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Biomedical subjects

A F Lever

Publications and source records attributed to A F Lever.

At least 37 records · Page 2Linked to original sources
PubMed1994

Blood pressure and lifespan following brief ACE inhibitor treatment in young spontaneously hypertensive rats.

1. Brief treatment with angiotensin-converting enzyme (ACE) inhibitors in young spontaneously hypertensive rats (SHR) causes a reduction in blood pressure that persists into maturity. The lifetime effects of such treatment have not been studied. 2. Nineteen male SHR were treated with either water (n = 9) or perindopril (3 mg/kg per day) (n = 10) by daily gavage between 6 and 10 weeks of age and systolic blood pressure and bodyweight were measured each month until all animals died in old age. 3. Following treatment the systolic blood pressure of SHR treated with perindopril remained consistently lower than control SHR until about 82 weeks of age. After this age the blood pressure of control SHR fell spontaneously so that smaller differences were observed between the two groups in the last 4 months of the study. 4. Rats that received perindopril lived on average 1 month longer than control rats, but this difference was not statistically significant. 5. Thus, brief ACE inhibition in early life in SHR ameliorated the hypertension throughout life.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1994

Effect of sex-related changes in blood pressure at entry to the MRC trial on prediction of cardiovascular risk.

1. Using the MRC trial placebo group as the data source, we examined relationships between cardiovascular risk, gender, and blood pressure (BP) at screening, on entry to the trial, and after 3 months of follow up. 2. Blood pressure on entry to the trial (162/98 mmHg) was significantly higher than at the second screening (154/95 mmHg) visit and at 3 months (144/91 mmHg). The entry BP was higher, and the changes from screening to entry and from entry to 3 months were greater in females. Females had a low cardiovascular risk, but because of the greater changes of BP at entry they were over-represented at the top of the entry BP distribution, whereas males were over-represented at the bottom. The result of these effects was that the relationship between cardiovascular risk and entry BP was shifted to the right and was flatter than the corresponding curves measured at screening or after 3 months of follow up. 3. In consequence, the severity of hypertension in the trial population was overestimated from measurement of BP at entry, and the capacity of trial entry BP to predict cardiovascular risk was weakened. 4. BP on entry to the MRC Trial was affected by a pressor effect that diminished the value of BP as a cardiovascular risk factor because it differentially affected sub-populations by gender.

Blood Pressure↗
PubMed1994

Serum sodium concentration and risk of stroke in middle-aged males.

BACKGROUND AND METHODS: Clinical disturbances of the circulating sodium concentration are both a cause and a consequence of cerebrovascular disease. We examined the relationship between serum sodium level and risk of stroke and major ischaemic heart disease in a prospective study of 7690 middle-aged males drawn from general practices in 24 British towns followed over a 9.5-year period. RESULTS: The mean serum sodium level was 141.5 mmol/l and 375 males on antihypertensive treatment were excluded from the analyses. A significant inverse trend was seen between serum sodium and risk of stroke up to 144 mmol/l; above this the risk of stroke was increased. Those with levels of 143-144 mmol/l showed over a 70% reduction in risk of stroke compared with those with levels of < or = 140 mmol/l. The inverse relationship between sodium and stroke up to 144 mmol/l was seen in males with and without pre-existing ischaemic heart disease or stroke, in normotensives and untreated hypertensives, and in non-smokers and current smokers. A weak but significant inverse association was seen between serum sodium and diastolic but not systolic blood pressure. The association between serum sodium level and stroke remained significant after adjustment for diastolic blood pressure and other factors associated with stroke: age, smoking, social class, body mass index, physical activity, heavy drinking, presence of diabetes, blood glucose and pre-existing ischaemic heart disease. No association was seen between serum sodium level and risk of ischaemic heart disease after adjustment for other risk factors. All-cause and non-cardiovascular mortality were significantly increased at serum sodium levels of < or = 138 mmol/l, probably due to an association between lung cancer and hyponatraemia. CONCLUSION: These findings suggest that sodium concentration may be related to risk of stroke even at levels of sodium usually regarded as normal.

Adult↗
PubMed1993

Incidence of and mortality from cancer in hypertensive patients.

OBJECTIVES: To assess incidence of and mortality from cancer in hypertensive patients taking atenolol, comparing the findings with two control populations and with hypertensive patients taking other drugs. DESIGN: Retrospective analysis of patients first seen in the Glasgow Blood Pressure Clinic between 1972 and 1990. Patients' records were linked with the registrar general's data for information on mortality and with the West of Scotland Cancer Registry for information on incident and fatal cancers. Cancers were compared in patients and controls and in patients taking atenolol, beta blockers other than atenolol, and hypotensive drugs other than beta blockers. SUBJECTS: 6528 male and female patients providing 54,355 years of follow up. SETTING: Hypertension clinic in Glasgow. MAIN OUTCOME MEASURES: Observed numbers of cancers in clinic patients were compared with expected numbers derived from cancer rates in two control populations adjusted for age, sex, and time period of data collection. RESULTS: Cancer mortality was not significantly different in clinic patients as a whole and controls. Incident and fatal cancers were not significantly increased in male or female patients taking atenolol. Cancer incidence did not rise in the clinic after a large increase in prescriptions for atenolol after 1976. CONCLUSION: This analysis does not suggest a link between atenolol and cancer.

Age Factors↗
PubMed1993

Haemodynamic and hormonal responses to losartan (DuP753/MK954) infusion during cardiac catheterization in conscious salt-deplete dogs.

1. Haemodynamic and hormonal responses to infused angiotensin II were studied in conscious salt-deplete dogs during infusion of D-glucose or losartan (DuP753/MK954). 2. Mean arterial pressure (118 +/- 13 mmHg) fell rapidly after losartan (60 min 106 +/- 18 mmHg) with a rise in heart rate (107 +/- 16 beats/min) from baseline (98 +/- 17 beats/min). Pressor responses to angiotensin II during D-glucose infusion (6 ng min-1 kg-1, 99 +/- 10 mmHg; 18 ng min-1 kg-1, 140 +/- 15 mmHg; 54 ng min-1 kg-1, 157 +/- 12 mmHg; 162 ng min-1 kg-1, 178 +/- 14 mmHg) showed a parallel shift during losartan infusion with very similar pressures in response to higher rates of angiotensin II infusion (54 ng min-1 kg-1, 108 +/- 17 mmHg; 162 ng min-1 kg-1, 138 +/- 14 mmHg; 486 ng min-1 kg-1, 155 +/- 14 mmHg; 1458 ng min-1 kg-1, 177 +/- 12 mmHg). Losartan caused a fall in baseline systemic vascular resistance. Despite the similar mean arterial pressure, the rise in systemic vascular resistance after angiotensin II during D-glucose infusion (162 ng min-1 kg-1, 8065 +/- 1967 dyn s cm-5) was reduced during losartan infusion (1458 ng min-1 kg-1, 6645 +/- 1720 dyn s cm-5. Losartan caused a small rise in cardiac output related to a rise in heart rate and increased stroke volume. Pressure infusions of angiotensin II caused a fall in cardiac output during D-glucose infusion, which was blocked during losartan infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldosterone↗
PubMed1993

MRC trial of treatment in elderly hypertensives.

The MRC trial was a random control comparison of placebo treatment with two active drug regimens: atenolol 50 mg daily and a combined tablet containing hydrochlorothiazide 25 mg and amiloride 2.5 mg. The trial was based on 226 general practices in the U.K. Its primary purpose was to determine whether hypotensive drug treatment in men and women aged 65-74 with systolic pressure in the range 160-209 mmHg and with diastolic pressure below 115 mmHg reduced stroke, coronary heart disease (CHD) and all-cause mortality. A secondary objective was to determine whether outcome differed with the two forms of active treatment. 4,396 patients were randomized: 50% to placebo; 25% each to the two forms of treatment. During the following 5.8 years 25,000 patient-years of experience accumulated. Blood pressure fell in the placebo group, larger falls occurred with the two active treatments. Active treatment (diuretic and beta-blocker groups combined) reduced stroke by 25% (95% CI 3 to 42%), CHD by 19% (-2% to 36%, p = 0.08), cardiovascular events by 17% (2% to 29%). Benefits were clearest for the diuretic regime: a 31% reduction of stroke events, a 44% reduction of CHD and a 35% reduction of cardiovascular events--all significant.

Aged↗
PubMed1993

Slow developing pressor effect of angiotensin II and vascular structure.

AIM: To summarize and discuss four experiments relating to a possible action of angiotensin (Ang) II as a vascular growth factor and to consider the importance of growth factors in hypertension. EXPERIMENT 1: Rats infused with a low dose of Ang II developed a slow pressor response. After 10 days vascular hypertrophy was evident. Other rats infused with Ang II and given hydralazine to prevent the rise in pressure also developed vascular hypertrophy. EXPERIMENT 2: The results of a second experiment suggested that Ang II caused vascular hypertrophy by a mechanism that involves the proto-oncogene c-fos, an intermediary in growth factor action. EXPERIMENT 3: In this experiment hypophysectomy arrested maturation of resistance vessels in the rat and prevented the structural vascular response to increased arterial pressure. Thyroxine and growth hormone prevented both these effects, presumably acting as growth factors. EXPERIMENT 4: In the fourth experiment, young spontaneously hypertensive rats (SHR) given an angiotensin converting enzyme (ACE) inhibitor for 4 weeks did not fully develop hypertension, even after the ACE inhibition had ceased. This effect was prevented by the infusion of Ang II during the ACE inhibition. These results suggest that the blood pressure rise in SHR has a reversible element related to Ang II. CONCLUSIONS: Ang II causes vascular hypertrophy by a non-pressor mechanism, possibly as a growth factor. Ang II and other growth factors may be important in the development of a normal vascular system and of abnormal vessels in hypertension.

Angiotensin II↗
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↗