Validation of blood pressure measuring systems.
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Blood Pressure Monitors↗
Biomedical subjects
J L Reid
Publications and source records attributed to J L Reid.
Dose-ranging study of the angiotensin type I receptor antagonist losartan (DuP753/MK954), in salt-deplete normal man.
In a dose-ranging study, the angiotensin type I receptor antagonist losartan (DuP753/MK954) was administered orally to normal volunteers in whom the renin-angiotensin system (RAS) had been activated by a low sodium diet (40 mmol) and frusemide (40 mg twice daily) for 3 days before study. On the fourth day, subjects (n = 12) received placebo and three active doses (5, 10, 25, 50, or 100 mg) in a randomized, double-blind, three-panel, dose-ranging design. On the study day, 24-h urinary sodium excretion was approximately 10-20 mmol Na, with an increase in renin and aldosterone levels at baseline. Dose-dependent decreases in supine and erect blood pressures (BP) were statistically significant for 50 and 100 mg and were associated with a modest increase in supine heart rate (HR) at the higher dose. The peak BP decreases observed suggested that the highest dose studied (100 mg) was not necessarily the maximal response. Active treatments caused no increase in the sodium loss on the study day. Renin was significantly increased by doses > 10 mg in a dose-dependent fashion but there was little change in plasma aldosterone profile. Increase in renin was evident at doses (10 mg) below those significantly affecting overall BP (50 mg). Adverse symptoms were uncommon and limited to postural lightheadedness which was largely dose related. Our results indicate a BP and plasma renin dose-response relation for the orally active angiotensin II (AII) receptor blocker losartan in normotensive subjects with an activated RAS.
Adult↗
Vasorelaxant properties of isolated human internal mammary arteries and saphenous veins: comparative effects of milrinone and sodium nitroprusside.
Internal mammary arteries (IMA) and saphenous veins (SV) are vessels currently used in human coronary artery bypass surgery. In addition to late complications, the vessels may develop spasm perioperatively. We studied isolated IMA and SV from patients undergoing coronary artery bypass graft to reproduce in vitro the phenomenon of vasospasm. Vascular rings were constricted with phenylephrine in a classic organ bath. The effects of two vasodilator agents, milrinone and sodium nitroprusside (SNP), on phenylephrine precontracted vessels and as a pretreatment to reverse or prevent the contraction, respectively, were studied. When added to a precontracted vessel, milrinone had the same vasorelaxant effect as SNP in artery rings (EC50: 7.4 x 10(-7) +/- 0.8 x 10(-7) vs. 5.9 x 10(-7) +/- 0.8 x 10(-7) M, milrinone vs. SNP). In veins, milrinone was less effective in relaxing the rings than SNP (EC50: 15 x 10(-7) +/- 3 x 10(-7) vs. 1.5 x 10(-7) +/- 0.1 x 10(-7) M, milrinone vs. SNP, p < 0.05). If milrinone or SNP was added as a pretreatment, using the EC50 values, the inhibitory effect of milrinone on phenylephrine-induced contractions was greater in arteries than in veins (71 +/- 4 vs. 36 +/- 11% inhibition of maximum contraction to phenylephrine, artery vs. vein, p < 0.05). In arteries, milrinone caused a greater inhibitory effect than SNP (71 +/- 4 vs. 52 +/- 9% inhibition, milrinone vs. SNP, p < 0.05), but similar inhibition in veins (36 +/- 11 vs. 42 +/- 16%, milrinone vs. SNP).(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
Effects of a xanthine oxidase/hypoxanthine free radical and reactive oxygen species generating system on endothelial function in New Zealand white rabbit aortic rings.
We investigated the effects of the xanthine oxidase (XO)/hypoxanthine (HX) free radical (FR) generating system on the relaxant properties of aortic rings from New Zealand White rabbits. This system generates superoxide anions, hydroxyl radicals, and H2O2. We wished to identify which of these species is responsible for impairment of vascular function. After obtaining dose-response curves to phenylephrine (PE) and carbachol or sodium nitroprusside (SNP), we exposed rings to the FR generating system or H2O2 for 30 min, either with or without a range of potentially protective agents. Dose-response curves to carbachol or SNP were then repeated. Exposure to the XO/HX system impaired endothelium-dependent, carbachol-induced relaxation. The hydroxyl radical scavengers mannitol, N-(2-mercaptopropionyl)-glycine (MPG), and captopril offered no protection. Superoxide dismutase (SOD) increased the impairment of response, catalase provided partial protection, and a combination of SOD and catalase completely prevented impairment of the response. H2O2 mimicked the effects of XO/HX system. H2O2 appears to be the primary species involved in mediating the toxic effects of the XO/HX FR generating system, but the superoxide anion is probably responsible for some of the loss of relaxation and a role for intracellular generation of hydroxyl radicals cannot be excluded.
Animals↗
The antihypertensive efficacy and tolerability of a low dose combination of ramipril and felodipine ER in mild to moderate essential hypertension.
1. The antihypertensive efficacy and tolerability of a low dose combination of the angiotensin converting enzyme inhibitor ramipril (2.5 mg) and the extended release formulation of the dihydropyridine calcium channel antagonist felodipine (5 mg) were assessed in a double-blind, double dummy placebo controlled, randomised, crossover study in 20 patients (mean age 55.4 years; range 46-69) with uncomplicated mild to moderate hypertension (supine diastolic > 90 mmHg < 115 mmHg after 4 weeks of single-blind wash-out on placebo). The four randomised, double-blind, crossover study phases evaluated the response to 4 weeks of once daily treatment with placebo, monotherapy with each drug and the combination. Noninvasive ambulatory blood pressure monitoring (Spacelabs 90207) was performed for 24 h at the end of each phase. 2. The mean 24 h ambulatory blood pressure (mmHg) was 147.9/92.0 following placebo, 141.3/87.8 following monotherapy with ramipril 2.5 mg, 136.8/85.8 following monotherapy with felodipine ER 5 mg and 131.1/82.6 following the combination of ramipril 2.5 mg and felodipine ER 5 mg. All active treatment phases significantly reduced mean 24 h ambulatory diastolic pressure by comparison with placebo. The antihypertensive efficacy of the combination was additive. 3. The coadministration of ramipril did not attenuate the incidence of headache attributable to felodipine ER.
Aged↗
The role of clinical pharmacology in the development and assessment of drugs for cerebrovascular disease and stroke.
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Anticoagulants↗
A comparison in young and elderly subjects of the pharmacokinetics and pharmacodynamics of single and multiple doses of benazepril.
1. The pharmacokinetics and pharmacodynamics of single and multiple oral doses of the ACE inhibitor benazepril were investigated in young and elderly normotensive subjects. 2. Following multiple doses the trough concentrations were significantly higher in the elderly and the areas under the plasma concentration-time curves (AUC0-24) were significantly greater, by approximately 23%. 3. The fall in blood pressure tended to be greater in the elderly subjects but this is likely to be attributable to their higher initial blood pressures, although it may reflect the small differences in pharmacokinetics. 4. The age related differences in kinetics and dynamics following multiple dosing are quantitatively similar to those obtained with single doses. However, there appears to be a quantitative difference between benazepril and other ACE inhibitors in that the age related increases were of a relatively smaller magnitude.
Administration, Oral↗
Haemodynamic and hormonal responses to oral enalapril in salt depleted normotensive man.
A combination of dietary sodium restriction (40 mmol day-1) and frusemide pretreatment has been used to activate the renin angiotensin system (RAS) in order to characterise the haemodynamic and hormonal responses to enalapril in young normotensives. Enalapril significantly reduced supine blood pressure with a mean maximum fall of 19 +/- 7.6, compared with 6.5 +/- 6.8 mm Hg with placebo. Similar but greater responses were seen in erect blood pressure. Mean maximal plasma ACE inhibition (78 +/- 5.7%) was associated with a significant increase in PRA from 5.2 +/- 2.1 ngAI ml-1 h-1 to a peak of 29.1 +/- 6 ngAI ml-1 h-1. This simple well tolerated regimen produced consistent RAS activation and gave readily measurable falls in blood pressure following enalapril. This model may be used to undertake detailed assessments of ACE inhibition, renin inhibition and angiotensin receptor blockade.
Analysis of Variance↗
Double blind controlled study of low dose intravenous perindoprilat or enalaprilat infusion in elderly patients with heart failure.
OBJECTIVE: Comparison of the first dose responses to low dose constant rate infusions of diacid angiotensin converting enzyme (ACE) inhibitors. DESIGN: Double blind, randomised, placebo controlled, parallel group prospective study. SETTING: General hospital inpatient admissions for supervised diuretic withdrawal (24-48 hours) and the introduction of ACE inhibitor treatment. PATIENTS: 36 unselected elderly (aged 60-87 years) patients with symptomatic but stable chronic cardiac failure (New York Heart Association grades II-IV). ACE inhibitor started under double blind conditions with blood pressure monitoring. INTERVENTION: Patients were randomly allocated to receive intravenous placebo (saline), enalaprilat (1.5 mg over six hours) or perindoprilat (1 mg over six hours) by constant rate intravenous infusion (5 ml/hour). The protocol allowed for discontinuation of infusion if mean arterial blood pressure fell by 30% from the value before treatment. MAIN OUTCOME MEASURES: Blood pressure and heart rate responses, drug concentration, plasma renin, and ACE activities. RESULTS: The three groups had similar age, severity of heart failure, diuretic dose before treatment, plasma renin activity, and serum electrolyte state. All patients remained symptom free throughout the study. Infusions were only ended early with active treatment: 5/12 perindoprilat cases, (mean (SD) dose 0.88 (0.18) mg, and 5/12 enalaprilat cases (mean (SD) dose 1.2 (0.4) mg. Both active treatments lowered mean arterial pressure until discontinuation of infusion. Heart rate was not altered. Two patients (one perindoprilat, one enalaprilat) showed transient and symptom free renal impairment. CONCLUSIONS: Slow intravenous infusion of diacid ACE inhibitors may allow safe initiation of treatment in patients with heart failure and with activated renin angiotensin systems. The similar effects of intravenous perindoprilat and enalaprilat on blood pressure contrast with previously reported differences when perindopril and enalapril were given orally.
Aged↗
The experiences of an acute stroke unit--implications for multicentre acute stroke trials.
The suitability of 200 consecutive patients admitted to a newly established acute stroke unit was assessed for participation in two multicentre trials currently in their pilot phase: the International Stroke Trial of aspirin and heparin, and the Multicentre Acute Stroke Trial of streptokinase versus placebo. Of the 200 patients (74 men, 126 women, mean age 71 years), 96% had cerebral CT, and 94% had a final diagnosis of cerebrovascular disease. Overall, 50% of patients presented within 6 hours and 70% within 12 hours of the onset of ictus. A total of 113 patients (56.5%) were potentially eligible for trial treatment with aspirin/heparin. Only 9 patients (4.5%) were eligible for streptokinase treatment: 50% were excluded because they presented after 6 hours; 23% had a previous stroke with clinical sequelae and 23% had severe systemic illness. Forty eight per cent of patients had more than one exclusion criterion. The potentially high enrollment rates in trials of antithrombotic agents contrast with the restricted recruitment for trials of streptokinase, emphasising the need for multiple centres to achieve useful study enrollment.
Adult↗
Comparison of endothelin-1 and noradrenaline stimulated inositol phosphate formation in cultured aortic smooth muscle cells from spontaneously hypertensive and Wistar Kyoto rats.
Total [3H]-inositol phosphate formation was measured in cultured aortic smooth muscle cells from 6 and 14 week spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) normotensive rats. Basal inositol phosphate formation was significantly increased in cells cultured from SHR compared to WKY at both 6 and 14 weeks as was basal phosphatidylinositol formation. This difference in basal values was apparent after 9 h or more incubation with [3H]-myoinositol. Both endothelin-1 and noradrenaline stimulated inositol phosphate formation was unchanged in cultured smooth muscle cells from 6-week SHR compared to WKY. In cultured smooth muscle cells from 14-week SHR a decrease was observed in endothelin-1 stimulated inositol phosphate formation compared to controls. Noradrenaline stimulated inositol phosphate formation was increased in cultured cells from 14 week SHR. Endothelin-1 and noradrenaline stimulated inositol phosphate formation does not appear to be involved in the development (at 6 weeks) of hypertension in this model. However, in established hypertension (14 weeks) cells from SHR have altered total [3H] inositol phosphate formation in response to stimulation with noradrenaline and endothelin-1 although these changes are in opposite directions. Therefore, in cultured smooth muscle cells from 14-week rats noradrenaline and endothelin-1 appear to be regulated independently with regard to their effects on the phosphatidylinositol cycle.
Age Factors↗
The place of alpha blockers in the treatment of hypertension.
Alpha 1 adrenoceptor antagonists are safe, effective, well tolerated drugs which can be used alone or in combination with other drug groups in a wide range of hypertensive patients. Alpha 1 blockers not only lower blood pressure but may improve insulin sensitivity and the adverse lipid profile in many hypertensive patients. In addition to causing few side effects, alpha 1 blockers are not contra-indicated in patients with associated cardiovascular or respiratory disease. Alpha 1 blockers offer the potential to improve the risk factor profile more than conventional antihypertensive drugs.
Adrenergic alpha-Antagonists↗
ACE inhibitors: future perspectives.
There are chemical differences among angiotensin-converting enzyme (ACE) inhibitors that profoundly influence the pharmacokinetics and dynamics of different drugs. Differences in potency, affinity, and duration of action can be readily identified. These factors, together with individual binding characteristics of drug (or metabolite) to ACE, may influence the profile of hemodynamics and adverse effects, including first-dose hypotension and renal impairment. Differential inhibition of ACE in tissues (e.g., heart, brain, adrenal, kidney, blood vessel) could be important in identifying a particular ACE inhibitor for a specific clinical indication.
Angiotensin-Converting Enzyme Inhibitors↗
Comparison of captopril, hydralazine and nifedipine as third drug in hypertensive patients.
The antihypertensive, biochemical and adverse effects of captopril, hydralazine, nifedipine and placebo were compared in 160 patients with BP inadequately controlled by atenolol 100 mg daily plus bendrofluazide 5 mg daily. Treatments were given for up to 12 weeks. Beta-blocker and thiazide were continued unchanged. All three active drugs reduced supine BP relative to placebo; mean BP changes attributable to active treatment (95% confidence intervals): captopril 13.4/10.3 mmHg (0.6/4.0 to 26.2/16.6), hydralazine 15.0/10.0 mmHg (1.7/3.4 to 28.3/16.6), nifedipine 16.8/8.1 mmHg (4.0/1.8 to 29.6/14.4). There were no significant differences between the agents. Results for erect BP were similar. Target BP (< 140/95 mmHg) was achieved more frequently on captopril (33%), hydralazine (29%) and nifedipine (17%) than on placebo (10%). Compared with the other treatments captopril increased serum potassium concentration (P = 0.01), and hydralazine reduced serum cholesterol concentration (median changes: captopril -0.2 mmol/l, hydralazine -0.8 mmol/l, nifedipine -0.2 mmol/l, and placebo +0.2 mmol/l, P < 0.001). Overall, side-effects did not differ significantly between the groups; withdrawals resulting from adverse reactions: captopril 15%, hydralazine 24%, nifedipine 22%, and placebo 3% (chi 2 = 8.2, P = 0.04). Captopril, hydralazine and nifedipine did not differ significantly in efficacy and tolerability when added to atenolol and bendrofluazide. However, there were trends in favour of captopril, on which drug the highest proportion of patients had their BP controlled and the lowest proportion were withdrawn because of side-effects. Thus, of the drugs tested, captopril appears to be the best option as third drug in hypertension.
Adrenergic beta-Antagonists↗
Hypertension and stroke: opportunities for prevention and prospects for protection.
UNLABELLED: Risks associated with hypertension: Hypertension is a major factor in haemorrhagic and atherothrombotic stroke. Reduction of blood pressure reduces stroke risk by up to 40% in all hypertensive populations. Many older patients who would benefit from antihypertensive therapy are currently not adequately treated. Need for further trials: Further controlled clinical trials are required to confirm the optimum regimen for secondary prevention after a stroke or transient ischaemic attack. Knowledge of the mechanisms of ischaemic damage to the brain is increasing, and several pharmacological approaches to neuroprotection have been shown to be of benefit in experimental models. Evaluation of humans requires an accurate diagnosis of stroke type and improved outcome measures. CONCLUSIONS: The optimal benefit of protection from acute strokes will depend on a better understanding of the ideal haemodynamic profile and the early and appropriate delivery of a neuroprotective drug to the site of ischaemia.
Acute Disease↗
Role of angiotensin in the extravascular system.
Angiotensin receptors are present in many tissue types, including adrenal cortex, renal glomeruli, heart, hypothalamus, liver, pancreas, pituitary, platelets, renal tubules, uterus and vascular smooth muscle. Two high-affinity receptor subtypes have been identified by radioligand binding with antagonists: losartan (DuP 753/MK954) identifies AT1 receptors; PD123177 and CGP42112A are markers for AT2 receptors. Angiotensin II may be produced locally in tissues outside the humoral system. For example, it is found in the brain, kidney and heart. Within the brain, the heptapeptide angiotensin(1-7) mimics some effects of angiotensin II, but may be formed directly from angiotensin I. Evidence for non-ACE-mediated angiotensin II production has been reported in the heart. Intravascular angiotensin II receptors are implicated in the central release of vasopressin and other hypophyseal hormones, in increasing sympathetic outflow, in the thirst response and, possibly, in cognitive function; in the inotropic and chronotropic effects of angiotensin II on the heart as well as in growth/hypertrophy; in the control of aldosterone release and in the balance between cortisol and aldosterone secretion; and in modulating sodium, chloride and bicarbonate transport within the kidney. Effects on the reproductive system, liver and pancreas have not been established. The pharmacological effects of angiotensin II antagonists will depend on their distribution characteristics as well as affinity for specific receptor subtypes. At present, however, the physiological role of AT2 receptors has not been defined.
Angiotensin II↗
Percutaneous transluminal renal angioplasty in the management of hypertension and renal failure in patients with renal artery stenosis.
Percutaneous transluminal renal angioplasty (PTRA) is an accepted method of treatment of hypertension resulting from renal artery stenosis. There is less information on the role of PTRA in patients with renal artery disease and renal impairment. We report on 30 patients who underwent PTRA for renal artery stenosis (13 had uncontrolled hypertension and normal renal function and 17 had hypertension and renal insufficiency; 26 patients had atheromatous disease, fibromuscular dysplasia was diagnosed in 2 and 2 patients had renal artery stenosis to a transplant kidney). These 30 patients had 43 PTRA procedures, with the 'initial technical success' rate of 81% and the 'overall success' rate of 79% after ten months. Results of renal PTRA on BP showed the initial benefit in 88% of patients: 71% 'cured' and 17% 'improved'. After ten months only 38% of patients could still be considered 'cured' and 33% 'improved'. Renal function 'improved' in 68% of patients who presented with renal insufficiency. An improvement of BP control or renal function was less likely in patients with bilateral severe atheromatous disease. PTRA is an effective treatment for renal artery stenosis. Satisfactory improvement of BP control and improvement or prevention of further deterioration of renal function may be achieved in a high proportion of patients.
Adult↗
Drug treatment of hypertension.
Over the last 40 years effective drug treatment of hypertension has become available. Newer classes of drugs offer efficacy with simplicity of dosing regimen and good patient acceptability. However, there is increasing interest in the long-term benefits of treatment, particularly influences on total mortality and morbidity and mortality from coronary artery disease and its complications. Established treatments with diuretics and beta blockers do reduce stroke risk but have less than predicted effects on coronary heart disease. While there is experimental evidence and clinical pointers that ACE inhibitors and calcium antagonists may influence atherosclerosis in the long-term, there is as yet no objective clinical confirmation. The aim of treatment in the 1990s is to control blood pressure (and other risk factors) in the short-term with a view to improving long-term outcome. Many clinicians have modified step-care approaches to individualize drug treatment using one or two agents, selected from older and newer classes, which on clinical grounds are most appropriate in the individual patient. Factors determining choice are race, other risk factors and associated diseases.
Animals↗