Slow pressor mechanisms in hypertension: a role for hypertrophy of resistance vessels?
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Animals↗
Biomedical subjects
A F Lever
Publications and source records attributed to A F Lever.
Mild hypokalaemia is not a risk factor in treated hypertensives.
The possibility that hypokalaemia might increase the mortality of treated hypertensives in the Glasgow Blood Pressure Clinic has been examined by comparison of serum potassium in decedents and survivors and by calculation of age-adjusted mortality rates for patients grouped in quartiles of serum potassium measured at the last clinic visit. In this study, 3783 patients with non-malignant hypertension were followed for an average of 6.5 years and of these 1907 had one or more measurements of serum potassium during their last year of attendance. Serum potassium fell in 414 patients given diuretics with or without other drugs except beta-blockers. This fall was similar in those who died of ischaemic heart disease (3.71 mmol/l) and in those who survived (3.72 mmol/l). Serum potassium rose in 167 patients who received beta-blockers with or without other drugs except diuretics and fell slightly among 1326 patients taking other combinations of drugs. There were no significant differences in serum potassium between decedents and survivors in either of these treatment groups. Age-adjusted mortality in deaths per 1000 patient-years in the lowest quartile of serum potassium (less than 3.7 mmol/l) was 28.1 for men and 15.0 for women. Higher serum potassium was associated with slightly, but not significantly, higher mortality in both sexes. There was no relation between serum potassium and mortality in patients with left ventricular hypertrophy, nor was there a relation when death due to ischaemic heart disease was considered separately. Failure of hypokalaemia to predict outcome was confirmed by univariate and multivariate analyses which included, in addition to potassium, assessment of cigarette smoking, initial blood urea and electrocardiographic findings.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic beta-Antagonists↗
Anatomy of the renin-angiotensin system in the normal and pathological kidney.
In this review we describe the contributions made by immunocytochemistry to our knowledge of the renin-angiotensin system in the normal and the pathological kidney. Most of the renin-secreting cells appear to be on the outer aspect of the vessel wall, supporting the view that renin is secreted mainly into the interstitium of the kidney rather than into the lumen of the vessel. Angiotensin II immunoreactivity is present within renin-secreting cells. The angiotensin II appears to be present in high concentration in the renin storage granules and is therefore presumably secreted from the cell with renin. The pathways by which renin is secreted from the cell have also been clarified. In pathological kidneys, the reactions of renin-secreting cells to variation in functional demand have been confirmed. Renin-containing cells have also been found in most types of renal tumours and occasional cases probably secrete renin or prorenin into the blood. In renal tumours and in the developing kidney (in all species studied) the renin-containing cells are also intimately associated with blood vessels.
Angiotensinogen↗
Pressor responsiveness in steroid-induced hypertension in man.
Pressor responsiveness to angiotensin II (AII) and phenylephrine (PE) was examined before and after 5 days of ACTH (1 mg, i.m., daily) or hydrocortisone (200 mg, orally, daily) in six normotensive men. Pulse pressure was higher prior to PE than AII infusion, presumably due to feeding. Systolic blood pressure (SBP) was increased by both ACTH and hydrocortisone treatment, but more by ACTH. There were no significant changes in AII pressor responsiveness with either ACTH or hydrocortisone. ACTH increased pressor responsiveness to PE at 1.35 and 2 micrograms/kg per min, and hydrocortisone at 0.6-2 micrograms/kg per min, with falls in pulse rate at 0.3-0.9 micrograms/kg per min. Changes in pressor responsiveness do not explain ACTH hypertension.
Adrenocorticotropic Hormone↗
Dose related in vitro effects of ranitidine and cimetidine on basal and ACTH-stimulated steroidogenesis.
Isolated bovine adrenocortical cells were incubated with and without 3 ng/ml ACTH, with various concentrations (10-1000 micrograms/ml) of either cimetidine or ranitidine. Cortisol, corticosterone, and deoxycorticosterone outputs were measured. Cimetidine and ranitidine at 320 and 1000 micrograms/ml inhibited ACTH-stimulated corticosterone and cortisol synthesis and cimetidine decreased basal cortisol synthesis. The inhibitory effects of cimetidine on cortisol synthesis were approximately 10 times greater than those of ranitidine. Cimetidine (1000 micrograms/ml), but not ranitidine increased deoxycorticosterone synthesis by ACTH-stimulated cells, indicating inhibition of 11 beta-hydroxylation in the adrenal steroidogenic pathway. Although doses of cimetidine and ranitidine which produce these in vitro effects are much greater than plasma concentrations in normal clinical use, they might be important in acutely ill patients given intravenous bolus injections of cimetidine, or if either antagonist were accumulated by the adrenal to produce high intracellular concentrations.
Adrenal Cortex↗
Factors affecting renal vein renin ratio in renal artery stenosis. Secretion of inactive renin.
All four factors which theoretically may affect the renal vein renin ratio in unilateral renal artery stenosis--increased renin secretion and diminished renal plasma flow on the stenotic side; suppressed renin secretion and renin extraction on the contralateral side--have been assessed. In a series of patients with unilateral renal artery stenosis, the renal vein ratio of active renin was more closely related to the reduction of renal plasma flow than to renin secretion rate on the affected side. On the contralateral side renin secretion was suppressed while angiotensin II was extracted. During long-term treatment with the converting enzyme inhibitor enalapril, peripheral plasma angiotensin II was lowered, while active renin concentration was markedly elevated, both in arterial plasma and in renal venous plasma of the stenotic kidney; the contralateral kidney became a net extractor of active renin. Thus, all 4 factors which theoretically affect the renal vein renin ratio can operate clinically. Both before and during enalapril, the affected kidney secreted inactive renin.
Angiotensin II↗
Dexamethasone-suppressible hyperaldosteronism. Adrenal transition cell hyperplasia?
Dexamethasone-suppressible hyperaldosteronism is a rare familial syndrome in which hypokalemia, suppression of plasma renin concentration, and elevated aldosterone secretion are corrected by treatment with glucocorticoids. Regulation of adrenocortical function and body electrolytes was studied in two affected brothers. Both were hypertensive (210/128 and 160/106 mm Hg) with hypokalemia (3.3 and 3.5 mM) and low plasma renin concentrations. Aldosterone was elevated intermittently with levels as high as 45 ng/dl (normal range, 4-16 ng/dl). Cortisol concentrations were normal but were correlated with aldosterone levels (r = 0.9 and 0.7). Concentrations of 11-deoxycorticosterone (19 and 21 ng/dl; normal range, 4-16 ng/dl) and 18-hydroxycortisol (1000 and 950 ng/dl; normal range, 34-150 ng/dl) were elevated, and diurnal changes in both were the same as those seen with aldosterone. Infusion of adrenocorticotropic hormone (ACTH) caused exaggerated increases of aldosterone, 11-deoxycorticosterone, and 18-hydroxycortisol; cortisol response was normal. A 4-week trial of dexamethasone normalized blood pressure and caused a natriuresis, a fall in aldosterone, and a rise in plasma renin. Administration of ACTH after dexamethasone treatment again caused exaggerated increases of aldosterone. Aldosterone did not respond to angiotensin II before dexamethasone therapy (r = 0.01), but it showed a normal response after therapy (r = 0.8, p less than 0.01). Neither administration of dopamine (1 microgram/kg/min) nor long-term therapy with bromocriptine (2.5 mg t.i.d. for 4 weeks) affected aldosterone biosynthesis. Thus, loss of dopaminergic inhibition of mineralocorticoid biosynthesis does not account for hyperaldosteronism in this condition.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenal Cortex Hormones↗
The pathophysiology of renovascular hypertension.
In hypertension associated with renal artery stenosis, the evolution of the raised blood pressure can conveniently be considered in three phases. In the first phase, blood pressure is raised by the direct pressor action of elevated peripheral plasma angiotensin II. In the second phase, circulating angiotensin II may be more modestly raised, but probably is still important in pathogenesis. Occasionally in phase II there is rapidly advancing elevation of renin, angiotensin II and aldosterone and severe hypertension, with sodium and potassium depletion. In the much later third phase, angiotensin II is not elevated, and the renin system may no longer be concerned in the hypertension. In phases I and II, but not in phase III, relief of the stenosis, removal of the affected kidney, or lowering of angiotensin II with converting enzyme inhibitors, can correct the hypertension. In the affected kidney with renal artery stenosis, the intrarenal content of renin is raised and its distribution altered; these changes represent compensatory local actions. The affected kidney secretes both active and inactive renin, while there is suppression of renin secretion by the contralateral kidney which becomes a net extractor of angiotensin II.
Aldosterone↗
A transition-state analogue inhibitor of human renin (H.261): test in vitro and a comparison with captopril in the anaesthetized baboon.
H.261, a new transition state inhibitor of human renin with an IC50 of 6.9 X 10(-10) M, was given by intravenous infusion to six anaesthetized baboons. The inhibitor was infused first at 0.1 mumol/kg/h for 15 min, then at 1.0 mumol/kg/h for a further 15 min. After a recovery period of 2 h in which the animals received 5% dextrose, they were infused with captopril, 25 mumol/kg/h for 15 min. At both rates of infusion H.261 markedly and significantly reduced the enzymatic action of renin in plasma, the blood concentration of angiotensin I, the plasma concentration of angiotensin II and mean arterial pressure. All changes reverted towards or to control values in the subsequent control period. Captopril also lowered plasma angiotensin II concentration and mean arterial pressure markedly and significantly but, as expected for an inhibitor of the angiotensin I-converting enzyme, plasma active renin concentration and blood angiotensin I concentration increased. The changes of angiotensin II and arterial pressure were similar with captopril and H.261.
Angiotensin I↗
A study of the renin inhibitor H142 in man.
The inhibitor of human renin, H142, was studied in nine male volunteers. On three occasions, in random order, volunteers were infused with 5% dextrose or with H142 at 1.0 or 2.5 mg/kg per h for 30 min while supine and thereafter with dextrose for 1 1/2 h. There was a marked reduction in plasma active renin concentration as assayed by an enzyme-kinetic method, with parallel falls in the circulating concentrations of angiotensins (ANG) I and II, all of which rebounded transiently to values above basal after the H142 infusion was stopped. In contrast, total renin concentration as measured by radio-immunoassay rose while ANG I and II fell, subsiding when H142 was discontinued. There was a slight but significant increase in plasma noradrenaline as renin became inhibited; plasma adrenaline was unchanged. H142 produced a slight fall in systolic blood pressure (SBP) and a clearer, highly significant, dose-related fall in diastolic blood pressure (DBP). There was a modest but significant increase in the heart rate. These studies confirm H142 as an effective inhibitor of human renin in vivo.
Adult↗
Renin inhibitors: their use in understanding the role of angiotensin II as a pressor hormone.
Infusion of H.261, the inhibitor of human renin in the baboon, lowered blood angiotensin I, plasma angiotensin II, and arterial pressure suggesting that in the sodium-depleted state angiotensin II contributes to the maintenance of arterial pressure. In a second experiment dose-response infusions of angiotensin II were given in conscious sodium-depleted dogs before and during infusion of the renin inhibitor H.77. These suggested that the contribution of angiotensin II to the maintenance of arterial pressure in this state was made mainly by a circulating peptide. Preliminary results in normal humans show that infusion of H.142 intravenously lowered angiotensin I, angiotensin II, and arterial pressure.
Adult↗
Factors influencing mortality in malignant hypertension.
In a study designed primarily to assess mortality, 139 consecutive patients presenting with malignant hypertension (MHT) in Glasgow between 1968 and 1983 were matched individually for age, sex and initial blood pressure with 139 non-malignant hypertensives attending the Glasgow Blood Pressure Clinic. Fifty-four patients with MHT and 34 controls died before 1 April 1984. Multivariate analysis showed that initial serum creatinine and blood pressure achieved during treatment were significantly and independently related to outcome among the patients with MHT, but that age, smoking habit, presence of papilloedema, underlying diagnosis, initial blood pressure and year of presentation were not. Overall survival among patients with MHT was 63% at 5 years and 47% at 10 years. Although this was better than in earlier studies patients with MHT were still twice as likely to die as non-malignant controls. The excess mortality was confined largely to patients with underlying renal disease and/or renal failure at presentation. Moreover, renal failure contributed to four times more deaths among patients with MHT than controls. Thus, despite an improvement in survival compared with previous years, renal failure remains the most serious manifestation of patients with this disease.
Female↗
Renal hypertension. The renin system in hypertension with unilateral renal artery stenosis.
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Animals↗
Abnormal haemostasis and blood viscosity in malignant hypertension.
We have previously shown abnormalities of haemostasis suggestive of intravascular coagulation in patients with malignant hypertension, a condition associated with retinopathy and renal fibrin deposition. To determine whether such abnormalities are specific to malignant hypertension, we have measured several haemostatic and haemorheological variables in 18 patients with malignant hypertension (Group 1), 18 matched healthy controls (Group 2), and 18 patients with non-malignant hypertension (Group 3) matched for renal pathology, blood pressure and serum creatinine with Group 1. Both Groups 1 and 3 had increased mean levels of fibrinogen, factor VIIIc, beta-thromboglobulin, plasma viscosity and blood viscosity (corrected for haematocrit); and decreased mean levels of haematocrit, antithrombin III and platelet count. Mean levels of fast antiplasmin and alpha2-macroglobulin were elevated in Group 1 but not in Group 3. We conclude that most blood abnormalities are not specific to malignant hypertension; are also present in patients with non-malignant hypertension who have similar levels of blood pressure and renal damage; and might result from renal damage as well as promoting further renal damage by enhancing fibrin deposition. However increased levels of fibrinolytic inhibitors in malignant hypertension merit further investigation in relation to removal of renal fibrin.
Adult↗
Enalapril in treatment of hypertension with renal artery stenosis. Changes in blood pressure, renin, angiotensin I and II, renal function, and body composition.
The converting enzyme inhibitor enalapril, in single daily doses of 10 to 40 mg, was given to 20 hypertensive patients with renal artery stenosis. The decrease in blood pressure six hours after the first dose of enalapril was significantly related to the pretreatment plasma concentrations of active renin and angiotensin II, and to the concurrent decrease in angiotensin II. Blood pressure decreased further with continued treatment; the long-term decrease was not significantly related to pretreatment plasma renin or angiotensin II levels. At three months, 24 hours after the last dose of enalapril, blood pressure, plasma angiotensin II, and converting enzyme activity remained low, and active renin and angiotensin I high; six hours after dosing, angiotensin II had, however, decreased further. The increase in active renin during long-term treatment was proportionately greater than the increase in angiotensin I; this probably reflects the diminution in renin substrate that occurs with converting enzyme inhibition. Long-term enalapril treatment increased renin secretion by more than 10-fold, and renal venous and peripheral plasma renin concentration by more than 20-fold; however, the mean renal venous renin ratio was not changed. Enalapril caused a reduction in effective renal plasma flow via the affected kidney but a marked and consistent increase on the contralateral side, where renal vascular resistance decreased. The overall increase in effective renal plasma flow was significantly related to the decrease in angiotensin II. Overall glomerular filtration rate was lowered, and serum creatinine and urea increased. Enalapril alone caused a long-term reduction in exchangeable sodium, with slight but distinct increases in serum potassium. In five patients with bilateral renal artery lesions, enalapril given alone for three months did not cause renal function to deteriorate. Enalapril was well tolerated and provided effective long-term control of hypertension; only two of the 20 patients studied required concomitant diuretic treatment.
Administration, Oral↗