How does posture influence the haemodynamic assessment of a cardiovascular drug? Experience with nicardipine.

The extent to which posture altered the haemodynamic response to slow calcium channel blocker nicardipine was evaluated in 22 male patients with angiographically confirmed coronary artery disease. Patients were randomly allocated to supine or upright posture and an otherwise identical protocol performed in each group. At rest, following a control saline period, four doses of the drug (log cumulative dosage: 1.25, 2.5, 5.0, and 10.0 mg) were administered by i.v. infusion over a total period of 40 min; haemodynamic indices were recorded during the 3-5 min following each 5 min infusion. The exercise effects of the drug, in each posture, were determined by comparison of a control predrug exercise with observations at the same workload following the maximal cumulative dose. Nicardipine reduced resting mean blood pressure (MBP) and systemic vascular resistance index (SVRI) in both postures, the decrease being more pronounced when upright (MBP, -12%, -18%; p less than 0.01: SVRI, -30%, -46%; p less than 0.01). The increases in cardiac index (CI) and stroke volume index (SVI) were higher when upright (29 and 54% vs. 10 and 27%; p less than 0.01). Pulmonary artery occluded pressure (PAOP) increased by 29% when upright, without change when supine. On exercise, the effects for HR, MBP, CI, SI, and SVRI responses were independent of posture; however, a qualitative difference was apparent for PAOP (-17% vs. +14%; p less than 0.05). Thus, although the actions of nicardipine were qualitatively similar, quantitative differences related to posture were confirmed. These differences appeared to relate to posture-related baseline haemodynamic differences between the groups but with similar postnicardipine absolute values.

Haemodynamic dose-response effects of UK-52,046 in ischaemic disease with or without impaired left ventricular function.

1. The haemodynamic effects of a new cardioselective postsynaptic alpha 1-adrenoceptor antagonist UK-52,046, were evaluated in 25 patients with stable coronary disease, with or without impaired left ventricular function. At rest the haemodynamic effects to two dose-response regimens were determined. In an initial eight patients 0.125, 0.125 and 0.25 micrograms kg-1 were administered peripherally at 15 min intervals; the haemodynamic measurements were determined between 10 to 15 min after each dose. In a further 17 patients, the dose regimen was doubled yielding a cumulative dose-regimen of 0.25, 0.5 and 1.0 micrograms kg-1. The exercise effects were determined by comparison of measurements during 4 min of supine sub-maximal bicycle exercise at a fixed workload before and after drug treatment. 2. At rest, the lower dose regimen of UK-52,046 significantly reduced systemic mean arterial blood pressure (-5 mm Hg; P less than 0.05) and increased cardiac index (+0.2 l min-1 m-2, P less than 0.01). The higher dose regimen of UK-52,046 reduced systemic mean arterial blood pressure (-7 mm Hg; P less than 0.01), pulmonary artery occluded pressure (PAOP) (-2 mm Hg, P less than 0.01) and vascular resistance index (-314 dyn s cm-5 m2; P less than 0.05) with an increase in heart rate (+7%, P less than 0.05) and cardiac index (+0.2 l min-1 m-2, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Measurement of conjugated diene lipids by derivative spectroscopy in heptane extracts of plasma.

A series of experiments are described which show that second derivative spectroscopy can be used to quantify conjugated lipid dienes as markers of lipid peroxidation in heptane extracts of plasma from patients with rheumatoid arthritis, osteoarthritis, and healthy controls. Results obtained by this method gave reasonable agreement with those derived from the measurement of simple absorbance in chloroform/methanol extracts. Two minima were observed in the derivative spectrum of plasma lipid extracts. These minima occurred at 233 and 241 nm and corresponded to absorbance maxima in the conventional UV spectrum. Using a combination of phospholipase hydrolysis, reverse phase high performance liquid chromatography (HPLC) and second derivative spectroscopy we confirmed that these two minima can be attributed to a single fatty acid (9 cis-, 11 trans-linoleic acid) shown previously to account for greater than 90% of diene conjugation in human plasma samples. When the biological isomer 9 cis-, 11 trans-linoleic acid was separated by reverse phase HPLC from the mixture of other plasma phospholipid-2-esterified fatty acids we observed a change in derivative spectroscopy minima from 233 and 241 nm to 228 and 237 nm. Minima at the latter two wavelengths were also seen with pure preparations of the Paint Research Isomer (9 trans-, 11 trans-linoleic acid) which eluted later than biological 9 cis-, 11 trans-linoleic acid using reverse phase HPLC, suggesting that the absorption spectra of these pure cis-, trans and trans, trans dienes are similar but can be altered by the presence of other fatty acids in the extract.

Haemodynamic and radionuclide effects of amlodipine in coronary artery disease.

1. The haemodynamic and radionuclide effects of a new long-acting slow-calcium channel blocking agent, amlodipine, were evaluated in 32 patients with coronary artery disease. 2. Haemodynamic measurements in 24 patients were made at rest and 10 to 15 min after 20 mg i.v. amlodipine. Amlodipine significantly reduced systemic arterial blood pressure and vascular resistance index with an increased heart rate and augmented cardiac index. Cardiac stroke volume index rose and stroke work fell without change in pulmonary artery occluded pressure (PAOP). 3. The exercise effects were determined by comparison of measurements during 4 min of supine bicycle exercise at a fixed workload before and after drug treatment. During dynamic exercise, amlodipine reduced systemic arterial pressure and vascular resistance index. Exercise cardiac index, stroke volume index and heart rate were higher. The left ventricular filling pressure was significantly reduced. 4. Radionuclide parameters were studied in 16 patients at rest and on exercise; ejection fraction was unaltered following amlodipine. 5. Pre-therapy haemodynamic values correlated with response following amlodipine for resting mean blood pressure, systemic vascular resistance and exercise PAOP. 6. Thus, the immediate impact of amlodipine in stable coronary artery disease was to reduce left ventricular afterload and thereby improve cardiac pumping performance.

Hemodynamic assessment of nicardipine alone and with atenolol in coronary artery disease using a modified echo-Doppler device.

We have used a modified noninvasive echo-Doppler cardiac output device, based on the principle of attenuated compensation volume flow, to assess the cardiovascular effects of the slow-calcium antagonist nicardipine in coronary disease. The dose-response effects of 2.5, 5.0 and 10.0 mg intravenous nicardipine were determined in 8 patients with angina. Dose-related decreases were seen in systemic mean arterial pressure (p less than 0.01) after administration of nicardipine. Cardiac pumping indexes were improved, as evident from linear increases in cardiac stroke volume (p less than 0.001), stroke length (p less than 0.01) and time-averaged mean velocity (p less than 0.01). The echo-Doppler device was also used to assess beta-blocking/nicardipine combination therapy in patients with angina. When nicardipine was given after the cardioselective beta blocker atenolol the reduction in heart rate and cardiac output after atenolol was reversed compared with a group that received atenolol followed by placebo. Cardiac performance improved and the 35% reduction in systemic vascular resistance was associated with markedly increased cardiac index (p less than 0.01), augmentation of time-averaged mean velocity (p less than 0.01) and cardiac stroke length (p less than 0.05). These data are consistent with previous invasive studies of nicardipine, either alone or when combined with beta blockade in coronary disease. The data also suggest that nicardipine/beta-blocking combination is safe in patients with coronary heart disease and that the echo-Doppler method of cardiovascular monitoring will prove useful in human pharmacodynamic studies.

Clinical evaluation of the Copal UA-251 and the Dinamap 1848 automatic blood-pressure monitors.

The Copal UA-251 is a small automatic blood-pressure monitor, which relies on a piezo-electric microphone for detection of Korotkoff sounds. The Dinamap 1848 automatic monitor uses the oscillometric method for blood-pressure determination. When compared with the Hawksley random-zero sphygmomanometer, the Copal UA-251 recorded higher systolic blood-pressure, with this discrepancy widening at the upper end of the systolic pressure range. The agreement between these machines was reasonable for diastolic blood-pressure. The Dinamap 1848 had a tendency to consistently over-read systolic and under-read diastolic blood-pressure compared with the Hawksley sphygmomanometer, with median differences of 7 mmHg and -2.5 mmHg respectively.

Plasma catecholamine levels in acute myocardial infarction: influence of beta-adrenergic blockade and relation to central hemodynamics.

In a prospective study, 20 patients with acute myocardial infarction were randomly assigned in a double-blind fashion to treatment with intravenous metoprolol followed by oral metoprolol or placebo. All patients underwent hemodynamic monitoring for 24 hours. Plasma adrenaline and noradrenalin levels were estimated at baseline (mean 6.0 +/- 0.9 hours from onset of symptoms) and at 1 and 24 hours after the start of therapy. Plasma adrenaline and noradrenalin levels were elevated in all but one patient, with a further increase at 1 hour after administration of metoprolol (p less than 0.05). At baseline pulmonary capillary wedge pressure was directly related to both plasma adrenaline (r = -0.44; p less than 0.05) and noradrenalin levels (r = -0.44; p less than 0.05). There was also an inverse relationship between stroke volume index and the plasma noradrenalin level (r = -0.44; p less than 0.05) but not the plasma adrenaline level. These relationships were lost after the baseline measurements. However, between baseline and 1 hour there was a close relationship between the change in systemic vascular resistance and the changes in both adrenaline (r = -0.48; p less than 0.05) and noradrenalin levels (r = -0.66; p less than 0.01). Thus, in the early stages of myocardial infarction high plasma catecholamine levels are associated with the hemodynamic markers of severe left ventricular damage. Beta-adrenergic blockade with metoprolol produced a further increase in catecholamine levels that was associated with an increase in systemic vascular resistance.

The clinical relevance of alcohol in the Blood Pressure Clinic.

There is a limited number of studies conducted in hypertensive patients which support the hypothesis that high alcohol intake is an important reversible cause of raised blood pressure. The validity and effectiveness of alcohol restriction as a treatment of hypertension is difficult to study as there is no suitable placebo substance that can be employed on a clinical trial basis. However, such clinical data that there are, taken with the confirmatory epidemiological work, strongly suggest that hypertensive patients should be questioned and investigated for evidence of high alcohol intake and advised accordingly.

'Neutropenia' in black west Indians.

A prospective case control study routine haematological parameters was conducted in 294 healthy Black and White age/sex-matched subjects. The most important finding relevant to clinical practice was a reduction of total white cell count in Blacks due mainly to reduced neutrophil numbers. Twenty-one percent of sickle negative Blacks had white cell counts below the lowest value seen in Whites. The haemoglobin concentration, erythrocyte mean cell volume and monocyte count were also significantly lower amongst Blacks though lymphocyte counts were higher. The racial differences in haemoglobin and white count were not accounted for by differences in smoking and drinking habits. They were also found when Blacks with sickle cell trait were compared to age/sex-matched Whites and in others taking the oral contraceptive pill. Awareness of racial group should aid interpretation of routine tests and avoid unnecessary investigation of normal 'neutropenic' Blacks.

Comparison of enalapril and bendrofluazide for treatment of systemic hypertension.

The antihypertensive and biochemical effects of the angiotensin-converting enzyme inhibitor enalapril were compared with those of the thiazide diuretic bendrofluazide. Patients with untreated mild to moderate essential hypertension were entered into a randomized, double-blind, double-dummy, parallel-group study. Blood pressure (BP) decreased significantly (p less than 0.001) with either drug therapy: from 172/103 to 147/87 mm Hg (n = 18) with enalapril and from 179/104 to 165/95 mm Hg (n = 22) with bendrofluazide; thus, enalapril produced a greater reduction (p less than 0.05) than bendrofluazide. The median dose of enalapril was 20 mg/day (range 10 to 40) and that of bendrofluazide was 5 mg/day (range 2.5 to 10). Both drugs reduced serum sodium levels by small amounts. This was significant only for enalapril (decrease of 1.3 mmol/liter, p less than 0.05). Hyponatremia was not seen in any patient. Three patients were withdrawn from each treatment group due to adverse effects, although both drugs were generally well tolerated.

The frequency of epilepsy preceding stroke. Case-control study in 230 patients.

In a case-control study, evidence of previous epilepsy was sought in 230 consecutive patients under the age of 70 admitted to hospital with acute stroke. 8 (4.5%) of the 176 patients having their first stroke were epileptic, compared with 1 (0.6%) of the matched controls. 6 of the 8 epileptics started their seizures after the age of 30 years. 5 (9.3%) of the 54 patients who had had a previous stroke were epileptic, compared with none of the control patients. The findings support the idea that otherwise clinically undetectable cerebrovascular disease may present with seizures and that these can be a warning sign for a future stroke.

Effect of nifedipine on glucose tolerance, serum insulin, and serum fructosamine in diabetic and nondiabetic patients.

The hypothesis that nifedipine may cause an insidious but reversible change in glucose tolerance, similar to that associated with thiazide therapy, was studied in six nondiabetic and six noninsulin-dependent diabetic patients with hypertension. After medium-term nifedipine therapy (mean duration, 11.5 months) was stopped for one month and then resumed for a month, values for fasting blood glucose, fasting serum insulin, serum fructosamine, glucose tolerance, and insulin release in response to oral glucose were unchanged in both groups. These findings suggest that nifedipine in conventional doses does not have important effects on glucose handling in either diabetic or nondiabetic patients.

The effects of bendroflumethiazide added to nifedipine in patients with hypertension.

It has been suggested that a diuretic added to a calcium antagonist may not reduce blood pressure further in patients with hypertension. Bendroflumethiazide 5 mg was given to 17 patients with essential hypertension who had persistent mild to moderate hypertension despite treatment with nifedipine slow-release tablets 20 mg bid. One group received bendroflumethiazide before (N = 8) and the other after placebo (N = 9) in a double-blind, randomized cross-over trial. Supine blood pressure following active bendroflumethiazide administration was significantly reduced in both groups compared with trial entry (166/105 to 150/96 mm Hg, P less than .01; 170/108 to 156/98 mm Hg, P less than .01). A reduction in serum potassium level and a rise in serum uric acid concentration were seen with combined treatment. We cannot substantiate theoretic arguments for the ineffectiveness of a bendroflumethiazide-nifedipine combination on blood pressure.

Rupture of a cerebral aneurysm associated with nifedipine treatment.

We describe rupture of a cerebral arterial aneurysm in a 32 year old hypertensive woman following the introduction of nifedipine treatment. It is suggested this relationship is causal rather than coincidental and mediated through cerebral arterial vasodilatation.

Stroke and alcohol consumption.

We conducted a retrospective case-control study to investigate a possible association between alcohol intake and stroke. Reported recent alcohol consumption and biochemical and hematologic markers of alcohol intake were examined for 230 patients with stroke (20 to 70 years old) and compared with concurrently collected data on controls matched for age, sex, and race. A single estimate of current intake was used as a measure of alcohol consumption. Among men, the relative risk of stroke (adjusted for hypertension, cigarette smoking, and medication) was lower in light drinkers (those consuming 10 to 90 g of alcohol weekly) than in nondrinkers (relative risk, 0.5), but was four times higher in heavy drinkers (consuming greater than or equal to 300 g weekly) than in nondrinkers. Because very few women in our study drank heavily, we were unable to determine whether heavy alcohol intake influenced the risk of stroke in women. With increasing serum concentrations of the biochemical markers of alcohol intake (aspartate aminotransferase, uric acid, and gamma-glutamyl transferase), we observed similar trends in the relative risk of stroke. Only the erythrocyte mean cell volume did not follow this pattern. We conclude that heavy alcohol consumption is an important and underrecognized independent risk factor for stroke in men, but our data are not adequate to settle the issue for women. Our conclusions are qualified by our reliance on reported recent alcohol consumption as the primary measure of intake.

The association of hypertension, the Ask-Upmark kidney and other congenital abnormalities.

We report 2 cases of hypertension with segmental renal hypoplasia (Ask-Upmark kidney) and other anomalies in the absence of vesicoureteral reflux. These cases support the view that the Ask-Upmark kidney is a defect of renal development rather than acquired as a consequence of vesicoureteral reflux. In 1 patient the abnormal renal vein renin ratio suggested that the renin-angiotensin system may have had a part in the pathogenesis of the hypertension.

An audit of nifedipine in a hypertension clinic.

The results of treating 235 hypertensive patients who had been prescribed nifedipine in a hypertension clinic were examined for factors affecting blood pressure response and the frequency of side-effects. Pretreatment systolic and diastolic blood pressure correlated significantly with the decrease in blood pressure but this effect was lost following statistical correction. No relation was found between response and age or race nor did any biochemical or haematological parameter predict the antihypertensive effect. Fifty-nine (25%) patients complained of side-effects which were dose related; the drug had to be discontinued in 30 patients (13%) but the remaining 29 continued at the same or reduced dosage. Small, but statistically significant, elevations were seen in serum albumin, alkaline phosphatase and bilirubin as well as a rise in average blood glucose levels. Although side-effects are fairly common nifedipine is an effective antihypertensive drug when given alone or in combination with other therapies.

Clinical evaluation of the Infrasonde D4000 blood pressure monitor.

Choosing a blood pressure machine from their ever increasing number is often difficult due to lack of performance data. We have evaluated a new automated non-invasive blood pressure recorder, the Infrasonde D4000. In comparison with the Hawksley random zero mercury sphygmomanometer the Infrasonde showed less variability for both systolic and diastolic readings. However, it was found to record significantly lower mean systolic and diastolic pressures.

Relation between initial blood pressure and its fall with treatment.

The relation between pre-treatment blood-pressure and the fall in pressure after treatment was examined for most classes of antihypertensive drugs. Positive correlations were demonstrated for all drugs, for placebo, and for bed rest. This suggests that for all manoeuvres response is related to the height of the pretreatment pressure. Substitution of the pre-treatment and achieved pressures by random numbers reveals that positive correlations are mathematically inevitable and do not indicate any action on a basic mechanism of essential hypertension. After statistical correction for mathematical associations between the variables the apparent effects were generally lost. A correlation between the pre-treatment value of any variable and its change after a therapeutic intervention thus may not be valid.