Salicylates are widely used in the treatment of rheumatic disorders, and they have been shown to induce minor changes in renal function. One of the major mechanisms of action of salicylates is the suppression of prostaglandin synthetase activity, and in animal rnodels renal prostaglandin production is closely related to renin release and the regulation of renal blood flow. Indomethacin has been shown to decrease the glomerular filtration rate and to lower plasma renin activity in human beings, and to reduce the antihypertensive effectiveness of cerÂ¬tain beta-adrenoreceptor-blocking agents. We there-fore studied the effects of aspirin, another commonly prescribed non-steroidal anti-inflammatory agent, on plasma renin concentration, both during administraÂ¬tion and after withdrawal

G. W. Boyd

P. A. Cossum

P. M. Brooks

Romero

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New England Journal of Medicine

Rebound Rise in Renin Concentrations after Cessation of Salicylates

Brooks, P. M.

Cossum, P.

Boyd, G. W.

University of Queensland eSpace

New England Journal of Medicine 303 (10): 562-564. 
REBOUND RISE IN RENIN CONCENTRATIONS AFTER 
CESSATION OF SALICYLATES  
 
P. M. BROOKS, F.R.A.C.P., 
P. A. COSSUM, B.SC., 
AND G .  W. BOYD, M.D., PH.D., F.R.A.C.P.  
 
 
Salicylates are widely used in the treatment of rheumatic disorders, and they have been 
shown to induce minor changes in renal function.1-3 One of the major mechanisms of 
action of salicylates is the suppression of prostaglandin synthetase activity,4 and in animal 
rnodels renal prostaglandin production is closely related to renin release and the 
regulation of renal blood flow.5,6 Indomethacin has been shown to decrease the glomerular 
filtration rate and to lower plasma renin activity in human beings,8 and to reduce the 
antihypertensive effectiveness of certain beta-adrenoreceptor-blocking agents.9 We there-
fore studied the effects of aspirin, another commonly prescribed non-steroidal anti-
inflammatory agent, on plasma renin concentration, both during administration and after 
withdrawal. 
METHODS 
Two studies of the effect of salicylate on plasma renin concentration were performed. 
The first was carried out in conjunction with a study of the effect of five weeks of 
salicylate ingestion on renal function in nine normal volunteers.11 Subjects were given 
3.9 g of salicylate per day as a sustained-release preparation (Bonis SRA) in two 
divided dunes The subjects were kept on a constant diet containing no added salt 
throughout both studies. Twenty-four-hour urinary collections were made before 
salicylate administration at weekly intervals for the five weeks of treatment, and, in 
six volunteers, two weeks after the treatment ceased. Blood was collected at the same 
time of day during each 24-hour urine collection; estimations of serum and urine 
electrolytes and creatinine concentrations were performed on a Technicon 
AutoAnalyzer. Blood was also collected for estimation of plasma renin concentration 
on Day 0, one and four weeks after salicylate administration began, and two and five 
weeks after it ceased. All blood samples were taken with the volunteers in the supine 
position for at least five minutes. Blood for the plasma renin estimation was collected 
in heparin and centrifuged immediately; plasma was stored at -20°C until assay. In the 
initial study (Study 1}, plasma renin assays were carried out as the study progressed. 
In the second study (Study 2), six of the original volunteers were given the same dose 
of salicylate for a two-week period, and blood was taken for estimation of plasma 
renin concentration before the commencement of the study, at three-day intervals 
during salicylate treatment, and three, seven, 14, and 21 days after the treatment 
ended. On this occasion the frozen plasma samples from any one subject were assayed 
together at the end of the study, to avoid the possibility of any influence from 
interassay variability. Plasma renin concentration was estimated in both studies by the 
method described by Boyd.11 Renal function and changes in plasma renin  
concentration, urea, and electrolytes were analyzed statistically by Student's t-test for 
paired variables. 
New England Journal of Medicine 303 (10): 562-564. 
RESULTS 
 
The changes in plasma renin concentration during Study 1 are shown in Figure 1. There 
was a significant decrease (P<0.01) from a mean of 2.94 ng per milliliter per hour to a mean 
of 1.41 ng per milliliter per hour when salicylate treatment was started. Plasma renin 
concentrations remained low during treatment but rose again after treatment, to a mean of 
7.75 ng per milliliter per hour - significantly higher than pre-treatment levels (P<0.005). 
Plasma renin concentrations returned to pre-treatment levels by 10 weeks. 
Plasma renin concentrations in Study 2 are shown in Figure 2; renin levels again fell 
significantly (P<0.05) and rose significantly above pre-treatment levels (P<0.001) when 
treatment ceased. During the second study, supine blood pressure was measured, and the 
patient was weighed whenever blood was withdrawn for renin estimation. No significant 
changes in blood pressure or weight occurred either during treatment or afterward. 
 
 
 
 
 
New England Journal of Medicine 303 (10): 562-564. 
 
 
In Study 1 serum potassium increased slightly but significantly during salicylate 
treatment, from a mean of 3.7 mmol per liter to a mean of 4.2 mmol per liter 
(P<0.0005). There was no change in serum sodium or urinary electrolytes during the 
study. Serum creatinine rose significantly during the initial phase of the study 
(P<0.001) but then fell while the volunteers were still taking salicylates. This pattern 
was reflected by a similar initial reduction in creatinine clearance and a return to pre-
treatment levels while salicylate treatment was continued.10 
 
DISCUSSION 
 
Rebound vascular phenomena, such as angina12 and hypertension, 13 have been 
described after the withdrawal of propranolol and clonidine. We describe here a 
rebound in plasma renin concentration after it was suppressed for some weeks by 
salicylate administration. Plasma renin concentration fell significantly when aspirin 
treatment began and remained low for the duration of the treatment. When salicylate 
administration ceased, plasma renin concentrations rose significantly above pre-
treatment levels before returning to normal. 
Renin is found predominantly in the kidney and is secreted by the 
juxtaglomerular cells in response to a number of factors. 14 The transient decrease in 
creatinine clearance noted during administration of salicylate may reflect changes in 
New England Journal of Medicine 303 (10): 562-564. 
renal blood flow that resulted in a reduction in renin release secondary to relative 
arteriolar constriction. The striking observation of a rebound rise in plasma renin after 
withdrawal of salicylate cannot be explained by the changes in serum potassium, 
which rose slightly during salicylate administration and then returned to the control 
level. 10  The rebound effect was most probably associated with the removal of 
suppression of prostaglandin production. During the suppressed period, receptor 
sensitivity to prostaglandin action at the afferent arteriole may become enhanced in a 
manner analogous to denervation hypersensitivity; if after any such increase, receptor 
sensitivity was slow to revert to normal after cessation of treatment and the return of 
prostaglandin secretion, an increased prostaglandin effect might ensue. This, in turn, 
might lead to an unusual dilatation of the afferent arteriole, with a resulting increase 
in renin secretion above control values. 
Whatever the mechanism of the rebound rise, this phenomenon may be 
clinically important; if a rebound renin release is common after suppression by 
prostaglandin inhibitors, it may be important in patients who take the drug 
intermittently. We did not observe any increase in blood pressure during the phase of 
increased renin concentration after salicylate withdrawal, but it is possible that 
increased renin release resulted in a redistribution of the blood flow in various organs. 
 
REFERENCES 
 
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4. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature [New 
Biol]. 1971: 231:232-5. 
5. McGiff JC, Itskovitz HD. Prostaglandins and the kidney. Circ Res. 1973; 33: 479-88. 
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renin-angiotensin system. Mayo Clin Proc. 1977; 52:462-4. 
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by inhibition of endogenous prostaglandin synthesis, Lancet 1977; 2:1005-7. 
10. Brooks PM, Cossum PA. Salicylates and creatinine clearance re-evaluated. Aust NZ J Med. 1978; 8:660-1. 
11. Boyd GW. An inactive higher-molecular-weight renin in normal subjects and hypertensive patients. Lancet. 
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12. Harrison DC, Alderman CL. Discontinuation of propranolol therapy: cause of rebound angina pectoris and 
acute coronary events. Chest, 1976; 59:1-2. 
13 Hansson L, Hunyor SN, Julius S, Hoobler SW. Blood pressure crisis following withdrawal of clonidine 
(Catapres, Catapresan), with special reference to arterial and urinary catecholamine levels, and suggestions for 
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Rebound Rise in Renin Concentrations after Cessation of Salicylates

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