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A F Lever

Publications and source records attributed to A F Lever.

At least 19 recordsLinked to original sources
PubMed1992

Angiotensin II, angiotensin-converting enzyme inhibitors, and blood vessel structure.

Angiotensin-converting enzyme (ACE) inhibitors are effective hypotensive agents in hypertension of different types and degree. Probably, they lower pressure by reducing angiotensin II (AII); the varied timing of their hypotensive effect suggests that AII increases blood pressure in more than one way. Infusion studies show two effects of AII: at moderate dose, a rapid vasoconstrictor action; at lower dose, a slow-developing but ultimately large hypertensive effect. Vascular hypertrophy develops during the slow pressor response; at least part of the hypertrophy results from a nonpressor mechanism. In vitro studies show that AII has mitogenic and trophic actions on vascular smooth muscle cells in culture and that it stimulates synthesis of extracellular matrix proteins. One of these actions may produce the nonpressor component of vascular hypertrophy. ACE inhibitors lower pressure in the spontaneously hypertensive rat (SHR) and when given in young animals produce a hypotensive effect that endures long after the period of treatment. An action of endogenous AII, possibly a paracrine effect within the vessel wall, may cause vascular hypertrophy in young SHR with long-lasting effects on arterial pressure.

Angiotensin II↗
PubMed1992

Relation between coronary risk and coronary mortality in women of the Renfrew and Paisley survey: comparison with men.

Most epidemiological and intervention studies in patients with coronary artery disease have focused on men, the assumption being that such data can be extrapolated to women. However, there is little evidence to support this belief. We have completed a fifteen-year follow-up of 15,399 adults, including 8262 women, who lived in Renfrew and Paisley and were aged 45-64 years when screened between 1972 and 1976. We identified 490 deaths from coronary heart disease (CHD) in women and 878 in men. Women were more likely to have high cholesterol, to be obese, and to come from lower social classes than men, but they smoked less and had similar blood pressures. The relative risk--top to bottom quintile (95% Cl)--of cholesterol for coronary death after adjustment for all other risk markers was slightly greater in women (1.77 [1.45,2.16]) than in men (1.56 [1.32, 1.85]), but absolute and attributable risk were lower. Thus, women in the top quintile for cholesterol had lower coronary mortality (6.1 deaths per thousand patient years) than men in the bottom quintile (6.8 deaths per thousand patient years). Moreover, it was estimated that there would have been only 103 (21%) fewer CHD deaths in women, yet 211 (24%) fewer in men, if mortality had been the same for women and men in the lowest quintiles of cholesterol. Trends showing similar relative risks in these women, but lower absolute and attributable risks than in men, were present for smoking, diastolic blood pressure, and social class. There was no relation between obesity and coronary death after adjustment for other risks. Our results suggest that some other factors protect women against CHD. The potential for women to reduce their risk of CHD by changes in lifestyle may be less than for men.

Age Factors↗
PubMed1992

Effects of the angiotensin II receptor antagonist Losartan (DuP 753/MK 954) on arterial blood pressure, heart rate, plasma concentrations of angiotensin II and renin and the pressor response to infused angiotensin II in the salt-deplete dog.

1. The blood pressure, heart rate, hormonal and pressor responses to constant rate infusion of various doses of the angiotensin (type 1) receptor antagonist Losartan (DuP 753/MK 954) were studied in the conscious salt-deplete dog. 2. Doses in the range 0.1-3 micrograms min-1 kg-1 caused no change in blood pressure, heart rate or pressor response to angiotensin II (54 ng min-1 kg-1), and a dose of 10 micrograms min-1 kg-1 had no effect on blood pressure, but caused a small fall in the pressor response to angiotensin II. Infusion of Losartan at 30 micrograms min-1 kg-1 for 3 h caused a fall in mean blood arterial pressure from baseline (110.9 +/- 11.2 to 95.0 +/- 12.8 mmHg) and a rise in heart rate (from 84.6 +/- 15.1 to 103 +/- 15.2 beats/min). Baseline plasma angiotensin II (42.5 +/- 11.8 pg/ml) and renin (64.5 +/- 92.7 mu-units/ml) concentrations were already elevated in response to salt depletion and rose significantly after Losartan infusion to reach a plateau by 70 min. The rise in mean arterial blood pressure after a test infusion of angiotensin II (35.3 +/- 11.6 mmHg) was reduced at 15 min (11.8 +/- 6.8 mmHg) by Losartan and fell progressively with continued infusion (3 h, 4.3 +/- 3.3 mmHg). The peak plasma angiotensin II concentration during infusion of angiotensin II was unaffected by Losartan, but the rise in plasma angiotensin II concentration during infusion was reduced because of the elevated background concentration. Noradrenaline infusion caused a dose-related rise in mean blood arterial pressure (1000 ng min-1 kg-1, +19.9 +/- 8 mmHg; 2000 ng min-1 kg-1, +52.8 +/- 13.9 mmHg) with a fall in heart rate (1000 ng min-1 kg-1, -27.9 +/- 11.5 beats/min; 2000 ng min-1 kg-1, -31.2 +/- 17.3 beats/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1992

Essential hypertension: a disorder of growth with origins in childhood?

PURPOSE: To review evidence that essential hypertension is a growth-related disorder with origins in childhood and manifestations in adult life. PRINCIPAL EVIDENCE: Blood pressure rises with age in children and adults. In children, the rise closely relates to growth and to skeletal and sexual maturation. Adolescents with highest pressure are heavier and had as children grown fastest; as adults, they show the greatest increase of pressure with age and are more likely to develop hypertension and coronary heart disease. In adults, the rate of increase of pressure relates to earlier pressure. One interpretation of this is that a self-perpetuating mechanism is at work. Genetic and environmental factors influence these events. HYPOTHETICAL MECHANISMS: Most forms of secondary hypertension have two pressor mechanisms; a primary cause, e.g. renal clip, and a second process, which is slow to develop, capable of maintaining hypertension after removal of the primary cause, and probably self-perpetuating in nature. We suggest that essential hypertension also has two mechanisms, both based upon cardiovascular hypertrophy: (1) a growth-promoting process in children (equivalent to the primary cause in secondary hypertension); and (2) a self-perpetuating mechanism in adults.

Adult↗
PubMed1992

Abnormalities of glucocorticoid metabolism and the renin-angiotensin system: a four-corners approach to the identification of genetic determinants of blood pressure.

AIM: To assess the feasibility and utility of a new method to identify factors associated with increased predisposition to high blood pressure in young people. SUBJECTS: Eight hundred and sixty-four people aged 16-24 years and their parents. SETTING: Ladywell Medical Centre, Edinburgh, Scotland, UK. METHOD: Blood pressure was measured in 864 young adults and in both of their parents. Four groups of approximately 50 offspring were selected from the corners of a scatter diagram, with offspring blood pressure scores on one axis and combined parental blood pressure scores on the other. Blood and urine samples were taken for biochemical and genetic analyses. RESULTS: Two groups of offspring had parents with high blood pressure and two groups had parents with low blood pressure. When parental blood pressure was low, comparison of offspring with high and low blood pressure revealed significantly higher mean body mass index in offspring with high blood pressure, but no significant elevation of biochemical or hormonal variables. When parental blood pressure was high, comparison of offspring with high and low blood pressure also revealed a significant difference in body mass index, but in addition, offspring with high blood pressure and high parental blood pressure had higher levels of angiotensinogen, cortisol and 18-OH corticosterone. Restriction fragment length polymorphism analysis revealed that 27% of offspring at the greatest genetic risk (high personal and parental blood pressure) were homozygous for the larger allele of the glucocorticoid receptor gene compared with only 9% of those at lowest genetic risk (low personal and parental blood pressure). CONCLUSION: The combined biochemical and genetic findings suggest that abnormalities of glucocorticoid metabolism and the renin-angiotensin system may help to explain genetic predisposition to high blood pressure. The new sampling method is practicable and could be applied to the investigation of other continuously distributed variables which show familial aggregation.

Adolescent↗
PubMed1992

Trophic effects of hypophyseal hormones on resistance vessels and the heart in normotensive and renal hypertensive rats.

UNLABELLED: Arterial pressure is an important determinant of cardiovascular structure and relates positively to it. The purpose of this study was to determine whether pituitary hormones influence the relation of pressure and structure. Male Sprague-Dawley rats, aged 5 weeks, were studied in three groups: the first underwent hypophysectomy; the second was hypophysectomized but received replacement therapy with growth hormone and thyroxine; the third served as controls. Four days later half of each group underwent unilateral renal artery clipping, the other half serving as normotensive controls. For 5 weeks estimates were made of systolic blood pressure, heart rate, body weight and plasma renin activity. Rats were then killed; left ventricular, kidney and adrenal weights were determined and, using hindquarter perfusion, estimates were made of resistance at maximal dilatation (reflecting inner radius), and of maximal pressor response (reflecting wall thickness). RESULTS: (1) Hypophysectomy in non-clipped rats reduced growth rate, systolic blood pressure and heart rate while plasma renin activity rose. As related to pressure and to body weight, resistance at maximal dilatation, maximal pressor response, left ventricular weight remained at the juvenile values of a 5-week-old rat. Hormone replacement restored values to those of control rats aged 11 weeks. (2) Clipping in the control group rats increased systolic blood pressure more than in hypophysectomized and growth hormone and thyroxine receiving hypophysectomized groups even though plasma renin activity remained higher in hypophysectomized than in control rats. Plasma renin activity was highest in hypophysectomized rats with highest pressure. (3) Systolic blood pressure related positively to left ventricle weight, resistance at maximal dilatation, maximal pressor response and calculated wall thickness to inner radius ratios in all groups. However, these regressions were all, like renal structural adaptation, considerably depressed in the hypophysectomized group. Hormone replacement restored the relation of structure and pressure towards that of control group rats. Thus, growth hormone and thyroxine influence maturation of the normal cardiovascular system and greatly enhance its structural upward resetting in hypertension.

Animals↗
PubMed1992

Angiotensin II, vascular structure and blood pressure.

Angiotensin II (Ang II) in low dose raises blood pressure slowly by a mechanism which is not understood, but which is clearly different from the better known direct vasoconstrictor effect. Vascular hypertrophy develops during this slow pressor response, but is not wholly a consequence of the increase of pressure. We discuss non-pressor mechanisms by which Ang II may act as a growth factor to promote structural vascular change. Studies with cultured vascular smooth muscle cells suggest at least three possibilities, but none of these has been tested in vivo during slow pressor infusion of Ang II. The action of growth factors may be important in hypertension since increased arterial pressure causes vascular hypertrophy. Growth factors influence markedly the extent of this hypertrophic response and, however produced, vascular hypertrophy has an important influence on resistance and arterial pressure in hypertension.

Angiotensin II↗
PubMed1991

Body concentration of caesium-137 in patients from Western Isles of Scotland.

OBJECTIVES: To compare caesium-137 concentrations in patients from the Western Isles Health Board, Glasgow area, and other parts of the Scottish mainland, and to investigate the source of 137Cs in patients from the Western Isles. DESIGN: Study of hypertensive patients having electrolyte concentrations measured, including 137Cs. Interview by questionnaire of island subjects about intake of foods likely to contain radiocaesium and the source of these foods. Measurement of 137Cs and 134Cs in food, urine, and vegetation. SETTING: Scottish mainland and Western Isles, 1979-86. All measurements before Chernobyl nuclear accident. PATIENTS: 413 consecutive patients referred to the blood pressure unit for investigation of hypertension. 60 from the Western Isles, including 44 from North Uist; 32 from North Uist participated in the dietary analysis. MAIN OUTCOME MEASURES: Concentration of radiocaesium in the body, urine, food, and vegetation. Islanders' consumption of local produce. RESULTS: Patients from the Western Isles had five times higher body concentrations of 137Cs (median 2.54 (interquartile range 1.25-3.73)) Bq/gK) than did patients from around Glasgow (0.47 (0.26-0.66) Bq/gK) and other parts of the Scottish mainland (0.42 (0.24-0.71) Bq/gK). Islanders often consumed local milk and mutton, but ate local fish rarely. 137Cs and 134Cs were present in coastal (21.6 Bq/kg 137Cs, 0.25 Bq/kg 134Cs) and moorland (135.9, 0.65 Bq/kg) grasses and in islanders' urine (2.01, 0.013 Bq/l). Lower concentrations (0.336, 0.004 Bq/l), were found in the urine of Glasgow controls (p less than 0.001 for both isotopes). CONCLUSIONS: Islanders have excess body 137Cs concentrations, most of which probably comes from local milk and lamb. The radioactivity is not above the recommended safety limit. The presence of 134Cs suggests that nuclear reprocessing is the source of some of the radiocaesium.

Adolescent↗
PubMed1991

Angiotensin II causes vascular hypertrophy in part by a non-pressor mechanism.

Angiotensin II, when given in low doses, raises blood pressure slowly. When tested in vitro on vascular smooth muscle cells, it has mitogenic and trophic effects; it is not known if it has these effects in vivo. Our purpose was to determine whether vascular hypertrophy develops during slow pressor infusion of angiotensin II and, if so, whether it is pressure induced. Three experiments were done in rats infused subcutaneously with angiotensin II (200 ng/kg/min) by minipump for 10-12 days. Experiment 1: Angiotensin II gradually raised systolic blood pressure (measured in the tail) from 143 +/- 2 to 208 +/- 8 mm Hg (mean +/- SEM), significantly suppressing plasma renin and increasing threefold (NS) plasma angiotensin II. There was no loss of peptide in the pump infusate when tested at the end of the experiment. Experiment 2: In the perfused mesenteric circulation, vasoconstrictor responses to norepinephrine, vasopressin, and KCl were enhanced in rats given a slow pressor infusion of angiotensin II, but sensitivity of responses was not altered. This combination of changes suggests that vascular hypertrophy develops during slow pressor infusion of angiotensin II. Experiment 3: Vessel myography was done after angiotensin II infusion with and without a pressor response. Angiotensin II raised systolic blood pressure, increased heart weight, and produced myographic changes of vascular hypertrophy in the mesenteric circulation, increasing media width, media cross-sectional area, and media/lumen ratio. Hydralazine given with angiotensin II prevented the rise of pressure and the cardiac effect but not the vascular changes. Two-way analysis of variance showed that angiotensin II significantly increased media width, media cross-sectional area, and media/lumen ratio, all independent of hydralazine. Thus, although hydralazine inhibits the pressor and cardiac effects of angiotensin II, suggesting a pressor mechanism for the cardiac change, it does not inhibit structural vascular change, which suggests that at least part of the effect has a non-pressor mechanism.

Angiotensin II↗
PubMed1990

The atriopeptidase inhibitor UK 69,578 increases atrial natriuretic factor and causes a natriuresis in normal humans.

The endopeptidase EC 3.4.24.11 (atriopeptidase) degrades atrial natriuretic factor (ANF). Intravenous administration of UK 69,578 (0.025 to 10.0 mg/kg), a new specific atriopeptidase inhibitor, in 16 normal volunteers produced a two- to three-fold rise in endogenous ANF. Peak levels were reached within 2 h declining to control values by 8 h. The rise in ANF was associated with an increase in urine volume and mean urinary sodium excretion rose from 64.9 mmoles/8 h after placebo to 116.1 mmoles/8 h after 10 mg/kg UK 69,578. Despite the natriuresis, plasma active renin concentration was suppressed for up to 8 h. We conclude that inhibition of the endopeptidase EC 3.4.24.11 in humans elevates endogenous ANF and causes a natriuresis and may offer a novel therapeutic approach to the treatment of hypertension and cardiac failure.

Adult↗
PubMed1990

Left ventricular hypertrophy and mortality in hypertension: an analysis of data from the Glasgow Blood Pressure Clinic.

Three thousand seven hundred and eighty-three patients with non-malignant hypertension attending the Glasgow Blood Pressure Clinic between 1968 and 1983 were followed prospectively for an average of 6.5 years. Left ventricular hypertrophy (LVH) was present at the outset in 34.5% of the men, and 12.8% had ST-T changes. The corresponding figures for women were 21.5% and 8.8%. The prevalence of LVH increased with the severity of hypertension and was higher for a given blood pressure level in men than in women. All-cause age-adjusted mortality, expressed as deaths per 1000 patient-years, was 27.6 for men with normal electrocardiographs, 43.2 for men with LVH only (P less than 0.001) and 56.9 for men with LVH and ST-T changes (P less than 0.001). Similar trends were seen in women. The excess risk associated with LVH, with or without ST-T changes, could not be explained by age, increased blood pressure at referral to the clinic, or smoking habit, when these factors were considered either separately or in combination (regression analysis). Thus, our study demonstrates that LVH, with or without ST-T changes is an independent risk factor for mortality in hypertensive patients.

Age Factors↗
PubMed1990

Brief angiotensin converting enzyme inhibitor treatment in young spontaneously hypertensive rats reduces blood pressure long-term.

Our study examines the long-term cardiovascular effects after a brief period of angiotensin converting enzyme (ACE) inhibitor treatment in young spontaneously hypertensive rats (SHR). SHR were treated with perindopril (3 mg/kg/day) by gavage from 2 to 6, from 6 to 10, or from 2 to 10 weeks of age. Systolic blood pressure was measured in the tail weekly until 25 weeks of age. Corresponding control groups received distilled water for the same periods. In each treatment group blood pressure was reduced significantly during treatment, rose when treatment stopped, but plateaued significantly below control SHR thereafter. This difference in blood pressure at 25 weeks of age was due to reduced total peripheral resistance as determined by microsphere methods, but plasma renin activity and angiotensin II concentrations were not different. Cardiac hypertrophy was also reduced in treated SHR. In a separate experiment, perindopril treatment from 6 to 10 weeks of age resulted in a significant reduction in the media/lumen ratios of mesenteric resistance vessels at 32 weeks of age. Concomitant administration of angiotensin II with perindopril from 6 to 10 weeks of age not only prevented the long-term effects on blood pressure seen with perindopril treatment alone but was associated with cardiovascular hypertrophy in excess of untreated control SHR. Finally, perindopril given for a shorter period (6 to 7 weeks) or later in life (20 to 24 weeks) had no significant long-term effects on blood pressure. These results demonstrate that a 4-week period of ACE inhibitor treatment in young SHR is sufficient to prevent the full expression of genetic hypertension and cardiovascular hypertrophy and that angiotensin II might be important in the development of hypertension in this model, its role in later life being less important.

Angiotensin II↗
PubMed1990

Blood pressure, change in blood pressure, and cardiovascular event rates in placebo-treated patients in the Medical Research Council Trial.

The relationship between cardiovascular event rate (stroke + coronary events), entry blood pressure (BP), change in BP over 6 months, and other variables was examined in the 8,654 placebo-treated patients in the Medical Research Council (MRC) trial. Entry BP was greater than screening pressures and fell significantly after randomization to placebo. The entry pressure was significantly greater but the fall after entry was less in those who had a cardiovascular event during 5.5 years of follow-up. Thus, patients with high entry pressure that remained elevated during follow-up had the highest event rates. This pattern was marked for stroke but was also found for coronary events. Other variables strongly related to event occurrence were sex, age, and smoking habit. Discriminant analysis based on these variables correctly identified 67% of those who had an event but incorrectly classified 40% of the much larger group who did not. These results suggest that failure of BP to fall after screening examinations is a cardiovascular risk factor. Thus, high-risk patients may be identified by repeated measurements of BP before treatment is started.

Age Factors↗
PubMed1989

Effects of UK 69 578: a novel atriopeptidase inhibitor.

UK 69 578 is a competitive inhibitor of endopeptidase 24.11 (the enzyme that degrades atrial natriuretic factor) in vitro. In vivo, UK 69 578 has renal and cardiovascular effects similar to low-dose atrial natriuretic factor infusion, and may be a useful agent in hypertension and heart failure.

Animals↗
PubMed1989

Plasma cholesterol, coronary heart disease, and cancer in the Renfrew and Paisley survey.

The relation between plasma cholesterol concentration and mortality from coronary heart disease, incidence of and mortality from cancer, and all cause mortality was studied in a general population aged 45-64 living in the west of Scotland. Seven thousand men (yielding 653 deaths from coronary heart disease, 630 new cases of cancer, and 463 deaths from cancer) and 8262 women (322 deaths from coronary heart disease, 554 new cases of cancer, and 395 deaths from cancer) were examined initially in 1972-6 and followed up for an average of 12 years. All cause mortality was not related to plasma cholesterol concentration. This was largely a consequence of a positive relation between cholesterol values and mortality from coronary heart disease being balanced by inverse relations between cholesterol and cancer and between cholesterol and other causes of death. These changes were highly significant for coronary heart disease and cancer in men and significant for coronary heart disease and other causes of death in women. The inverse association between cholesterol concentration and cancer in men was strongest for lung cancer, was not merely a function of the age at which a subject died, was present for the incidence of cancer as well as mortality from cancer, and persisted when new cases or deaths occurring within the first four years of follow up were excluded from the analysis.

Cause of Death↗
PubMed1989

Effects of the renin inhibitor H77 on angiotensin II, arterial pressure and cardiac function in conscious dogs: comparison with captopril.

The renin inhibitor H77 and the angiotensin I converting enzyme (ACE) inhibitor captopril were compared in separate experiments with infusion of 5% dextrose as a control for the effects on plasma angiotensin II (Ang II) concentration, arterial pressure and cardiac function, measured by Swan-Ganz catheter, in conscious dogs. The effects of a high dose of H77 (10 mg/kg per h) were similar to those of high-dose captopril (6 mg/kg per h). Both reduced plasma Ang II concentration, systemic vascular resistance and arterial pressure; both increased the heart rate; both increased cardiac output but the change was significant only with captopril; neither affected stroke volume, pulmonary artery pressure or pulmonary vascular resistance; both reduced left and right atrial pressures. The similar pattern of effects for the two inhibitors suggests that the mechanism by which they act is the same--reduction in Ang II--and that the cardiovascular effects of H77 are not a specific action of the peptide that is unrelated to the reduction in plasma Ang II concentrations.

Angiotensin II↗