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(Hypertension. 1997;30:1068-1071.)
© 1997 American Heart Association, Inc.
Articles |
Identification of a Renin Threshold and Its Relationship to Salt Intake in a Patient With Pure Autonomic Failure
From the Departments of Internal Medicine (H.H., U.S., A.M.S.) and Neurology (F.K., S.S.), Universitätsklinikum Benjamin Franklin, Free University of Berlin; and the Department of Physiology (P.B.P.), Universitätsklinikum Charité, Humboldt University of Berlin, Germany.
Correspondence to Dr Arya M. Sharma, Medizinische Klinik, Klinikum Benjamin Franklin, Freie Universität Berlin, Hindenburgdamm 30, D-12200 Berlin, Federal Republic of Germany. E-mail sharma{at}zedat.fu-berlin.de
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Abstract |
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Abstract Animal studies have demonstrated a threshold below which renin release increases proportionally to a decrease in renal perfusion pressure. Demonstration of a similar mechanism in humans, however, has proved difficult, as any attempt to lower blood pressure below the putative renin threshold results in renin release mediated by reflex activation of the sympathetic nervous system. In this study, we report on our observations in a 71-year-old woman who presented with a 20-year history of faintness and syncope and was diagnosed as having pure autonomic failure. Graded head-up tilting resulted in a stepwise reduction in mean arterial blood pressure to a minimum of 54 mm Hg, with no signs of increased sympathetic activity. A fall in blood pressure below 80 mm Hg resulted in a distinct rise in plasma renin activity, and a similar threshold pressure was observed under both a 50- and a 100-mmol/d sodium chloride diet. Below the threshold, response to changes in perfusion pressure was proportionally greater under the 50-mmol/d diet than under a 100- or 200-mmol/d diet. These observations demonstrate that a pressure threshold for renin release at 10 to 15 mm Hg below ambient blood pressure, as described previously in animal studies, is also present in humans. The significance of this pressure-dependent mechanism of renin release for the long-term regulation of blood pressure and water and mineral balance in humans remains to be determined.
Key Words: blood pressure • renal circulation • diet, sodium restricted • renin-angiotensin system • autonomic failure
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Introduction |
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The renin-angiotensin system has long been recognized as a key player in the regulation of systemic blood pressure and electrolyte and volume homeostasis. The major factors known to play a role in the regulation of renin release can be broadly categorized as those related to renal perfusion pressure, tubular-glomerular feedback, and the sympathetic innervation of the kidney.1 It is, however, important to realize that these factors are highly interrelated and that dissection of the individual role of each of these factors in the renin response to physiological stimuli remains a daunting task.
The concept of an intrarenal pressure–dependent mechanism that controls renin release originated from the seminal work of Goldblatt et al2 and Tobian et al3 and was first formulated as the baroreceptor mechanism of renin release by Skinner et al4 in 1964. It is now generally accepted that the pressure-dependent response of renin release is mediated within the renal vasculature itself and is not dependent on renal innervation or tubular events.1
The quantitative characteristics of the relationship between renal perfusion pressure and renin release have been extensively studied in chronically instrumented animal models, leading to the demonstration of a threshold below which renin release increases proportionally to the decrease in perfusion pressure.5 In humans, however, the study of pressor-dependent renin release is confounded by the hierarchy of blood pressure–regulating systems that antagonize any attempt to lower blood pressure below the putative renin threshold. Thus, reducing renal perfusion pressure by altering systemic blood pressure in healthy humans will immediately result in a rise in renin secretion mediated primarily by an increase in sympathetic outflow.6 Nevertheless, studies in tetraplegic patients have demonstrated a rise in plasma renin activity when hypotension was induced by head-up tilt,7 8 and ganglionic blockade in normal and hypertensive patients reduced but failed to abolish renin release in response to hypotension induced by sodium nitroprusside infusion.9 These findings do indeed suggest that renin-release mechanisms independent of autonomic renal innervation may be present in humans.
In this study, we report on our observations in a patient with pure autonomic failure, demonstrating the presence of a renin threshold and its resistance to modulation by subacute changes in dietary salt intake.
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Methods |
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A 71-year-old woman (158 cm, 65 kg) with a 20-year history of faintness and syncope on standing was studied. Clinical evaluation revealed that blood pressure levels, ranging between 140/90 mm Hg and 190/130 mm Hg in the supine position, dropped to 50/20 mm Hg within seconds of assuming an upright position. Apart from this finding, physical and neurological examination was unremarkable, except for a sluggish pupillary reaction to light. Laboratory parameters, including serum electrolytes, glucose, creatinine, and blood urea nitrogen, were normal, except for 24-hour urinary excretion of vanillin-mandelic acid below detection level. Electrocardiography and abdominal ultrasound were unremarkable. Electroencephalographic tracings in the awake patient showed sleep-onset rapid eye movement, and cranial computed tomography and magnetic resonance imaging showed discrete signs of age-related cerebral atrophy but were otherwise normal.
Neurographic stimulation of hands and feet failed to elicit a sympathetic reaction, and the ninhydrin test on hand and forehead failed to produce a sweat response. The cold pressor test, performed by placing a hand in ice slush for 2 minutes, did not result in a rise in blood pressure or heart rate. On the basis of these findings, the diagnosis of postural hypotension in pure autonomic failure was established, according to the recent consensus statement of the American Autonomic Society and the American Academy of Neurology.10
After explaining the study protocol and obtaining consent from the patient, the blood pressure response to exogenous norepinephrine and the plasma renin and catecholamine response to a head-up tilt were studied. Blood pressure response (DINAMAP 1846SX, Critikon) to norepinephrine was determined by graded intravenous infusion of 0.001, 0.002, 0.004, 0.008, and 0.014 µg · kg-1 · min-1 for 10 minutes each. Norepinephrine reagibility was calculated as the reciprocal value of the dose required to raise mean arterial blood pressure by 20 mm Hg, as previously described.11
The patient was given a standardized diet containing 50 mmol sodium chloride, 60 mmol potassium, and 20 mmol calcium per day for 9 days. In addition, a daily supplement of 15 tablets, consisting of either slow-release sodium (10 mmol NaCl per tablet; gift from CIBA-GEIGY, Horsham, UK) or placebo was administered in a single-blind fashion. From days 1 through 3 the salt intake was 200 mmol/d; from days 4 through 6, 100 mmol/d; and from days 7 through 9, 50 mmol/d. Compliance was assessed by daily measurement of urinary electrolyte excretion.
On days 3, 6, and 9, a head-up tilting protocol was performed between 10 and 12 AM in the fasting subject. Before the tilting procedure, the patient had been lying in a supine position for 2 hours. After cannulation of an antecubital vein, blood pressure and heart rate were monitored at 1-minute intervals with the DINAMAP. In addition, beat-to-beat blood pressure levels and heart rate were recorded by FINAPRESS (Ohmeda). After a resting period of 45 minutes, blood samples were drawn for the measurement of sodium, chloride, potassium, epinephrine, norepinephrine, and renin activity. The patient was then tilted head up at angles of 6°, 12°, and 18° for 10 minutes each. The patient had been familiarized with this procedure on a previous day. Mean arterial pressure was calculated as the mean of 10 recordings (±SD) over a period of 10 minutes at each angle, and blood samples were collected at the end of each period.
Serum and urinary sodium, chloride, and potassium levels were measured by standard laboratory techniques. Plasma renin activity was measured by radioimmunoassay, and epinephrine and norepinephrine were measured by high-performance liquid chromatography as previously described.11
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Results |
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The study procedure was well tolerated by the patient without adverse events. The infusion study revealed an exquisite sensitivity to norepinephrine. Thus, the dose of norepinephrine required to raise mean arterial blood pressure by 20 mm Hg was 0.006 µg · kg-1 · min-1, resulting in a norepinephrine reagibility of 166 µg · kg-1 · min-1. The corresponding value in normotensive control subjects studied in our laboratory ranges from 5 to 13 µg · kg-1 · min-1.11 Despite the marked rise in blood pressure, heart rate remained constant at 68 to 70 beats per minute.
Although urinary sodium excretion changed as expected during the
dietary protocol (day 3, 201 mmol/24 h; day 6, 82
mmol/24 h; and day 9, 47 mmol/24 h), supine mean
arterial blood pressure was not affected (day 3, 91±2
mm Hg; day 6, 94±3 mm Hg; and day 9, 93±4 mm Hg). The
tilting procedure resulted in a stepwise drop in mean
arterial blood pressure to a minimum of 54 mm Hg (day
6), but despite this marked fall in blood pressure, heart rate
increased by no more than two to four beats per minute. The
relationship between the tilt-induced change in mean
arterial pressure and plasma renin activity is shown in the
Figure
. Dietary salt intake significantly
affected both the basal level and the slope of the rise in renin
activity during head-up tilt. Under the 50- and 100-mmol/d NaCl
diets, renin activity increased when blood pressure dropped below
80 mm Hg. In contrast, under the 200-mmol/d NaCl diet,
there was a small but continuous rise in renin activity despite a
similar fall in blood pressure. There was no consistent effect
of dietary salt intake on plasma levels of norepinephrine
(day 3, 0.56 nmol/L; day 6, 0.83 nmol/L; and day 9, 0.61
nmol/L; reference values, 1.3 to 2.8 nmol/L) and a
negligible change in this parameter on tilting (day 3,
+0.01 nmol/L; day 6, -0.04 nmol/L; and day 9, +0.13
nmol/L). Plasma levels of plasma epinephrine were below
detection range (<55 pmol/L; reference values, 170 to 520
pmol/L) both before and after tilting at all levels of salt
intake.
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Discussion |
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The rather rare syndrome of pure autonomic failure as diagnosed in our patient allowed us to study the effect of a stepwise reduction in systemic blood pressure on plasma renin activity without the confounding reflex activation of the autonomic nervous system. Under both the moderate and low salt diets, there was a steep rise in plasma renin activity as mean blood pressure fell to below 80 mm Hg. This finding is well in line with the previous demonstration of a renin threshold at about 90 mm Hg in conscious, chronically instrumented dogs12 and at about 80 mm Hg in conscious rats.13 As noted by Finke et al,14 pressure-dependent renin release in dogs is characterized by (1) a plateau in the high-to-normal blood pressure range, at which little renin is released; (2) a renin threshold at roughly 10 to 15 mm Hg below the normal arterial pressure; and (3) a range below the threshold pressure, at which renin release increases proportionally to the decrease in blood pressure. Our present observations are in line with these findings and indicate that a similar threshold for renin release is also present in humans at about 10 to 15 mm Hg below ambient mean arterial blood pressure.
As mentioned above, reflex stimulation of the sympathetic nervous system confounds the study of pressure-dependent renin release in normal humans. In our patient, lack of a central and peripheral sympathetic response was demonstrated not only by failure to increase heart rate and plasma catecholamine levels in response to tilting but also by failure to elicit a blood pressure or heart rate response to the cold pressor test or a sweat response to ninhydrin.10 The strikingly increased peripheral responsiveness to exogenous norepinephrine is well in line with the denervation supersensitivity to sympathomimetic drugs commonly observed in patients with complete autonomic failure.15 It is therefore very unlikely that the rise in renin observed in our patient resulted from an increase in renal sympathetic nerve activity.
Previous attempts to demonstrate a renin release independent of renal innervation in humans have had conflicting results. While Mathias et al7 8 clearly demonstrated a rise in plasma renin activity during a 45° head-up tilt in tetraplegic patients, similar studies by Biaggioni et al16 failed to find a marked rise in renin activity in patients with pure autonomic failure or multiple system atrophy when studied on a 150-mmol/d NaCl diet. Given our current finding that pressure-dependent renin release can be almost entirely suppressed by a high dietary salt intake, the discrepancy between the findings of Biaggioni et al and those in our patient could possibly be accounted for by differences in salt balance.
A direct effect of a transient unilateral reduction of renal perfusion pressure on renin release was also demonstrated in normal and hypertensive humans by reducing renal blood flow to 50% with the help of a balloon-tipped catheter.17 18 The investigators in these studies observed a fourfold increase in plasma renin activity, although systemic blood pressure remained constant. Nevertheless, a dominant role for adrenergic control of renin release in humans with intact renal innervation is suggested by the finding that ß-blockade can markedly reduce the renin response to upright posture7 or the response to a unilateral reduction in perfusion pressure19 in normotensive7 19 and hypertensive19 subjects. It is, however, important that in these studies, despite ß-blockade, systemic or renal perfusion pressure was lowered nowhere near the renin-threshold levels observed in our study. These findings, therefore, do not rule out a renin release, independent of adrenergic stimuli, at lower perfusion pressures in individuals with intact renal innervation.
Interestingly, a recent study by Bertolino et al20 in rats also provides evidence that the renin threshold is apparently not markedly modulated by the activity of the autonomic nervous system. In that study, reduction of renal perfusion pressure by using an inflatable aortic cuff in intact, pharmacologically sympathectomized or renal-denervated animals resulted in a similar increase in plasma renin concentration at threshold pressures ranging from 83 to 87 mm Hg. This threshold level is remarkably similar to that observed in our patient.
In our study, both basal levels of renin activity and the renin response to the fall in perfusion pressure induced by tilting were markedly affected by subacute modulation of dietary salt intake. This finding is in keeping with previous observations in dogs with autotransplanted kidneys21 and in humans after renal transplantation,22 showing that chronically denervated kidneys can maintain normal rates of renin release in response to sodium depletion. In dogs23 or rats24 maintained on a low salt diet for prolonged periods of time, basal renin secretion increased and the response to changes in perfusion pressure were proportionally greater over the whole pressure range without significant alteration of the threshold pressure. This finding corresponds to our present observation of a similar threshold pressure at around 80 mm Hg under both the 50- and 100-mmol/d NaCl diets, despite markedly higher baseline levels and a greater rise in renin activity under the 50-mmol/d diet. Whether or not the renin threshold was shifted or merely concealed as a result of almost total suppression of renin release under the 200-mmol/d NaCl diet remains unclear. Nevertheless, our findings, together with those in dogs23 and rats,24 suggest that dietary salt intake (at least in the 50- to 100-mmol/d NaCl range) affects the basal and stimulated rate of renin secretion without markedly affecting the threshold pressure of renin release.
In this regard, it must also be noted that both baseline concentrations and the renin response to orthostasis and sodium depletion are well known to be blunted in older individuals.25 Therefore, the magnitude of the rise in renin activity observed in our 71-year-old patient may well be greater in younger individuals.
The physiological and pathophysiological significance of pressure-dependent control of renin secretion remains the subject of much debate.5 On the basis of observations in chronically instrumented conscious dogs that increased renal sympathetic activity can shift the blood pressure threshold for renin release to higher values12 and that during the course of a day, a significant proportion of blood pressure levels is likely to fall below the renin threshold, resulting in repeated acute stimulation of the renin-angiotensin system, Ehmke et al26 proposed that pressure-dependent renin release is an important factor influencing the normal blood pressure level in an individual animal. The demonstration of a renin threshold in our patient at blood pressure levels similar to those found in animal models suggests that pressure-dependent renin release may also be an important determinant of blood pressure levels in humans.
In conclusion, we observed a pressor-dependent rise in plasma renin activity when mean blood pressure levels were reduced below a threshold of 80 mm Hg by passive tilting in a patient with pure autonomic failure. Subacute changes in dietary salt intake markedly affected both the basal levels and the magnitude of the rise in renin activity, but not the threshold for renin release. The factors determining the level of this renin threshold in humans and its importance for blood pressure regulation in health and disease remain to be determined.
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Acknowledgments |
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We are grateful to our patient, who kindly agreed to participate in this study. The slow-release sodium tablets were a gift from CIBA-GEIGY, Horsham, UK.
Received February 24, 1997; first decision March 17, 1997; accepted April 30, 1997.
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