroprusside. Control subjects showed vasoconstriction to ET-1 of 5 (p0.05), 10 (p0.05), and 20 pmol/min (p0.01). In the diabetic group, there was no significant response to ET-1 at 5 pmol/min (p0.05); however, significant vasoconstriction developed at 10 and 20 pmol/min (p0.01). There was a significant difference in response to ET-1 at 5 pmol/min between the diabetic and control groups (p0.05). Responses to sodium nitroprusside were similar in both groups (p0.05). Patients with type 2 diabetes have a blunted vasoconstrictor response to ET-1 despite preserved vascular smooth muscle function.

Use non-pharmacological measures in all hypertensive and borderline hypertensive people. Initiate antihypertensive drug therapy in people with sustained systolic blood pressures (BP)/=160 mm Hg or sustained diastolic BP/=100 mm Hg. Decide on treatment in people with sustained systolic BP between 140 and 159 mm Hg or sustained diastolic BP between 90 and 99 mm Hg according to the presence or absence of target organ damage, cardiovascular disease or a 10-year coronary heart disease (CHD) risk of/=15% according to the Joint British Societies CHD risk assessment programme/risk chart. In people with diabetes mellitus, initiate antihypertensive drug therapy if systolic BP is sustained/=140 mm Hg or diastolic BP is sustained/=90 mm Hg. In non-diabetic hypertensive people, optimal BP treatment targets are: systolic BP140 mm Hg and diastolic BP85 mm Hg. The minimum acceptable level of control (Audit Standard) recommended is150/90 mm Hg. Despite best practice, these levels will be difficult to achieve in some hypertensive people. In diabetic hypertensive people, optimal BP targets are; systolic BP140 mm Hg and diastolic BP80 mm Hg. The minimum acceptable level of control (Audit Standard) recommended is140/90 mm Hg. Despite best practice, these levels will be difficult to achieve in some people with diabetes and hypertension. In the absence of contraindications or compelling indications for other antihypertensive agents, low dose thiazide diuretics or beta-blockers are preferred as first-line therapy for the majority of hypertensive people. In the absence of compelling indications for beta-blockade, diuretics or long acting dihydropyridine calcium antagonists are preferred to beta-blockers in older subjects. Compelling indications and contraindications for all antihypertensive drug classes are specified. For most hypertensives, a combination of antihypertensive drugs will be required to achieve the recommended targets for blood pressure control. Other drugs that reduce cardiovascular risk must also be considered. These include aspirin for secondary prevention of cardiovascular disease, and primary prevention in treated hypertensive subjects over the age of 50 years who have a 10-year CHD risk/=15% and in whom blood pressure is controlled to the audit standard. In accordance with existing British recommendations, statin therapy is recommended for hypertensive people with a total cholesterol/=5 mmol/L and established vascular disease, or 10-year CHD risk/=30% estimated from the Joint British Societies CHD risk chart. Glycaemic control should also be optimised in diabetic subjects. Specific advice is given on the management of hypertension in specific patient groups, ie, the elderly, ethnic subgroups, diabetes mellitus, chronic renal disease and in women (pregnancy, oral contraceptive use and hormone replacement therapy). Suggestions for the implementation and audit of these guidelines in primary care are provided.

Objective—To study underlying vascular responses in chronic heart failure in patients without ACE inhibitor treatment, and to compare them with age matched controls. Design—Forearm blood flow was studied using venous occlusion plethysmography in patients with chronic heart failure (n = 12) and matched controls (n = 13), after infusion of L-NMMA (a nitric oxide synthase inhibitor), glyceryl trinitrate (an endothelium independent vasodilator), and serotonin (an endothelium dependent vasodilator). Results—L-NMMA produced significant vasoconstriction in normal subjects (forearm blood flow reduced by 24%), but not in patients (6%; difference between groups p

In conventional doses, thiazide diuretics impair glucose tolerance and decrease insulin sensitivity, making them an unpopular choice for treating diabetic patients with hypertension. However, use of low-dose thiazide diuretics may avoid the adverse metabolic effects seen with conventional doses. In a double-blind, randomised crossover study we assessed peripheral and hepatic insulin action in 13 hypertensive non-insulin-dependent diabetic patients after a 6-week placebo run-in and following two 12-week treatment periods with either low (1.25 mg) or conventional (5.0 mg) dose bendrofluazide. There were no differences between doses in their effects on systolic and diastolic blood pressure. Bendrofluazide 1.25 mg had significantly less effect on serum potassium, uric acid, fasting glucose and HbA1c concentrations than the 5.00 mg dose. Exogenous glucose infusion rates required to maintain euglycaemia were significantly different between doses (p < 0.05) with conventional-dose bendrofluazide worsening peripheral insulin resistance compared to baseline (23.8±2.9 vs 27.3±3.5 μmol · kg-1 · min-1, p< 0.05) and low-dose bendrofluazide producing no change compared to baseline (26.8±3.6 vs 27.3±3.5 μmol · kg-1 · min-1, p = NS). Postabsorptive endogenous glucose production was higher on treatment with bendrofluazide 5.0 mg compared to 1.25 mg (11.7 ±0.5 vs 10.2±0.3 μol · kg-1 · min-1 p < 0.05) and suppressed to a lesser extent following insulin (4.0±0.7 vs 2.0±0.4 μ±mol · kg-1 · min-1, p < 0.05). Treatment with bendrofluazide 5.0 mg increased postabsorptive endogenous glucose production compared to baseline (11.7±0.5 vs 10.6±0.4 μmol · kg-1 · min-1, p

Objective: To see whether low dose thiazide diuretics given to patients with essential hypertension might avoid the adverse metabolic consequences seen with conventional doses. Design: Double blind randomised crossover study of two 12 week treatment periods with either low dose (1.25 mg) or conventional dose (5.0 mg) bendrofluazide given after a six week placebo run in period. Setting: Outpatient clinics serving the greater Belfast area. Subjects: 16 white non-diabetic patients (9 male) under 65 with essential hypertension recruited from general practices within the greater Belfast area. Main outcome measures: Systolic and diastolic blood pressure and peripheral and hepatic insulin action. Results: One man failed to complete the study. There were no differences between doses in their effects on systolic and diastolic blood pressure. Bendrofluazide 1.25 mg had substantially less effect20on serum potassium concentration than the 5.0 mg dose. There were no intertreatment differences in fasting glucose, insulin, cholesterol, and triglyceride concentrations. Bendrofluazide 5.0 mg significantly increased postabsorptive endogenous glucose production compared with baseline (mean 10.9 (SD 1.2) v 10.0 (0.8) μmol/kg/min), whereas bendrofluazide 1.25 mg did not. Postabsorptive endogenous glucose20production was significantly higher with bendrofluazide 5.0 mg compared with 1.25 mg (10.9 (1.2) v 9.9 (0.8) μmol/kg/min) but was suppressed to a similar extent after insulin (bendrofluazide 5.0 mg202.8 (1.5) μmol/kg/min v bendrofluazide 1.25 mg 2.2 (1.5) μmol/kg/min). Exogenous glucose infusion rates required to maintain euglycaemia were not significantly different between doses and were20similar to baseline. Conclusions: Bendrofluazide 1.25 mg is as effective as conventional doses but has less adverse metabolic effect. In contrast with conventional doses, how dose bendrofluazide has no effect on hepatic insulin action. There is no difference between low and conventional doses of bendrofluazide in their effect on peripheral insulin sensitivity.

The endothelium plays a pivotal role in modulating the reactivity of vascular smooth muscle through the formation of several vasoactive substances. We examined the effects of endothelium-dependent and independent vasodilators on forearm blood flow in 29 patients with Type 2 (non-insulin-dependent) diabetes mellitus and in 21 control subjects, using venous occlusion plethysmography. Via a brachial artery cannula, increasing amounts of acetylcholine and glyceryl trinitrate were infused in doses of 60, 120, 180 and 240 mmol per min and 3, 6 and 9 nmol per min respectively. NG monomethyl-L-arginine, a stereospecific inhibitor of endothelium derived relaxing factor, was infused to inhibit basal and stimulated release of this dilator substance. Reactive hyperaemic forearm blood flow did not differ between groups. Forearm blood flow responses to each dose of acetylcholine were significantly greater in control than diabetic subjects (p less than 0.01 for all doses). NG monomethyl-L-arginine attenuated forearm blood flow from maximal stimulated values when responses were compared with the natural decline to acetylcholine in forearm flow in both control and diabetic subjects (p less than 0.05 for both groups), but had no effect on basal blood flow responses. Forearm blood flow responses to each dose of glyceryl trinitrate were significantly greater in control than diabetic subjects (p less than 0.05 for all). These data provide evidence for endothelial and smooth muscle dysfunction in diabetes which may have important therapeutic implications.

Aims To determine the role of nitric oxide (NO) in forearm reactive hyperaemia in healthy human subjects. Methods Ten healthy subjects aged 19–34 years underwent brachial artery cannulation. Forearm circulatory arrest was achieved by means of an upper arm cuff inflated to 200 mmHg for 5 min. The blood flow responses during reactive hyperaemia were measured using venous occlusion plethysmography following a 10 min intra-arterial influsion of 8 μmol min−1N-monomethyl l-arginine (-NMMA) and following matching placebo administered in random order. Results were analysed by repeated measures anova and t-tests. Results -NMMA resulted in a significant reduction of basal forearm blood flow indicating inhibition of basal NO release (P=0.005). There was no significant difference between the blood flow responses during reactive hyperaemia following -NMMA and placebo (P=0.97). Conclusions Nitric oxide production does not make a significant contribution to the vasodilatation associated with reactive hyperaemia in the human forearm.

1. Since salt depletion stimulates the renal prostaglandin system to maintain renal function, the effects of indomethacin and ibuprofen upon renal haemodynamics, electrolyte excretion and renin release were examined in eight healthy male volunteers on a salt restricted diet, before and after frusemide administration. 2. Neither indomethacin (50 mg) nor ibuprofen (400 mg and 800 mg) affected renal blood flow, glomerular filtration rate or electrolyte excretion before frusemide. 3. Renal blood flow and glomerular filtration rate were significantly increased in the first 20 min after frusemide. These changes were significantly attenuated by indomethacin compared with placebo and ibuprofen 400 mg. Frusemide-induced diuresis but not natriuresis was inhibited by all treatments. 4. Both nonsteroidal agents inhibited equally the rise in renin activity seen after frusemide. 5. In this group of healthy volunteers on a salt restricted diet, ibuprofen and indomethacin had no detrimental effects on renal function in the absence of frusemide. The changes in renal haemodynamics due to frusemide were suppressed more by indomethacin than by ibuprofen, probably reflecting the more potent nature of indomethacin as an inhibitor of prostaglandin synthesis.

Vasodilation to acetylcholine is mediated at least in part by endothelium-derived hyperpolarising factor (EDHF) which causes membrane hyperpolarisation by activating potassium channels. It is however uncertain which potassium channel mediates this effect. The aim of this study was to determine the role of the potassium-ATP (K(+)-ATP) channel in mediating endothelium-dependent vascular responses to acetylcholine.In 10 healthy volunteers acetylcholine, an endothelium-dependent vasodilator, and sodium nitroprusside as a control assessing endothelium-independent vasodilatation were infused into the non-dominant brachial artery. Forearm blood flow (FBF) in response to each dose was measured by strain-gauge venous occlusion plethysmography. The K(+)-ATP channel blocker glipizide (2.5 mg) was then administered orally. After 45 min the infusions with FBF measurements were repeated.Acetylcholine (P0.01) and sodium nitroprusside (P0.01) both caused an increase in FBF. There was no significant difference in vascular responses to acetylcholine (P0.05) or sodium nitroprusside (P0.05) following K(+)-ATP channel blockade.The K(+)-ATP channel does not modulate forearm arteriolar endothelium-dependent responses in healthy volunteers and therefore does not play a role in membrane hyperpolarisation.

The involvement of cyclooxygenase-derived substances in the forearm arteriolar responses to serotonin was determined in 10 healthy male volunteers. Serotonin was infused in five incremental doses (0.003-30 micrograms min-1) for 2 min each into the brachial artery of the non-dominant forearm. Forearm blood flow (FBF) responses to each dose were measured by strain-gauge venous occlusion plethysmography. The cyclooxygenase inhibitor indomethacin (100 mg) was administered orally following the serotonin infusions. After 90 min the serotonin infusions were repeated and FBF responses measured. Serotonin caused a biphasic response with vasodilatation occurring at low doses (0.003-3 micrograms min-1, P < 0.01) and vasoconstriction occurring at the highest dose (P < 0.01). There was no significant difference in vascular response to serotonin following cyclooxygenase inhibition. In conclusion, cyclooxygenase products are not involved in the forearm vascular responses to serotonin in healthy human subjects.

Microvascular disease is an important cause of morbidity in diabetes. There is evidence that impaired autoregulation of blood flow is involved in the pathogenesis of diabetic microangiopathy. The vascular endothelium plays a central role in the regulation of vascular tone. Endothelin (ET)-1 is a potent endothelium-derived vasoconstrictor substance that contributes to basal vascular tone. Impaired vasoconstriction in response to endogenous ET could result in hyperperfusion and subsequent microvascular damage. The purpose of our study was to determine whether vascular responses to locally administered ET-1 are impaired in NIDDM. Nine patients with NIDDM and 12 control subjects underwent cannulation of the nondominant brachial artery. Forearm blood flow (FBF) was measured at baseline and during the drug infusion using strain-gauge venous occlusion plethysmography. ET-1 (5 pmol/min) was infused for 60 min at a rate of 1 ml/min. FBF was measured during the first 5 min of the infusion and at 5-min intervals thereafter. Results were expressed as change in FBF from baseline (ml.100 ml−1 · min−1) and were analyzed using repeated measures analysis of variance and Dunnett's test of multiple comparisons. Control subjects showed a gradual onset of vasoconstriction in response to ET-1, which reached maximum at 35 min (1.1 ml.100 ml−1 · min−1; P < 0.01). There was no reduction in FBF in response to ET-1 in the diabetic group. The differences between the diabetic and control groups were significant (P < 0.03). In conclusion, ET-1 infused locally at 5 pmol/min does not cause vasoconstriction in patients with NIDDM.

OBJECTIVE--To determine the use of new drugs in one United Kingdom region. DESIGN--Examination of data on prescribing of angiotensin converting enzyme inhibitors, new broad spectrum antibiotics, and H2 receptor antagonists. Calculation of number of defined daily doses prescribed each month. SETTING--All general practices in Northern Ireland. MAIN OUTCOME MEASURES--Drug use index and market share of each drug. RESULTS--During 1988-91 prescribing of angiotensin converting enzyme inhibitors increased by 126%, of H2 receptor antagonists by 46%, and of new antibiotics by 207%. The first drug on the market usually retained the largest market share. Use of oral antibiotics increased threefold irrespective of the reporting policy of the general practitioners' local laboratory. CONCLUSIONS--The increase in prescribing of these drugs seems to be greater than can be accounted for by an increase in patients with specific indications for these drugs. This suggests that the profession has not instituted effective checks to ensure that the legitimate promotion of new products does not lead to inappropriate and wasteful use.

BACKGROUND--An association between hypertension and obstructive sleep apnoea (OSA) has been found by some researchers but remains controversial. Since such an association would have important implications for the investigation and management of hypertension, the rate of nocturnal hypoxaemic episodes has been compared in hypertensive and normotensive men. METHODS--The study was carried out in the community in Belfast and its environs. Thirty four men with mild to moderate hypertension aged 40-64 years were identified from general practice and a hypertension clinic. Normotensive men, matched for age and body mass index, were selected from a community survey. Subjects answered a sleep questionnaire and underwent overnight pulse oximetry at home. Computer analysis of the results gave the number and magnitude of dips in oxygen saturation (SaO2 dips, 4% or greater). RESULTS--The median number of SaO2 dips/hour for hypertensives was 2.0, and for normotensives was 0.8. Lowest SaO2 and mean SaO2 levels were significantly lower in the hypertensive group. Only one subject had a rate of SaO2 dips/hour greater than five and symptoms suggestive of OSA. CONCLUSIONS--Both hypertensive and normotensive men had relatively few episodes of nocturnal hypoxaemia. The small increase in the rate of SaO2 dips in hypertensive subjects has not yet been fully explained. These results imply that OSA is not common in hypertensive subjects and is unlikely to be an important cause of hypertension.

This article summarises the new British Hypertension Society guidelines for management of hypertension, which have been published in full.1 Since the previous guidelines 2 3 much new evidence has emerged on optimal blood pressure targets4; management of hypertension in diabetic patients4–7; treatment of isolated systolic hypertension8; comparison of the antihypertensive efficacy and tolerability of different drug classes9–11; the role of non-pharmacological measures for prevention 12 13 and treatment of hypertension14; and additional benefits associated with the use of aspirin and statins. Of concern is that national surveys continue to reveal incomplete detection, treatment, and control of hypertension.15 Furthermore, treated hypertensive patients still die prematurely from cardiovascular disease.16 These guidelines aim to present the best currently available evidence on hypertension management and their implementation. #### Summary points Use non-pharmacological measures in all hypertensive and borderline hypertensive people Initiate antihypertensive drug treatment in people with sustained systolic blood pressure ≥160 mm Hg or sustained diastolic blood pressure ≥100 mm Hg Decide on treatment in people with sustained systolic blood pressure between 140 and 159 mm Hg or sustained diastolic blood pressure between 90 and 99 mm Hg according to the presence or absence of target organ damage, cardiovascular disease, diabetes, or a 10 year coronary heart disease risk ≥15% according to the Joint British Societies coronary heart disease risk assessment programme or risk chart Optimal blood pressure treatment targets are systolic blood pressure

We present a case of non-specific vasculitis presenting as a pyrexia of unknown origin to illustrate the diagnostic difficulty which can arise with this condition. The diagnostic event was central retinal artery occlusion and the disease was also associated with pyoderma gangrenosum. History, examination, investigations and management are discussed.

EDITOR, - Three letters1 comment on our article on the market penetration of new drugs in Northern Ireland.2 J P Griffin attacks our article as flawed in its conclusions without revealing the flaws.1 We did not state that it was “always the first medicine in the field which continues to be…the market leader.” We did not advocate that the search for better products in the same therapeutic class should not be pursued. We …

Decreased release of nitric oxide from damaged endothelium is responsible for the impaired endothelium-dependent vasodilator responses found in animal models of vascular disease. Dietary supplementation with fish oils has been shown to augment endothelium-dependent relaxations, principally by improving the release of nitric oxide from injured endothelium. Using forearm venous occlusion plethysmography we studied vascular responses to 60, 120, 180 and 240 nmol/min of acetylcholine (an endothelium-dependent vasodilator) and 3, 6 and 9 nmol/min of glyceryl trinitrate (an endothelium-independent vasodilator) infused into the brachial artery in 23 patients with Type 2 (non-insulin-dependent) diabetes mellitus. NG monomethyl-L-arginine was employed to inhibit stimulated and basal release of nitric oxide from the endothelium. On completion of the baseline studies patients randomly received either fish oil or matching olive oil capsules in a double-blind crossover fashion for 6 weeks followed by a 6-week washout period and a final 6-week treatment phase. Studies, identical to the initial baseline studies, were performed at the end of the active treatment periods at 6 and 18 weeks. Fish oil supplementation significantly improved forearm blood flow responses to each dose of acetylcholine when compared to the vasodilator responses recorded at baseline and after olive oil administration (p < 0.01). Neither fish oil nor olive oil supplementation produced any significant changes in forearm blood flow to the incremental infusions of glyceryl trinitrate when compared with responses recorded during the baseline studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Paracetamol is an effective, simple analgesic that is well tolerated by adults and children at therapeutic doses. In many countries it is available without prescription. Unfortunately, its ready availability is associated with episodes of poisoning that prompt 3.3% of inquiries to US regional poisons centres,1 10% of inquiries to the UK National Poisons Information Service,2 and up to 43% of all admissions to hospital with self poisoning in the United Kingdom.3 In the United States paracetamol alone accounted for 4.1% of deaths from poisoning reported to American poisons centres in 1997.1 Most deaths are associated with deliberate self poisoning, but therapeutic misadventures do occur rarely, in both adults and children...

Focal points □ It is estimated that only 50 per cent of hypertensive patients adhere to medication regimens □ In this study evaluation of self-efficacy and the theory of planned behaviour was used to identify psychosocial factors which impact on patient adherence to antihypertensives □ High self-efficacy, intentions to comply with the medication regimen, possessing a positive attitude towards taking medication, perceiving pressure from significant others to take medication as prescribed, and perceiving control over taking medication were determinants of good adherence □ The successful identification of factors which influence adherence will allow health-care providers to implement interventions, aimed at enhancing adherence with antihypertensive medication.

A low dose atenolol/bendrofluazide combination in patients with mild to moderate hypertension

Previous biochemical and clinical data suggest there may be an interaction between digoxin and lithium. The pharmacodynamics and pharmacokinetics of an intravenous infusion of digoxin were studied in six male subjects before and after 2 weeks treatment with lithium carbonate. The effects of lithium on sodium pump activity, intracellular electrolytes and extracellular electrolytes were studied. No significant interaction between digoxin and lithium was found. No significant effects of lithium on sodium pump activity or electrolyte concentrations were found.

Animal experiments have suggested that salt-balance, prostaglandin synthesis, and renal function are important determinants of the nondiuretic vascular effects of furosemide. To investigate the influence of these factors in humans, we studied 10 normal volunteers and five anephric patients. The volunteers were studied on three occasions: when on a 10 mEq/day sodium diet, on a 250 mEq/day sodium diet, and on a 10 mEq/day sodium diet with indomethacin, 200 mg/day. The anephric patients were studied immediately after dialysis. Plethysmographic methods were used to measure venous capacitance and blood flow in the calf before, and at 5, 10, and 15 minutes after furosemide, 80 mg, iv. Blood was obtained before and 15 minutes after furosemide for determination of plasma renin activity by radioimmunoassay and of plasma 6-keto-prostaglandin F1 alpha by chromatography-mass spectrometry. We found that furosemide significantly increased venous capacitance in the calf of the normal volunteers on a low salt diet. Indomethacin, high salt intake, or lack of renal function was sufficient to inhibit this effect. Plasma renin activity increased only in the group that had the increase in venous capacitance. Limb blood flow decreased gradually in the 15 minutes following administration of furosemide in the normal volunteers, regardless of salt balance or indomethacin, but remained unchanged in the anephric patients. Plasma 6-keto-prostaglandin F1 alpha was less than 30 pg/ml in all samples. Indomethacin concentration averaged 1.3 micrograms/ml in volunteers on the drug. To determine whether indomethacin, salt intake or renal function affected another venodilator, we studied an additional group of normal and uremic volunteers who received 0.6 mg nitroglycerin sublingually.(ABSTRACT TRUNCATED AT 250 WORDS)

A total of 136 patients with mild to severe uncomplicated essential hypertension were evaluated in a multicenter, randomized, double-blind, double-placebo, parallel study to compare the effect of lisinopril, a new angiotensin-converting enzyme inhibitor, with that of nifedipine. Following a 2-week placebo control period the patients were treated with either 20-80 mg/day of lisinopril (n = 89) or with 40-80 mg/day of nifedipine (n = 47). Blood pressure was significantly reduced in both groups after 4, 8, and 12 weeks of treatment. There was no difference in the effect of lisinopril compared to nifedipine. No serious clinical or laboratory adverse experiences were observed during the study. The incidence of clinical side effects was significantly lower in the lisinopril group than in the nifedipine group (21.3 vs. 48.9%, p less than or equal to 0.01). There were no significant changes in laboratory data in either group. The results indicate that lisinopril is as effective as nifedipine in the treatment of uncomplicated essential hypertension and that lisinopril is well tolerated and has an acceptable safety profile.

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. The responses to 80 mg frusemide given orally during the 1 1 h period after administration were also examined. Increases in venous capacitance 5 min after administration of 5 and 10 mg frusemide were observed (P less than 0.05) but no significant increases were apparent after the higher doses. At 10 min, the increases in venous capacitance showed a flat dose response effect with significant increases throughout the dose range (5-80 mg). Decreases in forearm blood flow occurred at 5 and 10 min after frusemide administration at all the doses studied (P less than 0.05) while blood pressure responses at 10 min showed increasing effect with increasing dose. An oral dose of 80 mg frusemide produced a rise in venous capacitance 15 min after administration and a decrease in forearm blood flow during the period 15-60 min without any alteration in heart rate or blood pressure.

1. In a fourway double-blind placebo controlled study, the effects of cilazapril, a new angiotensin converting enzyme inhibitor, on renal function and the responses to intravenous frusemide were studied in a group of twelve salt depleted male volunteers. 2. Cilazapril produced an increase in effective renal plasma flow and urinary output of prostaglandin E2 metabolite (PGE2-M) but no effect on sodium, potassium or water excretion. 3. Pretreatment with cilazapril antagonised the effects of frusemide on glomerular filtration, PGE2-M and sodium excretion.

In a double-blind, placebo controlled, randomised parallel study we investigated the antihypertensive activity and metabolic adverse effects of three doses of cyclopenthiazide in 53 patients with mild hypertension. After a 4 week placebo washout period, patients with diastolic blood pressures between 90-110 mm Hg were randomly assigned to receive 50 micrograms, 125 micrograms and 500 micrograms of cyclopenthiazide or matching placebo, over an 8 week active treatment period. Blood pressure was recorded at 2 weekly intervals during the trial. Venous samples were taken for evaluation of drug effect on indices of carbohydrate and lipid metabolism just prior to, and on completion of, the active treatment period. Systolic and diastolic blood pressure decreased significantly (P less than 0.05) with the 125 micrograms and 500 micrograms doses of cyclopenthiazide. No change was apparent in any index of glucose and lipid metabolism over time. Low and conventional doses of cyclopenthiazide lower blood pressure without alteration to the metabolic profile in the short term.

A double-blind placebo-controlled crossover trial of digoxin withdrawal was undertaken in 22 patients with sinus rhythm who had a previous history of frank heart failure and were taking therapeutic doses of the drug. During the course of the study, 14 patients showed no clinical change whether taking digoxin or placebo, five patients deteriorated on placebo (four with heart failure and one with supraventricular tachycardia), and three on digoxin (two with heart failure and one with digoxin toxicity). These differences were not statistically significant. Compared to placebo, patients, while taking digoxin, had lower resting heart rates and significant shortening of all the systolic time intervals. The drug appears to exert a sustained positive inotropic effect during maintenance therapy, but this is not of clinical benefit to the majority of patients.

The acute peripheral vascular and diuretic effects of intravenous frusemide 10 mg and 20 mg were compared with those of bumetanide 250 micrograms and 500 micrograms in a group of 10 salt depleted volunteers. Significant reductions in forearm blood flow (FBF) were observed after frusemide 10 mg (-0.77 ml 100 ml-1 min-1 P less than 0.05) and 20 mg (-0.75 ml 100 ml-1 min-1 P less than 0.01 at 15 min). No changes were observed after bumetanide. The reductions in blood flow produced by frusemide were significantly different from those of bumetanide (P less than 0.05) at 15 min. Increases in venous capacitance (VC) and mean arterial blood pressure (MAP) were observed after frusemide but these differences were not statistically different from placebo or bumetanide. No increases were seen after bumetanide. Plasma aldosterone concentrations were unchanged after either drug but plasma renin activity (PRA) was increased after frusemide 10 mg (4.42 +/- 1.01----8.50 +/- 1.90 ng A I ml-1 h-1 P less than 0.01) and 20 mg (4.01 +/- 0.72----7.81 +/- 2.27 ng A I ml-1 h-1 P less than 0.05). No increases were observed after bumetanide and significant differences between bumetanide and frusemide were observed (P less than 0.01). This study demonstrates that the acute peripheral arterial effects of frusemide are not observed after comparable diuretic doses of bumetanide. The differences appear to be related to the ability of the drugs to stimulate acute renin release from the kidney.

Lisinopril, a long-acting angiotensin converting enzyme inhibitor, and the calcium channel blocker nifedipine in its retard formulation, were compared as monotherapy in a group of 45 patients with essential hypertension. Lisinopril in single daily doses (range 20-80 mg, median dose 40 mg) and nifedipine retard in twice daily doses (total daily dose range 40-80 mg, median dose 60 mg) were equally effective in controlling hypertension. The lisinopril group (n = 30), at baseline supine blood pressure 178/109 +/- 23/9 mm Hg (mean +/- 1 SD), after 12 weeks' therapy measured 148/88 +/- 27/14 mm Hg; the nifedipine group (n = 15), at baseline 185/110 +/- 23/11 mm Hg, after 12 weeks' therapy measured 151/89 +/- 14/10 mm Hg. The number of patients who experienced clinical adverse effects was significantly greater in the nifedipine group: 8 of 15 (53%) compared to 4 of 30 (13%) in the lisinopril group. The commonest adverse effects of patients on nifedipine were swollen ankles, flushing, and headache. Two patients on nifedipine were withdrawn from the study because of their adverse experiences. Of the patients on lisinopril there were single reports of flushing, ankle swelling, tiredness, and chest pain. No patient withdrew from lisinopril because of an adverse experience. No adverse laboratory experiences were recorded in either group. In conclusion, lisinopril and nifedipine retard were equally effective in controlling essential hypertension. Lisinopril was, however, better tolerated during this study.

The effects of maintenance indomethacin therapy on single dose digoxin pharmacokinetics and dynamics were studied in six healthy volunteers with normal renal function. Indomethacin did not alter the elimination half-life, systemic clearance or distribution of digoxin. No pharmacodynamic interaction as assessed by changes in the systolic time intervals QA2 and LVET was found. This study does not lend support for a significant digoxin-indomethacin interaction in 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. Pre-treatment with digoxin had no effect on the acute peripheral vascular responses to frusemide and failed to inhibit the acute increases in plasma renin activity and plasma aldosterone produced by frusemide. The study provides further evidence of a relationship between acute frusemide-induced renin release and the acute peripheral vascular effects of frusemide in man.

In a placebo controlled open study in six healthy male volunteers (+)-sotalol in the dose range 0.125 mg kg-1-2.0 mg kg-1 intravenously, was found to have little or no beta-adrenoceptor blocking activity in comparison to the racemic mixture (+/-)-sotalol. The repolarization effects of (+)- and (+/-)-sotalol on the QTc interval however were comparable over the same dose range. The beta-adrenoceptor blocking activity and repolarization effects of sotalol appear to be unrelated.

Plasma digoxin concentrations on admission to hospital have been compared with levels on day 8 in a group of 50 patients who were maintained on their preadmission digoxin doses for 7 days. In the absence of a change in renal function, 18 patients (36%) had higher levels on day 8 and were considered to be non-compliant: a further 7 patients (14%) had lower levels on day 8 suggesting that before admission they had been taking more than their prescribed digoxin dose. Fifty per cent were, therefore, taking their digoxin improperly. In addition, an incorrect dose of digoxin may have been prescribed in 14 patients (28%) with plasma digoxin concentrations either below 0.8 ng/ml (1.02nmol/l) or above 2.0 ng/ml (2.56 nmol/l) on day 8. Long-term compliance was assessed by comparing day 8 'steady state' digoxin levels with those obtained at outpatient follow-up. Thirty of the original group were studied at 4 weeks when 27 per cent were considered non-compliant, and 20 at 3 months when 30 per cent were non-compliant. These results have serious implications both for drug prescribing and for the treatment of disease, and suggest that a problem of communication exists between doctors and their patients.

1. This study has compared the effects of ibuprofen and indomethacin upon renal haemodynamics, electrolyte excretion and renin release in the presence and absence of frusemide under sodium replete conditions in eight healthy volunteers. 2. Neither ibuprofen (400 mg and 800 mg) nor indomethacin (50 mg) affected renal blood flow, glomerular filtration rate or electrolyte excretion in the basal state. 3. Frusemide had no effect on renal blood flow, but significantly increased glomerular filtration rate. This latter change was suppressed significantly only by ibuprofen 400 mg. Frusemide-induced diuresis was inhibited by all treatments, while natriuresis following frusemide was inhibited by indomethacin only. 4. Significant increments in plasma renin activity, which were suppressed by all treatments, were observed after frusemide. The degree of inhibition of the renin responses was significantly greater in the presence of indomethacin than with either dose of ibuprofen. 5. In a sodium replete setting in healthy volunteers, indomethacin and ibuprofen had no detrimental effects on basal renal function. In the presence of frusemide, indomethacin had more anti-natriuretic and renin-suppressing effect than ibuprofen. There was no evidence for a dose-related effect of ibuprofen.

Lisinopril, a long-acting angiotensin converting enzyme inhibitor, and the calcium channel blocker nifedipine in its retard formulation, were compared as monotherapy in a group of 45 patients with essential hypertension. Lisinopril in single daily doses (range 20-80 mg, median dose 40 mg) and nifedipine retard in twice daily doses (total daily dose range 40-80 mg, median dose 60 mg) were equally effective in controlling hypertension. The lisinopril group (n = 30), at baseline supine blood pressure 178/109 +/- 23/9 mm Hg (mean +/- 1 SD), after 12 weeks' therapy measured 148/88 +/- 27/14 mm Hg; the nifedipine group (n = 15), at baseline 185/110 +/- 23/11 mm Hg, after 12 weeks' therapy measured 151/89 +/- 14/10 mm Hg. The number of patients who experienced clinical adverse effects was significantly greater in the nifedipine group: 8 of 15 (53%) compared to 4 of 30 (13%) in the lisinopril group. The commonest adverse effects of patients on nifedipine were swollen ankles, flushing, and headache. Two patients on nifedipine were withdrawn from the study because of their adverse experiences. Of the patients on lisinopril there were single reports of flushing, ankle swelling, tiredness, and chest pain. No patient withdrew from lisinopril because of an adverse experience. No adverse laboratory experiences were recorded in either group. In conclusion, lisinopril and nifedipine retard were equally effective in controlling essential hypertension. Lisinopril was, however, better tolerated during this study.

A total of 136 patients with mild to severe uncomplicated essential hypertension were evaluated in a multicenter, randomized, double-blind, double-placebo, parallel study to compare the effect of lisinopril, a new angiotensin-converting enzyme inhibitor, with that of nifedipine. Following a 2-week placebo control period the patients were treated with either 20-80 mg/day of lisinopril (n = 89) or with 40-80 mg/day of nifedipine (n = 47). Blood pressure was significantly reduced in both groups after 4, 8, and 12 weeks of treatment. There was no difference in the effect of lisinopril compared to nifedipine. No serious clinical or laboratory adverse experiences were observed during the study. The incidence of clinical side effects was significantly lower in the lisinopril group than in the nifedipine group (21.3 vs. 48.9%, p less than or equal to 0.01). There were no significant changes in laboratory data in either group. The results indicate that lisinopril is as effective as nifedipine in the treatment of uncomplicated essential hypertension and that lisinopril is well tolerated and has an acceptable safety profile.

The pharmacokinetics of 1 mg, 2 mg and 4 mg of cilazaprilat administered intravenously were determined in a group of eight volunteers. The fall in plasma concentration was polyphasic. Elimination was predominantly by renal excretion of the unchanged drug. The mean renal clearance values following 1 mg, 2 mg and 4 mg doses were 5.3 +/- 0.5, 8.1 +/- 0.5, and 9.8 +/- 0.5 l h-1 and plasma clearances were 7.8 +/- 0.5, 10.4 +/- 0.5 and 11.8 +/- 0.6 l h-1, respectively. Thus, plasma and renal clearances were dose dependent. ACE inhibition was greater than 82% for the first 4 h and about 55% at 24 h, after all three doses. There were no significant haemodynamic effects at any dose.

We compared the effects of a cardioselective beta-adrenergic blocking drug, metoprolol, with a nonselective beta-adrenergic blocker, propranolol, on the response of 10 normal men to dynamic treadmill exercise. The volunteers underwent a standard graded exercise test to exhaustion while receiving placebo; propranolol, 40 mg every 6 hours; propranolol, 80 mg every 6 hours; metoprolol, 50 mg every 6 hours; or metoprolol, 100 mg every 6 hours. The drugs were given in a double-blind fashion for 48 hours before exercise. Five days were allowed between successive drug administrations and the order of drug administration was randomized. Heart rate, arterial pressure, oxygen consumption, minute ventilation and CO2 production were monitored. Plasma drug concentrations were measured at the time of exercise. Judged by plasma levels, propranolol was about three times more potent than metoprolol in attenuating heart rate. Both drugs produced a wide variation in plasma levels after a given oral dose, and both drugs attenuated the systolic blood pressure response to exercise. Neither drug affected diastolic blood pressure or maximum oxygen consumption, maximum minute ventilation or the anaerobic threshold. We conclude that there is no evidence that the cardioselective drug metoprolol is superior to propranolol in terms of the ability to perform or respond to short-term maximal exercise. In addition, the fact that maximal oxygen consumption and the anaerobic threshold were unaffected implies that fatigue during exercise while on beta-adrenergic blocking drugs is not due to an effect of these drugs in limiting blood flow to the exercising extremities.

1. The effects of equipotent doses of frusemide (10 mg and 100 mg) and bumetanide (250 micrograms and 2.5 mg) upon renal and peripheral vascular responses, urinary prostaglandin excretion, plasma renin activity, angiotensin II and noradrenaline were compared in nine healthy volunteers. 2. Frusemide (10 mg and 100 mg) and bumetanide (2.5 mg) increased renal blood flow acutely compared with placebo but bumetanide (250 micrograms) had no effect. The changes in peripheral vascular responses were not significantly different from placebo. 3. Urinary prostaglandin metabolite excretion was acutely increased by all treatments, with no inter-treatment difference. Plasma renin activity was increased acutely by both doses of frusemide and by bumetanide (2.5 mg) compared with placebo and to bumetanide (250 micrograms). There were no differences between the latter two treatments. Angiotensin II was increased significantly 30 min after frusemide 100 mg and bumetanide 2.5 mg, and by all four treatments at 50 min when compared with placebo. There were no significant differences between either of the low doses or the higher doses. Plasma noradrenaline was unchanged by all treatments. 4. Frusemide 100 mg and bumetanide 2.5 mg have the same effects on the renal vasculature and the renin-angiotensin-prostaglandin system. Under the conditions of this study, frusemide 10 mg had different effects on plasma renin activity than bumetanide 250 micrograms.

1. The effect of captopril 12.5 mg three times daily for 14 days on baroreflex sensitivity was investigated in six normotensive salt-replete male subjects. 2. Baroreflex sensitivity [delta R-R interval ms/mmHg systolic blood pressure (SBP)] was assessed following decreases and increases in SBP with glyceryl trinitrate and phenylephrine respectively and during Valsalva's manoeuvre. 3. Captopril had no effect on supine intra-arterial SBP or R-R interval on days 1 and 15 compared with placebo. However decreases (P less than 0.05) which occurred in plasma angiotensin II on day 1 (12.3 +/- 0.8 to 7.6 +/- 1.5 pg ml-1) and on day 15 (14.5 +/- 1.5 to 6.3 +/- 0.5 pg ml-1) and increases (P less than 0.02) in plasma renin activity on day 1 (1.2 +/- 0.7 to 4.8 +/- 0.8 ng A I ml-1 h-1) and on day 15 (1.1 +/- 0.2 to 5.4 +/- 0.9 ng A I ml-1 h-1) compared with placebo, indicated angiotensin-converting enzyme inhibition. 4. Baroreflex sensitivity was unchanged by captopril on day 1 and day 15 compared with placebo following the use of glyceryl trinitrate and phenylephrine to deactivate and activate respectively the baroreceptors, and during the strain and release phases of Valsalva's manoeuvre.

This study investigates the hypothesis that lipid soluble antioxidants may increase the resistance of low-density lipoprotein (LDL) to oxidation and also enhance vascular endothelial responses in humans. In a double-blind parallel group study, 24 hypercholesterolaemic patients, already on treatment with simvastatin (20 mg day-'), were randomized to supplementary treatment with probucol (500 mg bd), vitamin E (400IU daily) or placebo for 8 weeks. Mean serum cholesterol before antioxidant treatment was 7.00mmoll-'. Resistance of LDL to oxidation by copper was increased by 830% in the probucol group and by 30% in the vitamin E group. However, thiobar- bituric acid reacting substances in whole serum were not altered by either antioxidant. Probucol lowered HDL- and LDL-cholesterol levels and increased the QT inter- val. Forearm vascular responses, as measured by venous occlusion plethysmography, to acetylcholine, glyceryl trinitrate and NG-monomethyl-L-arginine, were not significantly changed by antioxidant treatment. Probu- col has a major, and vitamin E a minor, effect on LDL resistance to oxidation but neither compound appears to alter forearm vascular responses in vivo.