Metabolic syndrome, impaired fasting glucose and obesity, as predictors of incident diabetes in 14 120 hypertensive patients of ASCOT-BPLA: comparison of their relative predictability using a novel approach.

AIMS: To evaluate, in hypertensive patients, whether the metabolic syndrome is a better predictor of new-onset diabetes compared with impaired fasting glucose, obesity or its other individual components alone, or collectively. METHODS: Cox models were developed to assess the risk of new-onset diabetes associated with the metabolic syndrome after adjusting for a priori confounders (age, sex, ethnicity and concomitant use of non-cardiovascular medications), its individual components and other determinants of new-onset diabetes. Area under receiver operator curves using the metabolic syndrome or models of impaired fasting glucose were compared, and the ability of these models to correctly identify those who (after 5-years of follow-up) would or would not develop diabetes was assessed. RESULTS: The metabolic syndrome adjusted for a priori confounders and its individual components, and further adjusted for other determinants, was associated with significantly increased risk of new-onset diabetes [1.19 (1.00-1.40), P = 0.05 and 1.22 (1.03-1.44), P = 0.02, respectively]. The discriminative ability of the metabolic syndrome model [area under receiver operating curve: 0.764 (0.750-0.778)] was significantly better than the model of impaired fasting glucose [0.742 (0.727-0.757)] (P < 0.001). The metabolic syndrome correctly allocates the risk of new-onset diabetes in a significantly higher proportion of patients (62.3%) than impaired fasting glucose status (37.7%) (P < 0.001). The presence of both the metabolic syndrome and impaired fasting glucose were associated with an approximately 9-fold (7.47-10.45) increased risk of new-onset diabetes. Among normoglycaemic patients, the metabolic syndrome was also associated with significantly increased risk of new-onset diabetes, after adjusting for BMI and a priori confounders [1.66 (1.29-2.13)]. CONCLUSIONS: Both impaired fasting glucose and the metabolic syndrome predict the risk of new-onset diabetes; however, the metabolic syndrome is a better predictor than impaired fasting glucose in assigning the risk of new-onset diabetes in hypertensive patients, and among those with normoglycaemia.

The economic consequences of non-adherence to lipid-lowering therapy: results from the Anglo-Scandinavian-Cardiac Outcomes Trial.

BACKGROUND: Adherence to lipid-lowering therapy in clinical practice is less than ideal. Analysis of registry data has indicated that this is associated with poor outcomes. The objective of the present analysis was to assess the impact of high adherence to drug (defined as > 80% of days covered), compared with low adherence to drug (< 50% of days covered) in terms of risk of events and long-term economic consequences. DESIGN: Open-label follow up of a randomised placebo-controlled trial in hypertensive patients. METHODS: Cox proportional hazards and Poisson regression models were used to assess the hazard ratio of patients with high adherence compared with low adherence while controlling for cardiovascular risk. A Markov model was used to predict the long-term costs and health outcomes associated with poor adherence during the follow-up period. RESULTS: Both statistical models indicated that high adherence is associated with improved prognosis [Cox model: 0.75; 95% confidence interval (CI): 0.56-0.98, Poisson model hazard ratio: 0.73; 95% CI: 0.58-0.98]. Discounted at 3.5% per year, the Markov model predicts that as a consequence of higher adherence during the follow-up period, costs would be higher (1689 pounds per patient compared with 1323 pounds per patient) because of higher drug costs, but the projected survival and quality-adjusted survival (QALY) would also be longer (10.83 compared with 10.81 life years and 8.13 compared with 8.11 QALYs). CONCLUSION: Given the higher risk of cardiovascular events associated with low adherence shown here, measures to improve adherence are an important part of the prevention of cardiovascular disease.

Measurement of intracellular magnesium in a vascular smooth muscle cell line using a fluorescent probe.

Until recently, direct measurement of intracellular free magnesium has been complex and difficult. However, fluorescent probes are now available, based on the same principle as well-established probes for free calcium. Using one such probe, mag-fura-2, we have estimated basal intracellular magnesium concentrations in the A7r5 rat vascular smooth muscle cell line. This level was unaffected by numerous pharmacological manipulations, including agonist stimulation and depolarisation. The possible implications of these findings are discussed.

Role of polyamines in hypertension induced by angiotensin II.

OBJECTIVE: The aim was to investigate the involvement of polyamines in the development of cardiovascular hypertrophy in a rat angiotensin II infusion model of hypertension. METHODS: Rats were chronically infused with a low dose of angiotensin II (83 ng.min-1.rat-1) or vehicle by osmotic minipumps. The polyamine content of the cardiovascular organs and liver was measured by HPLC, and the blood pressure of conscious rats was determined by a tail cuff method. The mesenteric arterial beds were perfusion fixed in situ and medial and luminal cross sectional areas were determined by computer assisted planimetry. Cardiac hypertrophy was assessed by determination of ventricular:body weight ratios. RESULTS: Angiotensin II infusion caused an increased concentration of polyamines in the ventricles and aorta within hours of beginning the infusion, and within days in the mesenteric arteries. Polyamine content of the liver was unaffected. Hypertrophy of the myocardium and mesenteric arteries in association with the increased blood pressure was evident. CONCLUSIONS: A low dose of angiotensin II stimulates an early biochemical marker of growth, the polyamines, in cardiovascular tissues but not in the liver. The increase in tissue polyamines is associated with cardiovascular hypertrophy and the development of hypertension.

Changes in plasma noradrenaline concentration following sympathetic stimulation by gradual tilting.

Plasma noradrenaline concentration was determined by a radioenzymatic method in 10 normal individuals who were subjected to a stepwise tilt through 45 degrees. A gradual increase in noradrenaline was observed with maximal values occurring in most subjects following the full 45 degrees of tilt. Maximal levels were sustained for up to 30 min. In two subjects who fainted, the syncopal episode followed an initial sympathetic postural response as shown by a rise in plasma noradrenaline. For the remaining subjects a significant correlation was found between changes in plasma noradrenaline and mean arterial pressure.

De novo cardiac beta adrenoceptor synthesis in adult rats under normoxic and hypoxic conditions.

Bromoacetylalprenololmenthane (BAAM), an alkylating irreversible beta adrenoceptor antagonist, was used to study in vivo beta adrenoceptor synthesis in adult rat left ventricle under normoxic and hypoxic conditions. In normoxic conditions cardiac beta adrenoceptor density decreased by 50% 15 h after treatment and recovered to control values after about 250 h. A similar decrease in receptor density and pattern of recovery was found in environmental hypoxia. Neither hypoxia nor treatment with BAAM had a significant effect on the dissociation constant of the radioligand. These results show that cardiac beta adrenoceptor synthesis occurs rather slowly and suggest that alteration of the rate of receptor synthesis in hypoxic states is not a major determinant of reported changes in density.

The effects of antihypertensive therapy on carotid vascular structure in man.

OBJECTIVE: An increased carotid intima-media thickness (IMT) has been found to be associated with a number of cardiovascular risk factors such as age, hypertension, cigarette smoking, hypercholesterolaemia and left ventricular hypertrophy. Our objective was to assess whether carotid intima-media thickness in hypertensive patients could be reduced by antihypertensive therapy. METHODS: 13 hypertensive patients, 10 previously untreated, were examined using carotid ultrasonography and echocardiography at baseline and then at 8 weeks and 39 weeks after commencement of antihypertensive therapy with ramipril and the second-line addition of felodipine. RESULTS: By the end of the study significant regression of IMT (0.1(0.05-0.16) mm, F-value 10.2, P < 0.01) and left ventricular mass index had occurred (25(10.7-39.3) g/m2, F-value 9.7, P < 0.01). The reduction in IMT was significantly related to the reduction in mean arterial pressure, r = 0.55, P = 0.05). CONCLUSION: Antihypertensive therapy with ramipril and felodipine causes regression of IMT in hypertensive patients, probably chiefly through blood pressure reduction. Large prospective studies are required to assess whether a reduction in IMT results in a reduction in morbidity and mortality.

Failure of plasma norepinephrine to consistently reflect sympathetic activity in humans.

To determine whether venous plasma norepinephrine concentrations consistently reflect changes in sympathetic nervous activity, the influence of mental arithmetic, static handgrip, and submaximal bicycle exercise on intra-arterial blood pressure, heart rate, and plasma norepinephrine was studied in 51 subjects with untreated essential hypertension (mean age, 46 years; range, 16-69 years). At rest, plasma norepinephrine was unrelated to age or blood pressure. Mental arithmetic increased mean arterial pressure from 108 +/- 18 to 127 +/- 18 mm Hg (mean +/- S.D.; p less than 0.001) and heart rate from 69 +/- 7 to 93 +/- 13 beats/min (p less than 0.001) but not plasma norepinephrine (547 +/- 297 to 518 +/- 250 pg/ml). Isometric exercise raised mean arterial pressure from 115 +/- 18 to 148 +/- 21 mm Hg (p less than 0.001) and heart rate from 76 +/- 9 to 95 +/- 13 beats/min (p less than 0.001) but not plasma norepinephrine (683 +/- 253 to 741 +/- 253 pg/ml). Bicycle exercise increased mean arterial pressure from 114 +/- 20 to 146 +/- 26 mm Hg (p less than 0.001), heart rate from 77 +/- 9 to 128 +/- 19 beats/min (p less than 0.001), and plasma norepinephrine from 645 +/- 228 to 1151 +/- 462 pg/ml (p less than 0.001). Both the maximum mean arterial pressure and the peak heart rate attained during bicycle exercise were related to the exercise plasma norepinephrine level (r = 0.33, p less than 0.02 and r = 0.28, p less than 0.03, respectively). Increases in plasma norepinephrine with exercise were not greater in older or more hypertensive subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood pressure and associated factors in a rural Kenyan community.

Blood pressure (BP) and associated factors were determined in 1737 men in a remote Kenyan agricultural community. Systolic BP showed no significant rise with age until after 54 years; diastolic BP showed a small rise with age. Both systolic and diastolic BP correlated with weight independent of age. Systolic and diastolic BP correlated positively with casual urinary sodium/potassium and negatively with potassium/creatinine ratios. Both systolic and diastolic BP correlated significantly with the number of years of education, as did urinary sodium/potassium and sodium/creatinine ratios. Potassium/creatinine ratios were negatively correlated with the number of years of education. Blood pressure and urinary sodium/creatinine ratios were significantly lower in subsistence farmers compared with those in other occupations, and potassium/creatinine ratios were significantly higher. Two pilot studies of Luo tribesmen showed a strong correlation between casual urinary electrolyte ratios and those derived from 24-hour urine samples and a greater variance of sodium excretion between these people than that found within individuals. These results suggest that a relationship between BP and casual urine electrolyte estimations may be identifiable in communities where there is less day-to-day dietary variation. They also suggest that some of the changes in BP associated with urbanization could be mediated by changes in dietary electrolytes.

Left ventricular hypertrophy and QT dispersion in hypertension.

The interlead variation in QT length on a standard electrocardiograph reflects regional repolarization differences in the heart. To investigate the association between this interlead variation (QT dispersion) and left ventricular hypertrophy, we subjected 100 untreated subjects to 12-lead electrocardiography and echocardiography. Additionally, 24 previously untreated subjects underwent a 6-month treatment study with ramipril and felodipine. In the cross-sectional part of the study, QT dispersion corrected for heart rate (QTc dispersion) was significantly correlated with left ventricular mass index (r = .30, P < .01), systolic pressure (r = .30, P < .01), the ratio of peak flow velocity of the early filling wave to peak flow velocity of the atrial wave (E/A ratio) (r = -.22, P = .02), isovolumic relaxation time (r = .31, P < .01), and age (r = .21, P < .04). In the treatment part of the study, lead-adjusted QTc dispersion decreased from 24 to 19 milliseconds after treatment, and after a subsequent 2 weeks of drug washout remained at 19 milliseconds (P < .01). The changes in left ventricular mass index at these stages were 144, 121, and 124 g/m2 (P < .01). Systolic pressure decreased from 175 to 144 mm Hg and increased again to 164 mm Hg after drug washout (P < .01). The E/A ratio (0.97, 1.02, and 1.02; P = 69) and isovolumic relaxation time (111, 112, and 112; P = .97) remained unchanged through the three assessment points. In conclusion, QT dispersion is increased in association with an increased left ventricular mass index in hypertensive individuals. Antihypertensive therapy with ramipril and felodipine reduced both parameters. If an increased QT dispersion is a predictor of sudden death in this group of individuals, then the importance of its reduction is evident.

Factors influencing blood pressure and heart rate variability in hypertensive humans.

We examined the influence of baroreceptor reflex sensitivity (the increase in pulse interval in response to a phenylephrine-induced increase in blood pressure), age, blood pressure, and beta-adrenergic receptor blockade on the variability of blood pressure and heart rate in essential hypertension. Fifty-six subjects were studied before treatment; intra-arterial blood pressure was recorded outside the hospital for 24 hours. Variability was defined (from all beats occurring while subjects were awake) as the standard deviation about the average waking value for mean arterial pressure (MAP) or pulse interval. The correlation (r) between baroreceptor reflex sensitivity and blood pressure variability was -0.47 (p less than 0.0002). Baroreceptor reflex sensitivity was the only independent determinant of blood pressure variability on multiple regression analysis. Thirty subjects were restudied after 5 months of beta-adrenergic receptor blockade. Ambulatory blood pressure was lower during treatment, whereas pulse interval, its variability, and baroreceptor reflex sensitivity were higher. Blood pressure variability was unchanged. The variability of MAP was inversely correlated with baroreceptor reflex sensitivity before (r = -0.42, p less than 0.02) and during (r = -0.45, p less than 0.02) treatment, but it was unrelated to the average ambulatory MAP or to the variability of pulse interval either before or during beta-blockade. Sixteen subjects whose average waking ambulatory blood pressure was 140/90 mm Hg or less were not treated. This group of borderline hypertensive subjects had less variable MAP than did the remaining 40 subjects (12.4 +/- 2.3 [SD] vs 14.5 +/- 2.5 mm Hg; p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Ethnic differences in the hypertensive heart and 24-hour blood pressure profile.

Black hypertensive persons have been observed to have a greater degree of left ventricular hypertrophy than white hypertensives. However, previous studies have matched groups for blood pressure (BP) measured in the clinic, and it has been demonstrated that black hypertensives have an attenuated nocturnal BP dip. Clinic BPs may thus underestimate mean 24-hour BP in this group. To investigate whether the differences in left ventricular hypertrophy can be accounted for by the greater mean 24-hour BP in black hypertensives, 92 previously untreated hypertensives were studied with 24-hour ambulatory BP monitoring and echocardiography. The 46 black hypertensives (24 men and 22 women) were matched with the 46 white hypertensives for age, gender, and mean 24-hour BP. Despite similar mean 24-hour BPs (blacks, 142/93 mm Hg; whites, 145/92 mm Hg; P=.53/.66), the black group had a smaller mean nocturnal dip than the white group (blacks, 8/8 mm Hg; whites, 16/13 mm Hg; P<.01). In addition, mean left ventricular mass index (LVMI) was greater (blacks, 130 g/m2; whites, 107 g/m2; P<.001). Mean 24-hour systolic BP was significantly related to LVMI in both groups (blacks, r=.45, P<.01; whites, r=.56, P<.01). However, systolic BP dip correlated inversely with LVMI only in the black group (blacks, r=-.30, P<.04; whites, r=.05, P=.76). In a multiple regression model, LVMI was independently related to both mean daytime BP and mean nocturnal BP dip in black subjects but only to mean daytime BP in white subjects. In conclusion, the increased left ventricular hypertrophy observed in black hypertensives compared with white hypertensives is not accounted for by differences in mean 24-hour BP. However, LVMI in black hypertensives appears to be more dependent on nocturnal BP than that in white hypertensives; this, coupled with the attenuated BP dip in black hypertensives, suggests that the BP profile rather than 24-hour BP may be important in determining the differences in left ventricular hypertrophy.

Platelet hyperaggregability and increased alpha-adrenoceptor density in anorexia nervosa.

Plasma norepinephrine concentrations in a group of malnourished patients with anorexia nervosa were significantly (P less than 0.002) lower than those in an age- and sex-matched group of normal subjects. Platelet total alpha-adrenoceptor densities of these patients significantly (P less than 0.002) exceeded those of the controls. The increased total alpha-adrenoceptor density was due to an increase in the alpha 2-adrenoceptor receptor subtype, which mediates epinephrine-induced platelet aggregation. Accordingly, the aggregation response of the patients' platelets was significantly (P less than 0.002) enhanced after epinephrine challenge. We suggest that the starvation-induced fall in plasma norepinephrine levels is associated with the up-regulation of platelet alpha-adrenoceptors. This, in turn, accounts for exaggerated epinephrine-induced platelet aggregation in anorexic patients.

Characterisation of a high-affinity VIP receptor in human lung parenchyma.

A method is described for preparing human lung parenchymal membranes essentially free of carbon contamination. Using this technique, a high-affinity 125I-VIP-binding site has been characterised. The receptor density is approx. 200 fmol/mg protein, and the Kd of 125I-VIP by saturation binding is 200 pM. The dissociation kinetics are complex and cannot be described by first-order kinetics. Several VIP-related peptides displace 125I-VIP from this binding site with a rank order of potency: VIP greater than rat GRF greater than PHM greater than PHI greater than human GRF greater than secretin greater than glucagon. Displacement curves of these peptides exhibited slope factors significantly less than unity with the exception of human GRF.

Autoradiographic localisation of VIP receptors in human lung.

Localisation and pharmacological properties of the VIP receptor in human lung sections are described. The receptor density determined by saturation analysis using 125I-VIP is approx. 100 fmol/mg protein, with a Kd of approx. 600 pM. Inhibition of 125I-VIP binding with VIP and related peptides gives a rank order of potency: VIP greater than peptide histidine methionine greater than secretin. Light microscope autoradiography reveals specific VIP binding sites, with a high density over the pulmonary artery smooth muscle and the alveolar walls and with a lower density over the bronchial epithelium.

Low-density lipoproteins increase intracellular calcium in aequorin-loaded platelets.

Low-density lipoproteins activate isolated human platelets. The mechanism of this activation is unknown, but may involve increased phosphoinositide turnover. We have examined the effect of low-density lipoproteins on intracellular calcium concentrations in platelets loaded with the photoprotein aequorin. The lipoproteins induced concentration-dependent increases in intracellular calcium, associated with shape change and aggregation. These responses could be partially inhibited by the removal of extracellular calcium and by pre-incubation with acetylsalicylic acid. They were also antagonised by agents which increase cellular concentrations of cyclic adenosine and guanosine monophosphates. It is not clear whether the platelet-lipoprotein interaction involves a 'classical' lipoprotein receptor.

Ventricular arrhythmias in hypertension: in which patients do they occur?

OBJECTIVE: It has been suggested that the increased incidence of sudden death in hypertensive patients, particularly those with left ventricular hypertrophy, may be casually related to the increased number and complexity of ventricular arrhythmias that have been demonstrated in these patients. The objective of the present study was to assess some of the factors which might be responsible for these arrhythmias. SUBJECTS AND METHODS: One hundred and three untreated subjects were divided into four groups on the basis of blood pressure and echocardiographic measurements: hypertensive patients with left ventricular hypertrophy (n = 38), hypertensive patients without left ventricular hypertrophy (n = 16), patients with borderline or white-coat hypertension (n = 26) and normotensive subjects (n = 23). Each subject underwent two-dimensional and Doppler echocardiography, 12-lead electrocardiogram examination, 12-lead electrocardiogram exercise stress testing, 24-h ambulatory blood pressure monitoring and 24-h Holter monitoring. A further 17 hypertensive patients with left ventricular hypertrophy who were on long-term antihypertensive therapy were also investigated in the same manner and compared with untreated hypertensive patients with left ventricular hypertrophy who were matched for age, sex and race. RESULTS: Untreated hypertensive patients, even with left ventricular hypertrophy, had a low prevalence of frequent or complex arrhythmias (seven out of 80 patients with Lown score 2+). In contrast, hypertensive patients with left ventricular hypertrophy on long-term antihypertensive therapy had a significantly greater prevalence of complex arrhythmias than untreated patients with left ventricular hypertrophy (eight out of 17 treated patients compared with two out of 17 untreated patients with Lown score 2+). CONCLUSIONS: Hypertensive patients with left ventricular hypertrophy who had received long-term antihypertensive therapy were found to have a high prevalence of complex ventricular arrhythmias, which was in contrast to untreated hypertensive patients, even those with left ventricular hypertrophy. This may reflect the consequences on the left ventricle of long-term antihypertensive treatment. If complex ventricular arrhythmias are implicated in the excess of sudden deaths in hypertensive patients, this might be an important factor.

Dopamine produces forearm vasodilatation following alpha-adrenoceptor blockade by an action on vascular dopamine (DA1) receptors in man.

The purpose of this study was to investigate the receptor type mediating dopamine-induced forearm vasodilatation following alpha-adrenoceptor blockade. Forearm blood flow (FBF) was measured using venous occlusion plethysmography in normal volunteers. Intra-arterial (i.a.) dopamine alone produced variable and small changes in FBF. However, following alpha-adrenoceptor blockade with phenoxybenzamine, dopamine infusion resulted in forearm vasodilatation in the infused arm. This effect was not antagonized by the beta-adrenoceptor antagonist propranolol, but was antagonized by the vascular dopamine receptor antagonist, sulpiride, the (d) enantiomer being more active than the (l). It is concluded that i.a. dopamine induces forearm vasodilatation following alpha-adrenoceptor blockade by an action on vascular dopamine (DA1) receptors similar to those described in the renal and mesenteric vasculature of other species.

An equivalence study of the safety and efficacy of a fixed-dose combination of perindopril with indapamide versus fixed-dose combinations of captopril with hydrochlorothiazide and enalapril with hydrochlorothiazide in the treatment of hypertension.

OBJECTIVE: The aim of this multicenter, randomly allocated, double-blind, parallel-group study was to evaluate the equivalence of three fixed-dose combination drugs in mild to moderate hypertension: perindopril + indapamide (4 + 1.25 mg), captopril + hydrochlorothiazide (50 + 25 mg) and enalapril + hydrochlorothiazide (20 + 12.5 mg). PATIENTS AND METHODS: After a single-blind, 4-week, placebo run-in phase, 527 patients (mean +/- SD age 54.5 +/- 1.2 years) with a supine diastolic blood pressure of 101.2-101.7 mmHg were randomly assigned to one of the three treatments for 8 weeks. The main evaluation criteria were diastolic blood pressure and serum potassium concentration. Equivalence was assessed on an intention-to-treat basis, using Schuirmann's method, which involves performing two one-tailed statistical tests on the data. Thirty-five patients were withdrawn from the study but there were no differences between groups in the reasons for withdrawal. RESULTS: Diastolic blood pressure decreased by between 13.1 and 14.2 mmHg in the three groups. The 90% confidence intervals for the differences between perindopril + indapamide and the other treatments were -1.1, +1.7 mmHg for captopril + hydrochlorothiazide and -0.4, +2.6 mmHg for enalapril + hydrochlorothiazide. Schuirmann's test was highly statistically significant (P<0.001 for perindopril + indapamide versus captopril + hydrochlorothiazide; P<0.002 for perindopril + indapamide versus enalapril + hydrochlorothiazide), so that the two one-sided hypotheses that the treatments were not equivalent were rejected at the nominal level of alpha = 0.05. Similarly, the safety of the treatments was equivalent in terms of serum potassium. The 90% confidence intervals of the differences between perindopril + indapamide and the other treatments were -8.7, -1.6% for captopril + hydrochlorothiazide (P = 0.004) and -1.5, +2.7% for enalapril + hydrochlorothiazide (P<0.001). CONCLUSIONS: We conclude that the safety and efficacy of perindopril + indapamide, captopril + hydrochlorothiazide and enalapril + hydrochlorothiazide were equivalent after 8 weeks of treatment in patients with mild to moderate hypertension.

Consequences of impaired arterial baroreflexes in essential hypertension: effects on pressor responses, plasma noradrenaline and blood pressure variability.

In 62 untreated patients with essential hypertension, arterial baroreflex sensitivity (BRS) for heart rate, i.e. the change in pulse interval in response to a phenylephrine-induced increase in blood pressure, was compared with (1) haemodynamic changes during mental arithmetic, a reaction time test, isometric and bicycle exercise; (2) plasma noradrenaline (PNA) concentrations at rest, and during bicycle exercise and; (3) the variability of ambulatory intra-arterial blood pressure. Subjects with diminished BRS showed the following responses: (1) higher mean arterial blood pressure (MAP) during all four stimuli; (2) a greater pressor response to cycling; (3) tended to have higher PNA concentrations during bicycle exercise and; (4) greater variation in ambulatory blood pressure. Furthermore, an increased pressor response to the reaction time test and increased ambulatory blood pressure variability was seen in younger subjects with reduced BRS. When subjects were subgrouped according to their WHO stage of hypertension, there were significant inverse relationships between BRS and the pressor responses to mental arithmetic, the reaction time test and cycling, and with ambulatory blood pressure variability only in those subjects without ECG or radiographic evidence of left ventricular enlargement (WHO stage I hypertension; n = 42). None of these correlations were present in subjects with one or both of these clinical findings (WHO stage II; n = 20). Pressor responses to the four laboratory stimuli and ambulatory blood pressure variability were similar in both groups, despite significantly higher arterial pressure and significantly lower BRS in WHO stage II subjects. These results suggest that differing mechanisms may be responsible for the regulation of blood pressure variation in these two groups. The arterial baroreflex can buffer acute changes in blood pressure in subjects with WHO stage I hypertension, but this ability is attenuated with progressive reduction of BRS. With the development of clinically evident cardiac adaptation to hypertension (WHO stage II), the contribution of the arterial baroreflex to the regulation of blood pressure is no longer detectable and the influence of cardiac and somatic afferents to reflex circulatory adjustments to activity may predominate.