Lindon M.H. Wing

Brachial Blood Pressure But Not Carotid Arterial Waveforms Predict Cardiovascular Events in Elderly Female Hypertensives

Central arterial waveforms and related indices of large artery properties can be determined with relative ease. This would make them an attractive adjunct in the risk stratification for cardiovascular disease. Although they have been associated with some classical risk factors and the presence of coronary disease, their prospective value in predicting cardiovascular outcomes is unknown. The present study determined the relative predictive value for cardiovascular disease–free survival of large artery properties as compared with noninvasive brachial blood pressure alone in a population of elderly female hypertensive subjects. We measured systemic arterial compliance, central systolic pressure, and carotid augmentation index in a subset of female participants in the Second Australian National Blood Pressure Study (untreated blood pressure 169/88±12/8 mm Hg). There were a total of 53 defined events during a median of 4.1 years of follow-up in 484 women with complete measurements. Although baseline blood pressures at the brachial artery predicted cardiovascular disease–free survival (hazard ratio [HR], 2.3; 95% CI, 1.3 to 4.1 for pulse pressure ≥81 versus <81 mm Hg; P=0.01), no such relation was found for carotid augmentation index (HR, 0.80; 95% CI, 0.44 to 1.44; P value not significant) or systemic arterial compliance (HR, 1.25; 95% CI, 0.72 to 2.16; P value not significant). Blood pressure, but not noninvasively measured central arterial waveforms, predict outcome in the older female hypertensive patient. Thus, blood pressure measurement alone is superior to measurement of arterial waveforms in predicting outcome in this group.

Increases in plasma neuropeptide Y concentrations during sympathetic activation in man.

Neuropeptide Y (NPY) coexists with noradrenaline in postganglionic sympathetic neurons. In order to test the hypothesis that NPY may be released along with catecholamines by activation of the sympathoadrenal system we measured plasma NPY-like immunoreactivity (NPY-LI) concentrations during cold pressor test, head up tilt and bicycle exercise in healthy volunteers. All 3 manoeuvres resulted in elevation of blood pressure, heart rate and plasma noradrenaline and adrenaline concentrations. These were accompanied by increases in plasma NPY-LI concentrations on cold pressor test and exercise, but not with head up tilt. The increases in both NPY-LI and catecholamines were greatest with exercise. These findings suggest that NPY is released at the same time as noradrenaline when sympathetic noradrenergic nerves are activated.

Effects of allopurinol on theophylline metabolism and clearance

The effects of allopurinol on the plasma clearance and metabolism of theophylline in man were investigated under single‐dose and multiple‐dosing conditions. No change in theophylline clearance was found with the concomitant use of allopurinol but 1‐methylxanthine (1MX), a theophylline metabolite not previously described in man, was detected in urine during control and allopurinol treatment phases under both single‐ and multiple‐dosing conditions. 1MX excretion increased at the expense of 1‐methyluric acid (IMU) during the allopurinol treatment phase. It is proposed that the secondary biotransformation of 1MX to IMU is mediated by xanthine oxidase.

A low-sodium diet supplemented with fish oil lowers blood pressure in the elderly.

Objective: To examine effects of dietary fish oil supplementation with sodium restriction on blood pressure in the elderly. Design: In a double-blind dietary intervention lasting 4 weeks, parallel comparisons of blood pressure were made in volunteers assigned to one of four treatment groups: fish oil and low sodium; fish oil and normal sodium; sunflower oil and low sodium; or sunflower oil and normal sodium. Setting: Subjects lived at home and attended our nutrition research clinic at fortnightly intervals for dietary counselling and blood pressure measurement. Participants: Health volunteers aged 60-80 years were sought by advertisement. A total of 114 men and women were enrolled in two cohorts; 106, with an initial mean blood pressure of 132/77 mmHg, satisfactorily completed the study. Intervention: All subjects adopted a low-sodium diet and dietary changes were effected by double-blind administration of slow-release sodium chloride or placebo tablets, along with capsules containing either fish or sunflower oil. Main outcome measure: The primary measure was the within-subject change in blood pressure after 4 weeks of intervention in each dietary treatment group. Results: Urinary sodium excretion in subjects on low-sodium diets decreased whilst potassium excretion was unaffected. Systolic blood pressure (SBP) fell in the group taking sunflower oil with low sodium, but there was only a transient fall in diastolic blood pressure (DBP). In those taking fish oil with normal sodium, the change in blood pressure was not significant, except after adjustment for initial blood pressure and weight changes. When fish oil was combined with low sodium, however, both SBP and DBP were substantially reduced; the reduction in DBP was significantly greater than in the other treatment groups. Conclusion: Dietary fish oil and sodium restriction can interact to lower DBP in the elderly.

Participation of Central Serotonergic Neurons in the Control of the Circulation of the Unanesthetized Rabbit A Study Using 5, 6-Dihydroxytryptamine In Experimental Neurogenic And Renal Hypertension

The role of central serotonergic neurons in circulatory control was studied in rabbits given intracisternal injections of 5, 6-dihydroxytryptamine (5, 6-DHT, 300 μg/kg) to cause degeneration of central serotonergic nerve terminals and depletion of central serotonin stores. In normal rabbits, intracisternally administered 5.6-DHT produced decreases in mean arterial blood pressure (11%, P < 0.001) and heart rate (9%, P < 0.001) that were maximum 1 week after injection. Central serotonin levels were reduced to less than 50% in the spinal cords of the rabbits treated with 5, 6-DHT compared with the levels in vehicle-injected controls. Pretreatment with intracisternally administered 5, 6-DHT completely prevented the sustained increases in mean arterial blood pressure and heart rate seen after sinoaortic denervation in control rabbits. In rabbits with neurogenic hypertension following sinoaortic denervation, treatment with intracisternally administered 5, 6-DHT caused a prompt, persistent reduction in mean arterial blood pressure and heart rate. Intracisternally administered 5, 6-DHT failed to interfere with the development or the maintenance of the hypertension that follows bilateral wrapping of the kidneys with cellophane. This study suggests that central serotonergic neurons participate in the baroreceptor reflex arc, possibly at the bulbospinal level. The integrity of these neurons appears to be necessary for the development of sustained neurogenic hypertension following sinoaortic denervation but to be of minimum importance in experimental renal hypertension in the rabbit.

Lidocaine disposition—Sex differences and effects of cimetidine

The effects of pretreatment with Cimetidine (1 gm daily for 3 days) on the disposition of lidocaine were examined in 18 healthy subjects, seven of whom were chronic cigarette smokers. Each subject received separate oral (200 mg) and intravenous (75 or 100 mg) doses of lidocaine before and after Cimetidine. After Cimetidine, lidocaine apparent oral clearance (Clo) reduced 42% ± 7%; oral bioavailability increased 35% ± 10%; and systemic clearance (Cls) and volume of distribution at steady‐state (Vdss) decreased 21% ± 6% and 20% ± 7%. Elimination t½ was unchanged. Calculated values for Cls after Cimetidine based on reduction in Cl0 and consequent decrease in hepatic extraction ratio correlated significantly with observed values for Cls (r = 0.67). Women had larger Vdss (64% ± 19%), longer t½ (50% ± 18%), and greater oral lidocaine bioavailability (63% ± 29%) than did men. There was no sex difference in and no influence of cigarette smoking on the effects of Cimetidine. The results indicate that Cimetidine reduces metabolic clearance of lidocaine. The consequent reduced hepatic extraction explains the observed reduction in Cls.

Similar Effects of Treatment on Central and Brachial Blood Pressures in Older Hypertensive Subjects in the Second Australian National Blood Pressure Trial

The Second Australian National Blood Pressure Trial reported better prognosis for hypertensive subjects randomly assigned to an angiotensin-converting enzyme inhibitor (ACE-I) compared with a diuretic-based regimen despite no difference in brachial blood pressure control. A possible explanation is that there was a difference in central aortic pressures despite similar brachial pressure reductions. We examined this hypothesis in a subset of the Second Australian National Blood Pressure Trial cohort evaluated both before and after 4 years of treatment. The average age of the 479 subjects was 71.6±4.7 years (mean±SD), and 56% were women. Brachial systolic and pulse pressures after treatment were 145±1 (mean±SEM), 143±1, 72±1, and 70±1 mm Hg for diuretic and ACE-I groups, respectively. The respective changes from pretreatment values were −17±2, −16±2, −9±1, and −7±1 mm Hg. None of the differences between diuretic and ACE-I groups were significant. Central arterial pressure waveforms were acquired from carotid tonometry and calibrated from brachial pressures. Central systolic and pulse pressures posttreatment were 144±2, 144±2, 71±2, and 72±2 mm Hg for diuretic and ACE-I groups, respectively. The respective changes from pretreatment values were −15±2, −17±2, −6±2, and −8±2 mm Hg. None of the differences between diuretic and ACE-I groups were significant. The similarity of central and brachial pressures in this cohort of older hypertensive subjects is most likely because of the influences of age and hypertension in increasing arterial stiffness. There is no evidence that the better prognosis for patients randomly assigned to ACE-I in Second Australian National Blood Pressure Trial resulted from a disproportionate lowering of central blood pressure.

Added predictive value of night-time blood pressure variability for cardiovascular events and mortality: The ambulatory blood pressure-international study

The association of ambulatory blood pressure (BP) variability with mortality and cardiovascular events is controversial. To investigate whether BP variability predicts cardiovascular events and mortality in hypertension, we analyzed 7112 untreated hypertensive participants (3996 men) aged 52±15 years enrolled in 6 prospective studies. Median follow-up was 5.5 years. SD of night-time BP was positively associated with age, body mass index, smoking, diabetes mellitus, and average night-time BP (all P<0.001). In a multivariable Cox model, night-time BP variability was an independent predictor of all-cause mortality (systolic, P<0.001/diastolic, P<0.0001), cardiovascular mortality (P=0.008/<0.0001), and cardiovascular events (P<0.001/<0.0001). In contrast, daytime BP variability was not an independent predictor of outcomes in any model. In fully adjusted models, a night-time systolic BP SD of ≥12.2 mm Hg was associated with a 41% greater risk of cardiovascular events, a 55% greater risk of cardiovascular death, and a 59% increased risk of all-cause mortality compared with an SD of <12.2 mm Hg. The corresponding values for a diastolic BP SD of ≥7.9 mm Hg were 48%, 132%, and 77%. The addition of night-time BP variability to fully adjusted models had a significant impact on risk reclassification and integrated discrimination for all outcomes (relative integrated discrimination improvement for systolic BP variability: 9% cardiovascular events, 14.5% all-cause death, 8.5% cardiovascular death, and for diastolic BP variability: 10% cardiovascular events, 19.1% all-cause death, 23% cardiovascular death, all P<0.01). Thus, addition of BP variability to models of long-term outcomes improved the ability to stratify appropriately patients with hypertension among risk categories defined by standard clinical and laboratory variables.

Second Australian National Blood Pressure Study (ANBP2) - Australian Comparative Outcome Trial of ACE inhibitor- and Diuretic-based Treatment of Hypertension in the Elderly

The Second Australian National Blood Pressure Study (ANBP2) is a comparative outcome trial being conducted in general practices throughout Australia of ACE inhibitor- and diuretic-based treatment in 6000 hypertensive patients aged 65-84 years. The study is using a prospective randomised open-label design with blinding of endpoint assessments. The primary objective is to determine whether there is any difference in total cardiovascular events (fatal and non-fatal) over a five year treatment period between the two treatment regimens. Eligible hypertensive patients (average sitting blood pressure at the 2nd and 3rd screening visits > 160 mm Hg systolic and/or > 90 mm Hg diastolic) may be either untreated or previously treated and should have no history of recent cardiovascular morbidity or serious intercurrent illness. Patients are randomised to one of the treatment arms with randomisation stratified for practice and for age. Following randomisation each patients blood pressure is managed by his/her general practitioner according to guidelines relevant to each treatment arm. Over 700 patients have now been randomised with recruitment intended to be complete by the end of 1997.

Australian Comparative Outcome Trial of Angiotensin-Converting Enzyme Inhibitor And Diuretic-Based Treatment of Hypertension in the Elderly (ANBP2): Objectives and Protocol

1. ANBP2 is a comparative outcome trial of angiotensin‐converting enzyme inhibitor‐ and diuretic‐based treatment of hypertension in the elderly using a prospective randomized open‐label design with blinding of endpoint assessments.