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Biomedical subjects

A F Lever

Publications and source records attributed to A F Lever.

At least 55 records · Page 3Linked to original sources
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↗
PubMed1989

Hypokalaemia in alcoholics.

Hyponatraemia has been described in beer drinkers and hypokalaemia resulting from increased levels of aldosterone is well recognised in patients with cirrhosis and ascites. We have encountered episodes of hypokalaemia in alcoholics accompanied by normal or increased serum concentrations of sodium. Despite a resemblance to syndromes of mineralocorticoid excess, increased levels of aldosterone and other mineralocorticoids were not found.

Adrenal Cortex Hormones↗
PubMed1989

Effects of cholesterol and lipoproteins on aldosterone secretion by bovine zona glomerulosa cells.

Freshly isolated bovine adrenocortical cells were pretreated with various concentrations of cholesterol and of high- (HDL) and low-density lipoprotein (LDL) fractions of known cholesterol content and then incubated in medium alone with and without angiotensin II. Preincubation with cholesterol (323 mumol/l) caused basal aldosterone synthesis to increase from 0.89 +/- 0.08 to 2.77 +/- 0.22 pmol/10(6) cells per hour (+/- S.E.M.) but did not significantly affect angiotensin-stimulated synthesis. Human HDL containing cholesterol at a final concentration of 129-647 mumol/l increased both basal and angiotensin-stimulated aldosterone synthesis. In HDL-treated cells, both the threshold response and responses to increasing concentrations of angiotensin were raised. Human LDL had no effect on basal or stimulated aldosterone synthesis nor did LDL alter the effects of HDL when cells were incubated with HDL and LDL in combination. Qualitatively similar results were obtained with bovine lipoproteins. These studies show that, in short-term incubations of fresh tissue, the supply of cholesterol may be a limiting factor in aldosterone synthesis and that HDL rather than LDL is the preferred source. These observations are discussed in relation first to the mechanisms by which cholesterol/HDL might augment steroid responses and secondly to other studies with cultured cells which have demonstrated a role for LDL.

Aldosterone↗
PubMed1989

The contractile effects of porcine tetradecapeptide renin substrate in human resistance vessels: evidence of activation by vascular wall renin and serine proteases.

In order to test the hypothesis that the contraction induced in human resistance arterioles by porcine tetradecapeptide renin substrate (TDP) is mediated by enzymes specific to the renin-angiotensin cascade, human resistance vessels from skin and subcutaneous fat were mounted in a myograph and exposed to TDP in the presence and absence of the human renin inhibitor H261, the serine protease inhibitor aprotinin, a polyclonal anti-human renin antibody and captopril. TDP induced a dose-dependent contraction that could be abolished by saralasin. The sensitivity to TDP was significantly attenuated by H261, aprotinin and combinations of captopril with aprotinin and captopril plus aprotinin and H261, as indicated by a significant reduction in pD2 (-log10ED50 [mmol/l]) for TDP. However, captopril alone was ineffective. It was concluded that at physiological pH, porcine TDP induces contraction in human resistance vessels by the action of enzymes not specific to the renin-angiotensin cascade. Whilst a clear inhibitory effect of H261 was demonstrated, a significant comparable inhibition by captopril and a polyclonal renin antibody was not observed. This may reflect the difficulty with which these inhibitors gain access to their intracellularly located substrates.

Electric Stimulation↗
PubMed1988

The importance of hypophyseal hormones for structural cardiovascular adaptation in hypertension.

The effect of renal artery clipping was tested in three groups of male Sprague-Dawley rats: (1) 30 control animals, (2) 30 hypophysectomized animals, and (3) 30 hypophysectomized animals treated with growth hormone and thyroxine. Fifteen rats in each group were clipped and 15 acted as controls. In the first group clipping raised arterial pressure and plasma renin activity. Thirty-five days after clipping, pair-perfused hindquarter preparations at maximal dilation and maximal pressor response were both increased, reflecting, respectively, decreased lumen diameters and increased media thickness in the resistance vessels. Clipping also increased left ventricular weight. Hypophysectomy eliminated the weight gain, and the maximal pressor response and maximal dilation were lower than in the control and treated groups. Hypophysectomy also considerably reduced the rise in blood pressure on clipping and, even more so, the associated structural cardiovascular changes. Replacement therapy with growth hormone and thyroxine almost restored the weight gain and also the structural responses of the heart and vessels to clipping. We conclude that pituitary hormones play an important, probably permissive, part in the development of normal vessel structure and in the adaptation of cardiovascular structure to chronic hypertension.

Animals↗
PubMed1988

Failure of chronic administration of growth hormone to affect blood pressure, vascular reactivity and sodium metabolism in normal rats.

To examine the effects of exogenous growth hormone on the cardiovascular system and sodium metabolism, ovine growth hormone was given daily to female rats for 5 weeks. Growth hormone resulted in a significant increase in body mass compared with controls. However, blood pressure in the treated rats was not significantly different from that in controls. Following treatment, the baseline resistances and pressor responses of the isolated mesenteric beds did not differ between the two groups. In addition, exchangeable sodium, erythrocytic intracellular sodium and transmembrane sodium efflux rate constants were not altered significantly by growth hormone treatment. The failure to observe cardiovascular or sodium effects of growth hormone despite significant potentiation of growth is, at present, unexplained.

Animals↗
PubMed1988

Angiotensin II activates Na+-H+ exchange and stimulates growth in cultured vascular smooth muscle cells.

Angiotensin II (Ang II) stimulated the growth of cultured vascular smooth muscle cells in a dose-dependent manner; a small but significant increase being seen at 10(-9) mol/l, whereas 10(-5) mol/l produced a 166% increase compared with control cells. Saralasin blocked the Ang II-mediated increase in cell number. Amiloride-sensitive Na+-H+ exchange was characterized (Km = 18 mmol/l, Vmax = 0.27 pH units/30 s) in cell monolayers using the fluorescent probe biscarboxyethylcarboxy fluorescein. Angiotensin II (10(-7) mol/l) produced a small overall net intracellular alkalinization. Raising intracellular pH via Na+-H+ activation might be one of the ways in which Ang II increases cell growth.

Angiotensin II↗
PubMed1988

Effects of sodium intake and aldosterone on the renal pressure-natriuresis.

To study the effects of dietary sodium and plasma aldosterone on pressure-natriuresis (PN) we examined six groups of adult, male Sprague-Dawley rats. Group 1 received normal-sodium diet, group 2 high-sodium diet, and group 3 low-sodium diet for 3 wk; group 4 was given low sodium for 3 wk then high sodium for 3 wk; groups 5 and 6 received high sodium for 3 wk but during the 3rd wk were also given aldosterone by subcutaneous infusion to mimic the plasma aldosterone seen in groups 1 and 3, respectively. After the diets, rats were killed, and urinary sodium excretion, glomerular filtration rate (GFR), and calculated tubular sodium reabsorption (FRNa) were measured during stepwise increases in perfusion pressure in isolated perfused kidneys from each group. No significant differences in blood pressure were seen between any of the groups. The PN curves for groups 2 and 3 were significantly different (P less than 0.001) and shifted to the left and right of group 1, respectively. These shifts appeared to be the result of significant (P less than 0.001) differences in FRNa rather than changes in GFR. PN was not significantly different in groups 4 and 2, indicating that the effects of low-sodium diet were reversible. The infusion of aldosterone in groups 5 and 6 was associated with modest and significant (P less than 0.001) shifts, respectively, of the PN curve to the right of the curve of rats in group 2. In group 6 this shift appeared to be due to significant (P less than 0.001) changes in FRNa, so as to resemble that seen in low-sodium rats of group 3.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldosterone↗