J. J. Brown

Comparison of surgery and prolonged spironolactone therapy in patients with hypertension, aldosterone excess, and low plasma renin.

The effect of prolonged preoperative treatment with spironolactone has been studied in a series of 67 patients with hypertension, aldosterone excess, and low plasma renin. In the series as a whole a highly significant reduction in both systolic and diastolic pressures was achieved, with no evidence of escape from control during therapy lasting several years in some cases. The drug was equally effective in controlling blood pressure in patients with and without adrenocortical adenomata. Occasional unresponsive patients were encountered in both groups; pretreatment blood urea levels in these were significantly higher than in the responsive patients. The hypotensive effect of spironolactone usually predicted the subsequent response to adrenal surgery. Spironolactone in all cases corrected plasma electrolyte abnormalities; significant increases in total exchangeable (or total body) potassium and significant reductions in total exchangeable sodium, total body water, extracellular fluid, and plasma volumes were seen. Plasma urea rose during treatment and there was a slight fall in mean body weight. Significant increases in peripheral venous plasma renin and angiotensin II concentrations occurred during treatment. In two patients no increase in aldosterone secretion rate was found during treatment, although plasma aldosterone rose in three of four subjects studied. Severe side effects were rare; in only two of the 67 patients did the drug have to be stopped. In addition to its routine preoperative use, spironolactone can now be advised as long-term therapy in selected patients.

PLASMA RENIN CONCENTRATION IN HUMAN HYPERTENSION. 1. RELATIONSHIP BETWEEN RENIN, SODIUM, AND POTASSIUM.

be only a measure of mucosal damage. In this connexion it is worth mentioning that the small-intestinal mucosa is frequently abnormal in ulcerative colitis, and the degree of abnormality is positively correlated with the clinical severity of the colitis (Salem et al., 1964, 1965). This raises the possibility that absorption of whole protein may occur from the small intestine, with resulting high levels of antibody that are then no more than an indication that the intestine has been widely affected, which in turn may indicate a relatively bad prognosis. Circulating antibodies to dietary proteins are present from birth and can be demonstrated in cord blood, commonly at a higher titre than in maternal blood (Wright et al., 1962). When infants are weaned and fed on cows milk the levels of circulating antibodies to cows-milk proteins rise considerably (Gunther et al., 1962). In ulcerative colitis, in coeliac disease, and in idiopathic steatorrhoea the titre of circulating antibodies to various dietary proteins are often high (Taylor and Truelove, 1961 ; Taylor et al., 1961, 1964). So far as ulcerative colitis is concerned, early weaning from the breast was found to be twice as common in the subjects of this disease as in control subjects (Acheson and Truelove, 1961). There is the possibility that immunological stimulation by dietary proteins during infancy may set the stage for a variety of diseases in later life and that ulcerative colitis is one of them.

Sodium and potassium in essential hypertension.

A study was carried out of arterial pressure and body content of electrolytes in 91 patients with essential hypertension and 121 normal controls. Exchangeable sodium was found to be positively correlated with arterial pressure in the patients, the correlation being closest in older patients; values of exchangeable sodium were subnormal in young patients; and plasma, exchangeable, and total body potassium correlated inversely with arterial pressure in the patients, the correlations being closest in young patients. Three hypotheses were proposed to explain the mechanisms relating electrolytes and arterial pressure in essential hypertension--namely, a cell-salt hypothesis, a dietary salt hypothesis, and a kidney-salt hypothesis. It was concluded that two mechanisms probably operate in essential hypertension. In the early stages of the disease blood pressure is raised by an abnormal process related more closely to potassium than to sodium. A renal lesion develops later, possibly as a consequence of the hypertension. This lesion is characterised by resetting of pressure natriuresis and is manifest by an abnormal relation between body sodium and arterial pressure and by susceptibility to increased dietary sodium intake.

Results of adrenal surgery in patients with hypertension, aldosterone excess, and low plasma renin concentration.

Fifty patients with hypertension, aldosterone excess, and low plasma renin concentration underwent adrenal surgery. There was a highly significant fall in mean systolic and diastolic pressures after the operation. The mean postoperative diastolic pressure fell to strictly normal levels, however, in only 19 out of 38 patients from whom an adrenocortical adenoma was removed and in only two out of 10 non-tumour patients. There was a significant correlation between the fall in blood pressure during spironolactone treatment and after adrenal surgery though levels were generally slightly lower during the former therapy. It is suggested that removal of an aldosterone-producing adenoma is the treatment of choice provided a good preoperative hypotensive response to spironolactone occurs, while the treatment of choice for non-tumour patients is often long-term spironolactone.

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 μmol/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.

Variations in Plasma Renin During the Menstrual Cycle

Intravenous infusions of renin or angiotensin stimulate aldosterone secretion and excretion (Laragh et al., 1960 ; Genest et al., 1961 ; Carpenter et al., 1961 ; Blair-West et al., 1962). The concentration of renin in plasma varies in several physiological and pathological states (Brown et al., 1964a) in a way which supports the suggestion (Gross, 1958 ; Davis et al., 1961) that the renin-angiotensin system might regulate aldosterone secretion. As the urinary excretion of aldosterone varies during the menstrual cycle (Reich, 1962 ; Nowaczynski et al., 1962), the present study was undertaken to determine whether these changes might be accompanied by variations in plasma renin.

Falsely High Plasma Potassium Values in Patients with Hyperaldosteronism

The common practice of encouraging forearm exercise as an aid to venepuncture is a potent source of erroneously high plasma potassium levels. This may be sufficient to obscure a suspicion of hyperaldosteronism, with possible serious repercussions in hypertensive patients, in whom the diagnosis of hyperaldosteronism has important therapeutic implications. Plasma is preferable to serum for potassium estimations, and forearm exercise should be avoided before venepuncture for potassium measurements.

Recurrent Hyperkalaemia due to Selective Aldosterone Deficiency: Correction by Angiotensin Infusion

A patient with recurrent weakness and blurring of consciousness associated with hyperkalaemia due to aldosterone deficiency is reported. The plasma concentrations of renin, angiotensin II, and aldosterone were low and did not increase during sodium deprivation. Blood angiotensin I was also low while renin-substrate concentration was normal. Infusion of angiotensin produced a distinct rise in plasma aldosterone. The patient was treated successfully with fludrocortisol. The results support the concept that the renin-angiotensin system is an important regulator of aldosterone secretion and that in the syndrome of acquired selective hypoaldosteronism the primary abnormality may be a deficiency of renin. It is suggested that a selective lack of aldosterone should be considered in all cases of otherwise unexplained hyperkalaemia.

Plasma Renin Concentration in Human Hypertension—III: Renin in Relation to Complications of Hypertension

The perinatal mortality for 5,893 single births occurring in the Oxford area in 1962 has been studied in relation to the local organization of maternity services. The perinatal mortality rate for single births was 23 per 1,000, and 25 per 1,000 for all births, results which compare favourably with those in other parts of England and Wales. Of the mothers 48% had been booked for consultant care, 51% for care under general practitioners either at home or in G.P. maternity units, and a little under 1 % had not been booked for any type of care. When the mothers were classified into three risk groups according to features evident at the time of booking (maternal age, parity, and a previous history of stillbirth) it was found that 57% of risk group I (all women aged 35 years or more, nulliparae aged 30 years or more, multiparae having had four or more children, and women with a past history of stillbirth), 58% of risk group II (nulliparae under 30 years), and 37% of the remainder had been booked for consultant care. For risk groups I and III the perinatal mortality rate was higher in consultantthan in G.P.-booked cases, a situation which at least in part reflects selection of difficult cases for consultant care within these groups. For young nulliparae, however (risk-group II), the perinatal mortality for legitimate births in 1962 was slightly higher in mothers booked for G.P. care (24 per 1,000) than in those booked for consultant care (21 per 1,000). This group also experienced the highest rate of emergency transfer to consultant care late in pregnancy or in labour (13%). In a study of 55 general practices a wide variation was found between practices in the proportions of mothers booked for consultant care. This was also present when each risk group was considered separately. Two important factors which influenced this variation were found. Firstly, the presence of a local G.P. obstetric unit greatly reduced the proportion of mothers booked for consultant care in each risk group. Secondly, when a G.P. obstetric unit was accessible to practices, increasing distance from a consultant unit further depressed the proportion of mothers in each risk group booked for consultant care. A reduction in consultant bookings with distance did not occur where no G.P. unit was accessible to practices. The perinatal mortality was significantly higher in practices with access to G.P. units (28 per 1,000) than in those without such access (19 per 1,000), and further analysis showed that this difference was limited to mothers in risk groups I and II. No evidence was found to support the hypothesis that the higher mortality in practices with access to G.P. units was due to an inherently less favourable population from the obstetric point of view, nor was it possible to show that differences in the arrangements for obstetric care were responsible.

Converting-enzyme inhibitor enalapril (MK421) in treatment of hypertension with renal artery stenosis.

Enalapril maleate (MK421), a new inhibitor of angiotensin converting enzyme, in single daily doses of 1.25-40 mg was assessed in five patients with hypertension and renal artery stenosis. Only small falls in plasma angiotensin II concentrations were seen at doses less than 10 mg; even with 10 and 20 mg, angiotensin II concentrations had risen again 24 hours from the last dose. During long-term treatment with 10-40 mg daily all patients achieved good blood-pressure control. No significant changes of body sodium or potassium values were seen. The drug was well tolerated with no serious side effects. These findings are evidence of the efficacy and acceptability of enalapril in the medical management of hypertension with renal artery stenosis.