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1 The ability of captopril, 150 mg three times daily by mouth, to effect sustained reduction in plasma angiotensin II, with converse increases in circulating angiotensin I, and in active, inactive and total renin concentrations, has been assessed. 2 During prolonged treatment with captopril alone, and 12 h after the last dose of the drug, plasma angiotensin II remained approximately one-sixth of basal concentrations, while angiotensin I and renin concentrations were proportionately increased. However, further increases in angiotensin I, and in active, inactive and total renin concentrations, were seen 2 and 6 h after the morning dose of 150 mg captopril. 3 Inter-dose variations in plasma aldosterone and blood pressure were not closely related to concurrent variations in the renin-angiotensin system. 4 Arguments are presented for relying on measurements of plasma renin and angiotensin concentrations rather than of renin activity or aldosterone in assessing the effectiveness of converting enzyme inhibition. [ABSTRACT FROM AUTHOR]

1 We have compared, in patients with severe hypertension, the administration of intravenous labetalol by single rapid injection, by repeated bolus injections, and by incremental infusion. 2 Incremental infusion was the most consistently (albeit not invariably) effective method, and that least prone to cause side-effects. 3 An occasional very marked decrease in blood pressure was seen with all these techniques but least often with incremental infusion. Thus close and continuous supervision is mandatory. 4 All three methods produced slight but significant decreases in heart rate, and in plasma angiotensin II and aldosterone. 5 Intravenous labetalol was also effective in controlling hypertensive crises of phaeochromocytoma and those following the withdrawal of clonidine. 6 In a total of 70 severely hypertensive patients given intravenous labetalol, none showed adverse neurological or cardiological sequelae. [ABSTRACT FROM AUTHOR]

1 Prolonged infusion (11 h) of both saralasin and angiotensin- converting enzyme inhibitor (SQ20881) gradually lowered BP in two- kidney hypertensive rats to levels similar to that in normotensive rats infused with dextrose. 2 Saralasin did not lower BP in DOCA-salt hypertensive rats. 3 These observations support the notion that in chronic renal hypertension, angiotensin II may maintain hypertension by a slowly developing action. 4 Plasma angiotensin II in rats infused with SQ20881 was suppressed relative to renin, but was not eliminated. 5 Chromatography of angiotensin II extracts from dogs infused with converting enzyme inhibitor (SQ14,225) showed that the very high levels of angiotensin I achieved after treatment with SQ14,225 can lead to falsely high estimated angiotensin II levels as a result of angiotensin I cross-reacting with the angiotensin II assay. [ABSTRACT FROM AUTHOR]

Previously we demonstrated that pulse pressure is a strong risk factor for coronary events in male hypertensive subjects in the MRC Mild Hypertension Trial, whereas stroke is best predicted by mean blood pressure. In this study, we have assessed the implications of this finding in the treatment of mild essential hypertension. We examined the relationship between diastolic blood pressure and both coronary disease risk and stroke when these events were predicted by the above blood pressure measures using an empirical linear model and multivariate logistic regression models that contained data from the MRC trial. Under these circumstances, the predicted stroke risk increased progressively with increasing values of diastolic blood pressure, but in both empirical and formal statistical models, the predicted risk of a coronary event exhibited a J-shaped relationship with diastolic blood pressure. These results suggest that if coronary event risk in mild essential hypertension is predicted by pulse pressure then it may increase at low values of diastolic blood pressure, in contrast to stroke risk, which declines continuously as diastolic blood pressure falls within the physiological range. This raises the possibility that different sequelae of hypertension are best predicted by different measures of blood pressure and that the effect of treatment on stroke and coronary events in some circumstances may be discordant.

Abnormal renovascular resistance and glomerular filtration rate are characteristic of established hypertension and may also be involved in its pathogenesis. To determine renal and body fluid correlates of the predisposition to high blood pressure, we examined 100 healthy young adults with high or low blood pressure. Within each group, half had parents with high blood pressures, and half had parents with low blood pressures. Renal function and hemodynamics, body fluid volumes, and relevant hormones and genotypes were measured. Subjects with high personal and parental blood pressures had the highest levels of glomerular filtration rate (P<0.02) and plasma active renin concentration and low levels of exchangeable sodium and plasma volume (P<0.02). High glomerular filtration rate was not associated with differences in urinary kallikrein or prostaglandins. Polymorphisms of the renin, angiotensin-converting enzyme, and angiotensinogen genes were not associated with differences in glomerular filtration rate or renin. Subjects with high personal, but low parental, blood pressures had low exchangeable sodium and plasma volumes (P<0.02) but normal glomerular filtration rates. In this population, extracellular volume depletion and high renin are correlates of high blood pressure in early adulthood, and glomerular hyperfiltration is a feature of those who also have familial predisposition to high blood pressure.

Established in 1968 the Glasgow Blood Pressure Clinic has over 11,000 patients on its computer record. Up to 1980, mortality from all-causes and from cardiovascular causes was high: relative risks compared with two local control populations were greater than 2.0. Since 1980, all-cause mortality has decreased to 1.31 (859 deaths, CI 1.23-1.39). Lower mortality from cardiovascular causes, particularly coronary heart disease, contributes to the decrease. Reasons for the decrease are under investigation currently. Referral of patients with slightly lower blood pressure contributes, as may better blood pressure control with newer antihypertensive drugs. ACE inhibitors and calcium channel blockers were introduced in 1980 and during the 16-year period to 1995, all-cause mortality has decreased most in patients taking ACE inhibitor. A decrease also occurred in patients taking antihypertensive drugs other than ACE inhibitor.

Three questions related to cancer and blood pressure are discussed. (i) Is cancer related in some way to hypertension, or to blood pressure? Several studies show a relation of blood pressure and cancer in populations. However, our own experience, based on a cohort of 15,411 subjects with BP measured in the 1970s and with 1,392 fatal cancers since, shows no relation of cancer risk and diastolic pressure. Nor were cancer numbers (n=72) observed in the 1,078 untreated hypertensives of the Glasgow Blood Pressure Clinic different from those expected (n=71.2) in a control population matched for age, sex and smoking habit. (ii) Do antihypertensive drugs promote cancer? Atenolol and calcium channel blockers have been suspected of this, but evidence of larger studies, including two of our own, is negative: relative risk for cancer in our patients taking CCB was 1.02 (CI 0.82-1.27). (iii) Do antihypertensive drugs protect against cancer? A study of ours based on the Glasgow Clinic raises this possibility: relative risk for incident cancer amongst 1,559 patients taking ACE inhibitor was 0.72 (CI 0.55-0.92).

Background: Previous studies have reported an increased risk of cancer with calcium-channel blockers in man. Other work in animals suggests that inhibitors of angiotensin-I-converting enzyme (ACE) protect against cancer. We aimed to assess the risk of cancer in hypertensive patients receiving ACE inhibitors or other antihypertensive drugs., Methods: Our retrospective cohort study was based on the records of 5207 patients who attended the Glasgow Blood Pressure Clinic between Jan 1, 1980, and Dec 31, 1995. The patients' records are linked with the Registrar General Scotland and the West of Scotland Cancer Registry., Findings: Compared with the West of Scotland controls, the relative risks of incident and fatal cancer among the 1559 patients receiving ACE inhibitors were 0.72 (95% CI 0.55-0.92) and 0.65 (0.44-0.93). Among the 3648 patients receiving antihypertensive drugs other than ACE inhibitors (calcium-channel blockers 1416, diuretics 2099, beta-blockers 2681), the corresponding relative risks were 110 (0.97-1.22) and 1.03 (0.87-1.20). The relative risk of cancer was lowest in women on ACE inhibitors: 0.63 (0.41-0.93) for incident cancer; 0.48 (0.23-0.88) for fatal cancer; and 0.37 (0.12-0.87) for female-specific cancers. The reduced relative risk of cancer in patients on ACE inhibitors was greatest with follow-up of longer than 3 years. Calcium-channel blockers, diuretics, and beta-blockers had no apparent effect on risk of cancer., Interpretation: Long-term use of ACE inhibitors may protect against cancer. The status of this finding is more that of hypothesis generation than of hypothesis testing; randomised controlled trials are needed.

Background: Increased activity of the sympathetic nervous system has been proposed as a cause of high blood pressure (BP) and may be related to diet and body weight. To determine the role of these factors in predisposition to high BP, we studied 100 young adults with high or low BP from families in which both parents had either high or low BP., Methods and Results: Plasma catecholamine, glucose, and insulin levels were measured before and after an oral glucose load. There was a significant correlation between fasting plasma norepinephrine and mean arterial pressure (P=.001). Subjects with high BP, irrespective of parental BP, were heavier (P=.003) and fatter (P=.002) and had a greater rise in plasma insulin (P=.003) following glucose than those with low BP. Offspring with high BP whose parents also had high BP showed an unexpected rise in plasma epinephrine (P=.004) following glucose. This adrenal medullary response was not the result of high parental or high personal BP alone as it was not seen in offspring with low BP whose parents had high BP or in offspring with high BP whose parents had low BP., Conclusions: Irrespective of family history, high BP is associated with increased body weight and hyperinsulinemia and reflects personal environment and behavior. However, abnormal epinephrine release is characteristic of the combination of genetic, environmental, and behavioral factors that is associated with high personal BP and a familial predisposition to high BP.

The relation between serum potassium level and all-cause mortality was examined in a prospective study of 7,636 middle-aged British men followed for 11.5 years (1978-1991). Men being treated for hypertension had a significantly lower mean (+/- standard error) potassium level than men not in treatment (4.24 +/- 0.03 mmol/liter vs. 4.32 +/- 0.01 mmol/liter; p < 0.01). During the follow-up period of 11.5 years, after exclusion of the 374 men under antihypertensive treatment, there were 771 deaths from all causes in the remaining 7,262 men. A low potassium level (< 3.7 mmol/liter) was not associated with increased mortality. Elevated potassium levels > or = 5.2 mmol/liter were associated with a significant increase in mortality, particularly noncardiovascular deaths, even after adjustment for potentially confounding factors. However, serum potassium was strongly related to smoking, and the increased risk of mortality associated with elevated potassium was seen only among current smokers. In current smokers with raised potassium levels (> or = 5.2 mmol/liter) compared with smokers with levels under 5.2 mmol/liter, the relative risks of mortality were 1.7 (95% confidence interval (CI) 1.2-2.5) for deaths from all causes, 1.8 (95% CI 1.0-3.2) for all cancer deaths, and 2.5 (95% CI 1.1-5.6) for lung cancer deaths. In the 374 men receiving regular antihypertensive treatment, a low potassium level was not associated with excess mortality; those with raised potassium levels had excess risks for both cardiovascular and noncardiovascular deaths. The findings suggest that either raised potassium levels in association with smoking have an influence on the risk of death from noncardiovascular disease, particularly lung cancer, or a raised serum potassium level is a marker for some other risk factor associated with smoking. The prognostic and therapeutic implications of these observations warrant further exploration.

Low blood pressure is reported in Down's syndrome (DS). To assess this and determine whether low pressure results from the disease or from long-term residence in hospital, we measured blood pressure with a random-zero sphygmomanometer in three groups of patients: 52 DS inpatients, 62 DS outpatients, and 60 outpatients with other forms of mental handicap. Relative to normal reference populations, blood pressure was low in both DS inpatients (systolic, score -33 mm Hg, P < .0001) and DS outpatients (-25 mm Hg, P < .0001). It was normal in non-DS outpatients (-4.0 mm Hg, P = .3). Blood pressure rose normally with age in the non-DS group but not in the DS group. We conclude that blood pressure is low in DS and that this is a feature of the disease rather than of the protected environment in which patients live. A mechanism related to trisomy 21 is likely, and there may be a link with Alzheimer's disease (AD) because blood pressure is also low in Alzheimer's and a high proportion of Ds patients develop this disease. If, as is likely, blood pressure is lowered in Alzheimer's by the neuropathy, the same neuropathy developing early in DS may also reduce blood pressure.

Background: We studied the correlates of left ventricular mass (LVM) in 84 healthy young adults aged 16 to 24 years from the general population. Subjects were selected according to predisposition to hypertension into four groups with either high or low personal blood pressures and either high or low parental blood pressures., Methods and Results: LVM was measured by echocardiography, and measurements of blood pressure, heart rate, body dimensions, and plasma concentrations of components of the renin-angiotensin system were made under resting conditions. LVM was similar in individuals predisposed to hypertension (high personal and parental blood pressures) and those with contrasting predisposition (low personal and parental pressures). Regression analysis of the combined groups showed that LVM correlated closely with body size, particularly lean body mass (r=.69, P<.0001) and systolic (r=.35, P<.0001) but not diastolic blood pressure. Plasma angiotensin II (r=.39, P<.0001), renin (r=.302, P<.01), and angiotensin-converting enzyme (r=.22, P<.05) showed significant correlation with LVM. Multiple regression analysis revealed that plasma angiotensin II was the most important component of the renin-angiotensin system and that its effect was independent of systolic blood pressure and body size., Conclusions: These findings provide evidence in humans that angiotensin II exerts a direct on myocardial size. This association may have important implications for the complications and treatment of left ventricular hypertrophy.

Clinical trials show that drug treatment significantly decreases stroke risk in hypertension. The benefit as measured in clinical trials may be affected by changes of blood pressure at entry and by departure from randomised treatment, but the magnitude of such effects is disputed. We have assessed benefit from reduction of stroke using data from the MRC Trial of mild to moderate hypertension, taking these factors into account, and have studied the likely effect of recent guidelines. The original analysis suggested that 850 patients needed treatment for 1 year to prevent one stroke. Under the more conservative of two assumptions made about the effect of treatment, this falls to 695 patients when allowance is made for reduction of stroke in placebo group patients withdrawn and actively treated, to 680 patients when allowance is made for the fall in blood pressure after entry, and to 556 patients with allowance for both. When benefit is assessed in patients whose entry diastolic blood pressure was > or = 100 mm Hg, 557 patients require treatment annually per stroke saved and this is decreased to 360 patients when allowance is made for withdrawal and active treatment of placebo group patients. These results suggest that benefit from reduction of stroke was underestimated in the MRC trial and that this is likely to be present in most trials. Changes to diagnostic criteria for hypertension in new management guidelines are likely to have significant effects on the number of patients treated per stroke prevented.

1. The SA gene is expressed in the kidneys and is associated with hypertension in man and experimental animal models. Predisposition to hypertension is associated with renal haemodynamic abnormalities and increased renal SA gene expression. 2. We studied the distribution of the SA gene alleles (A1, A2), defined by the PstI polymorphism, in young adults with contrasting predisposition to hypertension to determine whether genetic variation at the SA gene locus is associated with variations in renal haemodynamics, electrolyte metabolism and the renin-angiotensin system. 3. The frequency of the A2 allele was not significantly different between subjects with high personal and parental blood pressures and subjects with low personal and parental blood pressures. We detected no overall relationship between blood pressures and SA genotype, even after taking sodium intake into account. 4. Glomerular filtration rate, renal blood flow, renal vascular resistance, plasma volume, exchangeable sodium and total body water did not differ according to SA genotypes. Moreover, we detected no significant effect of SA genotype on circulating components of the renin-angiotensin system or atrial natriuretic peptide. 5. In our population, genetic variation at the SA gene locus defined by PstI polymorphism does not influence the renal characteristics that contribute to the development of hypertension.