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Biomedical subjects

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

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↗
PubMed1979

T and B lymphocytes in patients with acute anterior uveitis and ankylosing spondylitis, and in their household contacts.

During episodes of acute anterior uveitis, patients had a T-lymphopenia and a temporary increase in B-lymphocytes. The T-lymphopenia was not present in patients investigated early in their first attacks, and it persisted after the patients recovered clinically. In household contacts of patients with uveitis, there was a temporary T-lymphopenia. A similar degree of T-lymphopenia was present in patients with ankylosing spondylitis who had not had uveitis, but not in their household contacts. In patients with spondylitis, there was no greater reduction of T-cells when they had episodes of uveitis. In all groups of subjects studied, T-lymphopenia could be abolished, in vitro, with thymosin, a bovine thymic-hormone estract. The finding of T-lymphocyte depletion in the contacts of uveitis patients, as well as in the patients themselves, suggests that there may be lateral transmission of an infective agent (or agents) in the households during (or before) attacks of uveitis.

Acute Disease↗
PubMed1979

Hyponatraemic hypertensive syndrome with renal-artery occlusion corrected by captopril.

Malignant hypertension with severe hyponatraemia, hypokalaemia, depletion of sodium and potassium, and elevated blood levels of renin, angiotensin I, angiotensin II, aldosterone, and arginine vasopressin developed in a woman with renal-artery occlusion. Plasma angiotensin II was disproportionately high in relation to exchangeable sodium. Captopril, by inhibiting conversion of angiotensin I to angiotensin II, further elevated the blood levels of renin and angiotensin I but corrected all other abnormalities. Unilateral nephrectomy was subsequently curative.

Aldosterone↗
PubMed1979

Excess smoking in malignant-phase hypertension.

The smoking habits of 82 patients with malignant-phase hypertension were compared with those of subjects in three control groups matched for age and sex. Sixty-seven (82%) of the patients with malignant-phase hypertension were smokers compared with 41 (50%) and 71 (43%) of the patients in two control groups with non-malignant hypertension, and 43 people (52%) in a general population survey. The excess of smokers in the malignant-phase group was significant for men and women, together and separately, for cigarette smoking alone, and for all forms of smoking. There were no significant differences between the control groups. The chance of a hypertensive patient who smoked having the malignant phase was five times that of a hypertensive patient who did not. Twelve patients in the malignant-phase group had never smoked. All were alive three and a half years on average after presentation (range 11 months to seven years). Twenty-four (36%) of the smokers with malignant-phase hypertension died during the same period. The mortality rate was significantly higher among patients with renal failure, as was the prevalence of smoking. Eighteen patients with malignant-phase hypertension had a serum creatinine concentration higher than 250 mumol/l (2.8 mg/100 ml); 17 were smokers and one an ex-smoker. Eleven of these 18 patients died.It is concluded that hypertensive patients who smoke are much more likely to develop the malignant phase than those who do not, and that once the condition has developed it follows a particularly lethal course in smokers.

Age Factors↗
PubMed1979

Hypothesis:presynaptic receptors controlling renin release.

Presynaptic receptors have recently been identified on nerves supplying vascular smooth muscle. Renin is stored in juxtaglomerular cells in the wall of the afferent glomerular arteriole and the JG cell is probably derived from vascular smooth muscle. Nervous stimuli exert an important influence on release of renin, but the nature of the receptors involved is not agreed. We propose that there are presynaptic receptors associated with the JG apparatus as with vascular muscle and that a mechanism of this sort gives a better account of data on renin release.

Antihypertensive Agents↗