Mar 11, 1975 - Robertson, Tree & Wilson, 1974) by the finding of a mean plasma renin .... renin in normal individuals (Fraser, James, Brown,. Isaac, Lever ...
Clinical Science and Molecular Medicine (1975) 49, 353-358.
Effect of intravenous frusemide on plasma renin concentration: suppression of response in hypertension
P . L . P A D F I E L D , * M . E . M . A L L I S O N , ? J. J . B R O W N , * A . F. L E V E R , * R . G . L U K E , ? C . C . R O B E R T S O N , * J . I. S . R O B E R T S O N * A N D M . T R E E * *MRC Blood Pressure Unit, Western Infirmary, Glasgow, and
? University Department of Medicine, Royal Infirmary, Glasgo w Scotland (Received 11 March 1975)
Summary
1973; Dunn & Tannen, 1974), but whether or not this group represents a distinct entity remains unclear. The confusion arises partly from the variability of criteria for the diagnosis of low-renin hypertension; most workers employ some form of provocative test in an attempt to differentiate this group, as will be discussed below. The present paper assesses the value of one such test in a series of hypertensive patients.
1. Intravenous frusemide produced in normal subjects a prompt rise of plasma renin concentration which correlated with urinary sodium. 2. The renin response to frusemide was suppressed in patients with primary hyperaldosteronism. 3. In patients with low-renin hypertension and normal renin essential hypertension, the renin response to frusemide was similarly suppressed. 4. Suppression of the renin response to frusemide is therefore a feature of hypertension not confined to patients with primary hyperaldosteronism and low-renin hypertension. 5. Thus low-renin hypertension does not appear to constitute a distinct diagnostic entity. 6 . It is suggested that suppression of the renin response is part of a long-term renal adaptation to high blood pressure.
Patients and normal subjects Thirty-eight Caucasian hypertensive patients (twenty-nine female) aged 20-66 years (mean 49) and seven normotensive Caucasian males (five patients with untreated peptic ulcer and two healthy volunteers) were studied. All patients had a mean diastolic blood pressure (at least two readings) greater than 95 mmHg, taken while seated in the out-patient department before treatment. Details of the patients are presented in Table 1. N o female patient was pregnant and, at the time of the study, patients were either untreated or had had treatment withdrawn (diuretics and potassium supplements for at least 4 weeks, other hypotensive agents for at least 1 week and oral contraceptives for at least 3 months). No patient had clinical or biochemical evidence of Cushing’s syndrome, phaeochromocytoma (urinary normetadrenaline) or coarctation of the aorta and none had papilloedema, retinal haemorrhages or exudates. In no case was proteinuria detected. All patients had normal excretion
Key words : essential hypertension, frusemide, low-renin hypertension, plasma renin concentration, primary hyperaldosteronism, sodium excretion. Introduction Approximately 25 % of patients with apparently essential hypertension have been shown to have low plasma renin concentrations which are often unresponsive to stimulatory manoeuvres (Kaplan, Correspondence: Dr P. L. Padfield, MRC Blood Pressure Unit, Western Infirmary, Glasgow G11 6NT, Scotland. F
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P . L. Padfield et al.
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TABLE I . Comparisons between groups of patients and control subjects
Results are expressed as mean value+
SEM
with the range in parentheses.
Blood pressure (mmHg) Group
Normal control subjects
No.
7
Primary hyperaldosteronism
14
Essential hypertension Low-renin hypertension
12 12
Age (years)
45+ 5 (20-59) 49+ 3 (20-64) 45+ 1 (38-54) 52+ 1 (24-65)
Weight (kg)
68+ 1 (64-72) 695 2 (53-85) 67+ 3 (54-84) 69+ 4 (54-94)
urography with serum urea concentration less than 7.5 mmol/l. All patients and normal subjects gave their fully informed consent to the procedures. Group 1. Primary hyperaldosteronism was diagnosed as described previously (Brown, Davies, Ferriss, Fraser, Haywood, Lever & Robertson, 1972) in fourteen patients (nine female). Quadric analysis (Aitchison, Brown, Ferriss, Fraser, Kay, Lever, Neville, Symington & Robertson, 1971) indicated an adrenocortical adenoma in seven patients and bilateral adrenocortical hyperplasia in the remaining seven. These predictions were subsequently confirmed in the seven patients operated upon (four adenoma, three adrenocortical hyperplasia). Group 2. Essential hypertension with normal renin concentration was diagnosed in twelve patients (eight female) by exclusion (see above). Plasma aldosterone concentration was normal on at least two occasions in all cases. Group 3. Low-renin hypertension was arbitrarily defined as previously (Lebel, Schalekamp, Beevers, Brown, Davies, Fraser, Kremer, Lever, Morton, Robertson, Tree & Wilson, 1974) by the finding of a mean plasma renin concentration < 6 units/] in twelve patients (ten female). Four of these had a mean serum potassium less than 3.7 mmol/l. Plasma aldosterone and deoxycorticosterone concentrations were normal in all patients.
Out-patient Systolic
Diastolic
134+ 5
74+ 5 (58-88)
(1 14-146)
191+7 (1 52-220) 189+9
( I 50-260) 184+9 (140-250)
119+3 (102-140) 117+3 (100-1 36) 118+4 (100-150)
In-patient Systolic
Diastolic -
170+5 (150-200) 172+9 (140-264) l60+ 6 (134-200)
105f2 (95-120) 106+ 3 (95-120) 108+2 (95-120)
60 mmoliday). Basal blood samples were taken between 08.00 and 08.30 hours, with the patient in bed, after overnight fasting and recumbency, for measurement of plasma renin concentration (Brown, Davies, Lever, Robertson & Tree, 1964).(’) Frusemide (150 pmol, 50 mg; Lasix) was then injected intravenously and blood was again obtained for plasma renin concentration 1 h and 2 h after the injection. Patients and normal subjects were not catheterized. They micturated at the beginning of the experiment and urine was collected hourly thereafter for 2 h. All remained recumbent throughout, males standing to pass urine. Urinary sodium concentration was measured by flame photometry with lithium as an internal standard. Plasma concentrations of aldosterone (Fraser, Guest & Young, 1973) and deoxycorticosterone (Wilson & Fraser, 1971) were measured with the patient recumbent after an overnight fast on a fixed normal intake of sodium and potassium. Changes in plasma renin concentration were assessed by Student’s paired t-test and other comparisons between groups were made with Student’s unpaired t-test.
Results
Methods
There was no significant difference between the mean ages or weights of the groups studied, although the patients with low-renin hypertension were on average older than those with primary hyperaldosteronism and essential hypertension (Table 1).
Patients and normal subjects were studied after 3 days on a fixed intake of sodium (mean for all patients = 135 mmol/day) and potassium (mean =
( I ) Values for renin in this paper are given in ‘Glasgow’ units. The legend to Fig. 1 gives the relation of the ‘Glasgow’ unit to the recently agreed international renin standard.
Suppressed renin response in hypertension 36
355
t
28
s, 20 ._ t
C
c .-
c
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E
8 12
a
d A
(d
(b)
(C)
(d)
FIG.1. Mean values ( ~ S E M )of plasma renin concentration before (basal) and at 1 h and 2 h after intravenous injectionoffrusemide(150pmol, 50mg). (a)Normalgroup (n= 7): 13k 1.1+21 k 1.7(P< OOl), first hour; 21 f 1.7+26 22.9 ( 0 0 5 < P< 0.1), second hour. (b) Primary hyperaldosteronism group (0, adenoma; 0 ,hyperplasia) (n = 14): 4.8f0.5+4.8+0.8+52f 1.1 (not significant)over2 hperiod. (c)Essential hypertensiongroup(n = 12): 9.0+ 1.29.25 1.2+8.8+ 1.5 (not significant)over2 h period. (d) Low-renin hypertension group (n = 12): 3.7k 0.4+5.4+ 0 9 (P
