Scandinavian Journal of Clinical and Laboratory Investigation
ISSN: 0036-5513 (Print) 1502-7686 (Online) Journal homepage: http://www.tandfonline.com/loi/iclb20
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Effect of Sar -ala -angiotensin II on blood pressure and renin in Bartter's syndrome, before and after treatment with prostaglandin synthetase inhibitors Ava Rudin, Mattias Aurell, Lennart Hansson & Gunnar Westberg To cite this article: Ava Rudin, Mattias Aurell, Lennart Hansson & Gunnar Westberg (1979) 1
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Effect of Sar -ala -angiotensin II on blood pressure and renin in Bartter's syndrome, before and after treatment with prostaglandin synthetase inhibitors, Scandinavian Journal of Clinical and Laboratory Investigation, 39:6, 543-550, DOI: 10.3109/00365517909108832 To link to this article: http://dx.doi.org/10.3109/00365517909108832
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Scand. J . clin. Lab. Invest. 39, 543-550, 1979
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Effect of Sar’-ala’-angiotensin I1 on blood pressure and renin in Bartter’s syndrome, before and after treatment with prostaglandin synthetase inhibitors AVA R U D I N , M A T T I A S A U R E L L , L E N N A R T H A N S S O N & G U N N A R WESTBERG Department of Medicine, Sections of Endocrinology and Nephrology, Sahlgrenska sjukhuset, University of Goteborg, Goteborg, Sweden
Rudin, A., Aurell, M., Hansson, L. & Westberg, G. Effect of Sar1-ala8-angiotensin I1 on blood pressure and renin in Bartter’s syndrome, before and after treatment with prostaglandins synthetase inhibitors. Scand. J . din. Lab. Invest. 39, 543-550, 1979. Three patients suffering from Bartter’s syndrome were studied before and after 5 days of treatment with the prostaglandin synthetase inhibitors, aspirin and indomethacin. Saralasin was given by intravenous infusion in increasing doses from 0.6 to 42 pg/min.kg/BW. During saralasin infusion a blood pressure reduction was observed in all patients. Aspirin treatment did not affect this response and nor did it affect other manifestations of the syndrome. Indomethacin treatment changed the blood pressure response to saralasin in such a way that the blood pressure was increased in one patient and was unchanged in the other. Indomethacin also tended to normalize other features of Bartter’s syndrome, such as the hyperreninaemia and angiotensin unresponsiveness, but did not affect the hypokalaemia. The saralasin effect on blood pressure is thus evidently inversely related to the prevailing activity of the renin-angiotensin system in this condition also, and the patients obviously depended on the renin-angiotensin system to maintain their blood pressure. Our findings, together with data in the literature, indicate that angiotensin unresponsiveness of the vascular bed is not a primary feature in Bartter’s syndrome. Chloride loss is currently thought to be the basic abnormality and this may link the Bartter’s syndrome with other diseased states characterized by chloride loss, such as the syndrome of habitual vomiting and chronic treatment with loop diuretics. Key-words: renin-angiotensin system ; angiotensin responsiveness; indomethacin ; aspirin; hypokalemia Aoa Rudin, M . D . , Section of Endocrinology, Department of Medicine, II, Sahlgretiska sjukhuset, S-413 45 Goteborg, Sweden
The observation of Fichman et a/. [9] that the prostaglandin inhibitor indomethacin almost cured a patient with Bartter’s syndrome indicated a new treatment for this disease. They 0036-55 I3/79/1000-0.543$02.00
0 1979 Medisinsk Fysiologisk Forenings Forlag
showed that the hypokalaemia, alkalosis, hyperreninaemia and angiotensin unresponsiveness, which characterize this syndrome, all reverted towards normal in a patient afflicted by the disease. Other workers have confirmed the effectiveness of indomethacin and other inhibi-
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Ava Rudin et al.
tors of prostaglandin synthesis for normalising the hyperreninaemia and the responsiveness of thevascular bed to angiotensin [3, 4, 12, 13, 15, 20, 26, 30, 311. The effect on the potassium balance is unclear, however, as hypokalaemia has not been corrected in all patients [9, 12, 13, 20, 26, 311 and the period of observation in other studies is too short for an appraisal of the effectiveness of the new treatment [3, 151. The etiology of the syndrome is still not established. Unresponsiveness of the vascular bed to angiotensin was initially postulated to be the primary defect [2]. We have recently observed three patients suffering from Bartter’s syndrome and studied this aspect by using the angiotensin blocking agent Saralasin (sarl-alas-angiotensin 11) before and after treatment with indomethacin or aspirin. This paper reports the findings obtained.
MATERIAL AND METHODS The patients were studied in a metabolic ward and received a diet containing fixed amounts of sodium ( 1 50-1 75 mmol/day) and potassium (75 mmol/day). Except for supplementary KC1, no medication was allowed. Spironolactone was withdrawn 2 weeks prior to the present study in case 3. After a control period of 3 days, 100 mg of acetylsalicylic acid per kg BW per day was given to patient no. 1, and 150 and 200 mg of indomethacin per day to patients no. 2 and 3, respectively, for 5-7 days. Serum electrolytes were determined during fasting. Urine was collected in 24 h portions and electrolytes were measured by flame photometry. Total potassium was estimated by means of a whole body counter. Plasma renin activity, plasma renin concentration and renin substrate were assessed in the control period and treatment period after 8 h in the supine position by radioimmunoassay for angiotensin I according to the method of Giese et al. [ll], as previously described in detail [l]. The angiotensin 11 concentration was estimated by the method described by G. Diisterdieck & G. McElwee [8]. Angiotensin infusion tests were performed before treatment and on the fourth day of the treatment period. Angiotensin I1 amide (Hypertensin, Ciba) was diluted in isotonic sodium chloride solution and given intravenously by
infusion at rates of from 2.5 to 85 ng/min/kg BW until a diastolic blood pressure rise of 20 mmHg was achieved. The tests were performed at 0900 hours, after about 8 h in the supine position and at least 60 min stabilization of blood pressure after introduction of indwelling catheters. Saralasin infusion tests were done on the same day, 1 h after the angiotensin tests, and with the patient still in the supine position. Sariala’-angio-tensin I1 (Norvich Pharmacal Co) in isotonic sodium chloride solution was given intravenously by infusion pump at rates of from 0.6 to 42 pg/min/kg BW. Saralasin testing was done in exactly the same way on both occasions in each subject. Blood pressure was measured every minute using a mercury manometer. No cross-reaction between angiotensin I and saralasin was found in the assay system within the range of 5-500 ng/ml. A slight crossreaction between angiotensin 11 and saralasin was observed, indicating that a saralasin concentration of 500 ng/ml, which might be obtained during infusion of saralasin in the present experiments [17, 211, would indicate an apparent plasma angiotensin I1 concentration of at most 80 pglml. Case-reports Case I*. A boy, aged 14 years at the time of the present investigation, was first admitted to hospital with gastroenteritis at the age of 4, when a serum potassium level of 1.8 mmol/l was found. One year later he was more extensively studied because of persistent hypokalaemia. Blood pressure was 90/60 mmHg, s-K 2.8, s-Na 139 mmol/l, blood pH 7.49. Creatinine clearance and intravenous pyelography were normal. Plasma renin activity was markedly elevated and urinary aldosterone excretion slightly elevated. A renal biopsy specimen showed pronounced juxtaglomerular hyperplasia. The diagnosis of Bartter’s syndrome was made. KC1, 4 g/day, was prescribed and the serum potassium level has since been 2.5-3.3 mmolll on that regime. His development has been normal and he denies symptoms of any kind. Case 2*. This boy, aged 13 years, and a *Details are also found in a previous publication; Berglund, G . , Hood, B., Lindholm, B., Sigstrom, L. & Vikgren, P. Two brothers with hypokalaemia-Bartter’s syndrome. Lukarridningen 65, 5031. 1968.
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Blood pressure and renin in Bartter’s syndrome brother to case 1, developed alarming weakness and cerebral symptoms in connection with gastroenteritis at the age of 3. Persistent hypokalaemia in the range of 2.1-3.0 mmol/l was observed. Blood pressure was 110/75 mmHg, s-Na 134 mmolil and blood pH 7.44. Creatinine clearance and intravenous pyelography were normal. Urinary maximal concentration ability was 843 mosmikg. Plasma renin activity was extremely elevated and urinary aldosterone excretion moderately elevated. A renal biopsy specimen showed hyperplasia and hypergranularity of the juxtaglomerular cells. The diagnosis of Bartter’s syndrome was made and treatment with KCl, 3 giday, instituted, after which serum potassium stabilized at 2.2-2.9 mmol/l. His physical and mental development have been normal and he complains of no symptoms. Case 3. This patient was a 34 year-old woman in whom hypokalamia was discovered 3 years earlier, when serum electrolytes were assessed in connection with a gall-bladder operation. There were no symptoms which could be referred to hypokalaemia. Blood pressure was 100/70 mmHg. S-K ranged between 2.4 and 3.0 mmol/l. Blood pH was 7.49, s-creatinine 0.8 mg% and urine osmolarity 660 mosm/l. Intravenous pyelography was normal. Plasma renin activity was high and urine aldosterone excretion increased. Kidney biopsy was not performed. Other known causes of hypokalaemia associated with high renin concentration and normal blood pressure, such as abuse of diuretics or laxatives, diarrhoea and secret vomiting were as far as possible excluded. Frequent urinary screenings for diuretic agents were negative. Urinary chloride excretion was normal. The patient was therefore diagnosed as having Bartter’s syndrome. Treatment with spironolactone, 200 mgiday, and KCI, 8g/day, was instituted, whereafter s-K has been in the range 3.2-3.4 mmol/l. No symptoms have developed during the observation period of 3 years.
RESULTS Blood pressure, serum potassium and total potassium remained unchanged during the control and treatment period in all three patients. In patient no. 3 a slight weight gain (0.5 kg) was observed during the treatment period, while in the other two body weight remained
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unaltered. Excretion of sodium and potassium is shown in Fig. 1 . I n patient no. 1 the sodium balance became slightly negative and potassium balance slightly positive during treatment with aspirin. In the other two patients, treated with indomethacin, the sodium and potassium balance were unchanged in one (patient no. 2), and in the other (patient no. 3) a minor retention of sodium and potassium was observed during the first few days of treatment, which cleared within a few days when the treatment was stopped. Data on the renin-angiotensin system are given in Table I. Plasma renin activity (PRA), plasma renin concentration (PRC), angiotensin I1 concentration, renin substrate and the responsiveness to the pressor action of angiotensin 11, before and after treatment, are given in the table. PRA and PRC were increased while the angiotensin I1 concentration was almost within normal limits during conditions of strict overnight bedrest before plasma samples were taken. Renin substrate was decreased. Angiotensin unresponsiveness was prominent in all patients. No change during treatment was observed in patient no. 1, treated with acetylsalicylic acid. The other two patients were treated with indomethacin, which produced a marked reduction in PRA, PRC and angiotensin I1 concentration, while renin substrate increased by 36 and 38%, respectively. Angiotensin responsiveness increased and normalized in one patient and almost normalized in the other. The effect of the angiotensin blocking agent, saralasin, on blood pressure in the control and treatment periods is presented in Fig. 2. In patient no. 1 a marked blood pressure fall was elicted by saralasin in the control period and, but for a lower initial diastolic pressure, the response was identical after aspirin treatment. In patients no. 2 and 3 a moderate blood pressure fall was produced by saralasin in the control period. After treatment with indomethacin the response was different. A blood pressure rise was obtained in patient no. 2 and the blood pressure was unchanged in patient no. 3. Renin and angiotensin I1 concentrations were measured immediately before and after (1-2 min) the saralasin infusions. As shown in Table 11, angiotensin blockade resulted in a very marked increase in renin and angiotensin I1
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Patient 1
Patient 3 150 100
50
-
-
0
200
100
50
0
.
,
l
'
l
,
l
,
l
l
I
-
1
L
-
-1ndornetacin 1
0
1
1
2
1
4
1
6
1
B
1
,
1
I
0
I
i
2
Time (days)
1. Sodium and potassium excretion and intake in three patients with Bartter's syndrome, before and during treatment with aspirin (patient no. 1) and indomethacin (patients no. 2 and and 3).
FIG.
concentrations in the control period in all three patients. Aspirin did not change that response, but after indomethacin the increase was greatly reduced.
DISCUSSJON
Defective conservation of potassium, with ensuing hypokalaemia, is a cardinal feature of
Blood pressure and renin in Barttev's syndrome
547
TABLE I. Plasma renin activity (PRA), plasma renin concentration (PRC), angiotensin I1 concentration (AII), renin substrate and rate of angiotensin infusion producing a 20 nimHg diastolic blood pressure rise, before and after treatment with aspirin (patient no. I ) and indomethacin (patients no. 2 and 3) in Bartter's syndrome.
Renin PRA PRC All substrate A 11-infusion (ngAII/min.kg/BW) (ng Al/ml) Patient (ng Al/ml/h) (jcCU/ml) (p&/mU Control Treatnienr Control Treatment no. Control Treatment Control Treatment Control Treatment
Normal range
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7.0 1.1 1.8
8.1 3.9 7.8
I 2 3
326 I43 244
0.3-2 .0
32 25 62
274 43 73
6-60
E
I
a m
41 9 17
528 627 715
527 850 990
8OO--I ,160
5-30
36 30 85
36 10 25
7-10
8
70 6
a
10
Patient 3 S"SI0IIC
__ Aeforr Afte!
S a r a l a s i n pg m l n ' k q -5
0
5
10
15
20
~w-1
P5
Time (rninl
FIG.2. Saralasin-tests in three patients with Bartter's syndrome before and after treatment with aspirin and - - - - - after treatment. (patient no.. 1) indomethacin (patients no. 2 and 3). *-before,
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Bartter’s syndrome. Unresponsiveness of the vascular bed to angiotensin, initially postulated to be the primary defect in this condition [2], would explain not only the constant hyperreninaemia and high production of angiotensin, but also the deficit of potassium as a consequence of angiotensin-stimulated aldosteronism. Other reports have suggested that, at least in some of the patients, a defective renal sodium conservation might be the basic abnormality, which, through subtle volume depletion, causes secondary aldosteronism [7, 141. Doubts have been expressed, however, as to whether aldosteronism is a main cause of potassium loss in Bartter’s syndrome. Thus, adrenalectomy did not prevent continuing losses of potassium in a few reported cases [27, 281, and treatment with spironolactone [2, 14, 191, aminoglutethimide [14] or potassium sparing agents [26] is notoriously ineffective in Bartter’s syndrome. As to the hypothetical role of hypovolaemia for the stimulation of the renin-angiotensin system, volume expansion, using saline [19] or albumin [5, 6, 141, did not normalize overproduction of renin and/or aldosterone in several other studies. As renal prostaglandins are involved in the release of renin and are also actually overproproduced in Bartter’s syndrome [12, 151, considerable interest has been focused on the significance of this finding. Treatment with inhibitors of prostaglandin synthesis has been observed to reduce plasma renin activity and urinary prostaglandin excretion at the same time to increase the responsiveness to exogenous angiotensin I1 [9, 12, 15, 20, 30, 311. The present
study adds support to these reports by showing that indomethacin, an effective inhibitor of prostaglandin synthesis, can markedly attenuate or normalize the hyperactivity of the reninangiotensin system in Bartter’s syndrome (Table I ) . It also shows that this abnormality was probably not the cause of potassium loss in our patients, as the potassium balance did not become positive during treatment (Fig. I ) . A hypotensive response to another angiotensin analogue, sarl-ile*-angiotensin IT, has previously been demonstrated in two patients afflicted with Bartter’s syndrome [23, 331. In contrast, normal subjects are insensitive to saralasin on an ordinary salt intake or show an increase in blood pressure [16, 221. This dependency of blood pressure maintenance on the renin-angiotensin system now found in Bartter’s syndrome is shared by other patients with a high activity of the system [21, 221. When prostaglandin production (although not measured in our patients) was inhibited during indomethacin treatment, blood pressure was maintained in the supine position (Fig. 2), without participation of the renin-angiotensin system and-equally important-without prior volume expansion, as indicated by the absence of sodium retention or weight gain (Fig. I). I n other studies, however, sodium retention and weight gain occurred during the first few days of indomethacin treatment [3, 9, 12, 15, 30, 311. The cause of the different pattern of behaviour of our patients in this respect is not known. The results show, however, that sodium retention in our patients was not a prerequisite for normalization of the hyperactivity of the renin-angio-
TABLE11. Renin concentration and angiotensin I1 concentration immediately before and after Saralasin-infusion in the control and treatment period in three patients with Bartter’s syndrome. PRC Patient no.
Angiotensin
(PGUiml)
11
(pgml)
Before 326 214
After 3.920 1.840
Before 38 40
After 800
2 Control Treatment (indomethacin)
143 43
940 36
24 5
195 19
3 Control Treatment (indomethacin)
244 13
2.032 118
54 19
840 115
1 Control
Treatment (aspirin)
800
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Blood pressure and renin in Bartter’s syndrome tensin system during treatment with indomethacin. The marked release of renin and production of angiotensin I 1 elicited by saralasin before treatment with indomethacin should be noted (Table IT). This response is presumably mainly due to an interruption of the negative feed-back control of renin release [29] as the blood pressure reduction was only moderate (Fig. 2). It can be hypothesized that increased local production of prostaglandins makes the vascular bed less sensitive to angiotensin 11, as well as to noradrenaline, as this abnormality is abolished during treatment with inhibitors of prostaglandin synthesis [3, 9, 15, 251. In our two patients a few days’ treatment with indomethacin normalized the blood pressure response to angiotensin I1 (Table I). Hypokalaemia persisted, however, in spite of a daily intake of 115-195 mmol of potassium. Even long-term treatment with indomethacin, although effective in depressing prostaglandin production and normalizing the responsiveness to angiotensin 11, has lately been reported not to correct the hypokalaemia [4]. These findings argue strongly against prostaglandin overproduction or angiotensin unresponsiveness of the vascular bed as primary causes of Bartter’s syndrome. They are consistent with the view that potassium loss is an event nearer the initial or primary abnormality in Bartter’s syndrome [31]. Increased synthesis of prostaglandins has recently been linked to several other hypokalaemic conditions. Thus, it has been documented in patients with habitual vomiting [13, 311, a condition characterized by alkalosis and renal losses of potassium [24] but caused by gastric drainage. The induction of potassium deficiency in dogs has also been shown to increase prostaglandin synthesis and plasma renin activity as well as to decrease the blood pressure responsiveness to angiotensin 11, changes which could be reversed by indomethacin [lo]. Furthermore, the so-called loop diuretics also stimulate renal prostaglandin synthesis [32]. Indeed, a basic abnormality in Bartter’s syndrome may be a defect in chloride reabsorption in the ascending loop of Henle, promoting potassium loss by enhancing distal tubular flow [13, 181. Indomethacin and acetylsalicyclic acid are both known to inhibit prostaglandin synthesis. Successful depression of plasma renin activity has been reported [20]. In this study aspirin
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failed to suppress the plasma renin activity in patient no. 1 , while suppression was achieved with indomethacin in patients no. 2 and 3. Failure of medication was excluded by measurement of the plasma concentration of acetylsalicylic acid in patient no. 1 (34 mg/100 ml). As patients no. 1 and 2 are brothers, it seems justified to assume they have the same kind of basic abnormality. The reason for this difference in response is obscure. The obvious thing to do is of course to repeat the study in the reverse order i.e. to give patient no. 1 indomethacin and patient no. 2 aspirin. However, the brothers have refused further studies for the time being, but this differing response to aspirin and indomethacin obviously deserves further investigation. In summary, indomethacin normalized the hyperactivity of the renin-angiotensin system as well as the responsiveness to angiotensin I1 in two cases of Bartter’s syndrome but did not induce retention of sodium or potassium. These results are consistent with other reports indicating that unresponsiveness to angiotensin I1 is not a primary abnormality in Bartter’s syndrome, but probably a result of increased prostaglandin synthesis. Neither the abnormality nor the secondary aldosteronism explain the central phenomenon of the syndrome, the hypokalaemia, which is probably closer to the primary defect of the syndrome than any other abnormality so far observed. The cause of the increased production of prostaglandins in Bartter’s syndrome is unknown, but its relation to potassium deficiency must be a subject of further study.
ACKNOWLEDGMENT This work was supported by a grant from the Swedish Medical Research Council (B79-19x05230). REFERENCES 1 Aurell, M., Berglund, G. & Pettersson, M. Reninangiotensin system in essential hypertension. Lancet ii, 342, 1975. 2 Bartter, F.C., Pronove, P. Gill, J.R. & MacCardle,
R.C. Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. An?. J . Med. 33, 811, 1962. 3 Bartter, F.C., Gill, J.R., Frolich, J.C., Bowden, R.E., Hollifield, J.W., Radfar, N., Keiser, H.R.,
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Aua Rudin et ril.
Oates, J.A., Seyherth, H . & Taylor, A.A. Prostaglandins are overproduced by the kidney and mediate hyper reninemia i n Bartter’s syndronie. Tr. Ass. A m . Phys. 89, 77, 1976. 4 Bowden, R.E., Gill, J.R., Radfar, N., Taylor, A.A. & Keiser, H . R . Prostaglandin synthetase inhibitors i n Bartter’s syndrome-effect o n imrnunoreactive prostaglandin-E excretion. J A M A 233, 117, 1978. 5 Brackett,N.C., Koppel, M., Randall, F..E. & Nixon, W.P. Hyperplasia o f the juxtaglomerular complex with secondary aldosteronism without hypertension (Bartter’s syndrome). A m . J . Met/. 44, 803, 1968. h Bravo, E. & Bartter, F.C. The syndrome of juxtaglomerular hyperplasia and hyperaldosteronism without hypertension; studies on pathophysiological mechanisms. Clin. Rrs. 16, 263, 1968. 7 Chaimowitz, C., Levi, Y . , Better, O.S., Oslander, L. & Benderli, A . Studies on the site of renal salt loss in a patient with Bartter’s syndrome. f e d . Res. 7, 89, 1973. 8 Dusterdieck, G . & McElwee, G . Estimation of angiotensin 11 concentration in human plasma by radioimmunoassay. Some applications t o physiological and clinical states. Em-. J . d i n . Invest. 2, 32, 1971. 9 Fichman, M.P., Telfer, N . Zia, P., Speckart, P., Goluh, M . & Rude, M. Role of prostaglandins in the pathogenesis of Bartter’s syndrome. A m . J . M c 4 . 60, 785, 1976. 10 Galvez, O.G., Bay, W.H.. Roberts, B.W. & Ferris, T.F. The hemodynamic effect of potassium deficiency in the dog. Circ. Res., Suppl, I, 40, 1-1 I, 1977. 1 1 Giese, J., Jorgensen, M., Nielsen, M.D., Lund, J.O. & Munck, 0. Plasma renin measured by use of fadioimmunoassay for angiotensin 1. Scund J. d i n . Lah. Jnwst. 26, 455, 1970. 12 Gill, J.R., Frolich, J.C., Bowdens R.E.. Taylor, A.A., Keiser, H.R., Seyberth, H.W., Oates, J.A. & Bartter, F.C. Bartter’s syndrome: A disorder characterized by high urinary prostaglandins and a dependency of hyperreninemia on prostaglandin synthcsis. A , J . M r d . 61, 43, 1976. 13 Gill, J.R., Dartter, F.C., Taylor, A.A. & Radfar, N. Impaired tubular chloride reahsorption as a proximal cause of Bartter’s syndrome. Clin. Res. 25, 562 A, 1977. 14 Goodmans, A.D., Vagnucci, A.H. & Hartroft. P.M. Pathogenesis of Bartter‘s syndrome. N . Engl. J . Mcd. 281, 1435, 1969. 15 Halushka, P.V., Wohltmann, H., Printern, P.J., Huswitz, G . & Margolius, H.S. Bartter’s syndrome: Urinary prostaglandin-E like material and kallikrein. Indometacine elrects. A m . I n / . M e d . 87, 281, 1977. 16 Hollenberg, N.K., Williams, G.H., Burger, €3.. Ishikawa, I . & Adams, D.F. Blockade a n d stimulation of renal, adrenal and vascular angiotensin 11 receptors with I-sar, 8-ala angiotensin I I in normal man. J . d i n . Invest. 57, 39, 1976. 17 Kappelgaard, A.M., Ibsen., H., Nielsen, M.D. & Giese, J . Radioimmunoassay for saralasin by means of anti-angiotensin I1 sera. Clin. Chem. Actu, 83, 25, 1978. 18 Khuri, R.N., Wiederholt. M . , Stredos, N . & Giebisch. G. Effects of flow rate and potassium
intake on distal tubular potassium transfer. A m . J . Physiol. 228, 1249, 1975. 19 Modlinger, R.S., Nicolis, G.L., Krakoff, L.R. & Gahrilore. J . L . Some observations of the Dathogenesis of Bartter’s syndrome. N . Engl. J . Meh. 289, 1022 1977 -- - - - - - /
20 Norhy, L. & Flamenbaum. W. Prostaglandins a n d aspirin therapy i n Bartter’s syndrome. Lancet. ii, 604, 1976. 21 Pettinger, W.A., Keeton, K. & Tdnaka, K. T h e rddioimniunoassay and pharmacokinetics of saralasin in the rat and hypertensive man. Clin. Phtirmac. Ther. 17, 146, 1975. 22 Posternak. L., Brunner, H.R., Gavas. H. & Brunner. D. Angiotensin I[ blockade in normal man. Interaction of renin a n d sodium in maintaining blood pressure. Kidney Int. 11, 197, 1977. 23 Sasaki, H., Okumura, M., Ikeda, M., Kawasaki, T . & Fukivma. K . Hvootensive resoonse t o aneiotensin I I analogue. in Ba%er’s syndrome. N.Engl-J. Med. 294, 611, 1976. 24 Schwartz, W.B., van Ypersele de Strihou, C. & Kassirer, J . Role of anions in metabolic alkalosis a n d potassium deficiency. N . &ng/. J. Med. 279, 630, 1968. 25 Silverberg, A.B., Mennes, P.A. & Cryer, P.E. Kesistence to endogenous norepinephrine in Bartter’s syndrome. A m . J. Med. 64, 231. 1978. 26 Simatupang, T.A., Rado, J.P., Boer, P., Geyskes, G.G., Ves, J . & Dorhout Mees, E.J. Pharmacologic studies in Bartter’s syndrome: Opposite effects of treatment with anti-kaliuretic a n d anti-prostaglandin drugs. I n / . J . d i n . Phurmoc. 16, 14, 1978. 27 Takayashu, H . , Aso, Y., Nakauchi, K . & Kawabe, K . A case of Bartter’s syndrome with surgical treatment followed for 4 years. J. din. Endorr. Metoh 32, 842, 1971. 28 Trygstad, C.W., Mangos, J.A. & Bloodworth, J.M.B. A sibship with Bartter’s syndrome: failure of total adrenalectomy t o correct the potassium wasting. Prtliritrks. 44, 234, 1969. 29 Vander, A.C. & Goelhood, G.W. Inhibition of renin secretion by angiotensin II. Proc. Soc. e x p / . bid. M t d . 120, 399, 1965. 30 Verbercknioes, R., van Damme, B., Clement, J . , Amery, A. & Michielsen, P. Bartter’s syndrome with hyperplasia o f renomedullary cells: Successful treatment with indomethacin Kidney Int. 9, 302, 1976. 3 1 Vinci, J.M., Gill, J.R. Jr, Bowden, R.E.. Pisano, J.J., Izzo, J.L. Jr, Radfar, M.,Taylor, A.A.. Zusman, R.M., Bartter, F.C. & Keiser, H.R. T h e kallikrein and its respome t o prostaglandin synthetase inhibition. J. d i n . Inr>est.61, 1671, 1978. 32 Weher, P.C., Scherer, B. & Larsson, C. Increase of free arachidonic acid by fuoresmide in m a n as t h e cause of prostaglandin in renin release. Eur. J. Pharmac. 41, 329, 1911. 33 Yamamoto, T.. Doi, K., Ogihara, T., Ichihara, K., Hata, T. & Kumahara, M. Drugs affecting the renin-angiotensin-aldosteronesystem. f r o g . biochem. Phamac. 12, 174. 1975.
Received 7 November 1978 Accepted 16 February 1979
ISSN: 0036-5513 (Print) 1502-7686 (Online) Journal homepage: http://www.tandfonline.com/loi/iclb20
1
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Effect of Sar -ala -angiotensin II on blood pressure and renin in Bartter's syndrome, before and after treatment with prostaglandin synthetase inhibitors Ava Rudin, Mattias Aurell, Lennart Hansson & Gunnar Westberg To cite this article: Ava Rudin, Mattias Aurell, Lennart Hansson & Gunnar Westberg (1979) 1
8
Effect of Sar -ala -angiotensin II on blood pressure and renin in Bartter's syndrome, before and after treatment with prostaglandin synthetase inhibitors, Scandinavian Journal of Clinical and Laboratory Investigation, 39:6, 543-550, DOI: 10.3109/00365517909108832 To link to this article: http://dx.doi.org/10.3109/00365517909108832
Published online: 08 Jul 2009.
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Scand. J . clin. Lab. Invest. 39, 543-550, 1979
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Effect of Sar’-ala’-angiotensin I1 on blood pressure and renin in Bartter’s syndrome, before and after treatment with prostaglandin synthetase inhibitors AVA R U D I N , M A T T I A S A U R E L L , L E N N A R T H A N S S O N & G U N N A R WESTBERG Department of Medicine, Sections of Endocrinology and Nephrology, Sahlgrenska sjukhuset, University of Goteborg, Goteborg, Sweden
Rudin, A., Aurell, M., Hansson, L. & Westberg, G. Effect of Sar1-ala8-angiotensin I1 on blood pressure and renin in Bartter’s syndrome, before and after treatment with prostaglandins synthetase inhibitors. Scand. J . din. Lab. Invest. 39, 543-550, 1979. Three patients suffering from Bartter’s syndrome were studied before and after 5 days of treatment with the prostaglandin synthetase inhibitors, aspirin and indomethacin. Saralasin was given by intravenous infusion in increasing doses from 0.6 to 42 pg/min.kg/BW. During saralasin infusion a blood pressure reduction was observed in all patients. Aspirin treatment did not affect this response and nor did it affect other manifestations of the syndrome. Indomethacin treatment changed the blood pressure response to saralasin in such a way that the blood pressure was increased in one patient and was unchanged in the other. Indomethacin also tended to normalize other features of Bartter’s syndrome, such as the hyperreninaemia and angiotensin unresponsiveness, but did not affect the hypokalaemia. The saralasin effect on blood pressure is thus evidently inversely related to the prevailing activity of the renin-angiotensin system in this condition also, and the patients obviously depended on the renin-angiotensin system to maintain their blood pressure. Our findings, together with data in the literature, indicate that angiotensin unresponsiveness of the vascular bed is not a primary feature in Bartter’s syndrome. Chloride loss is currently thought to be the basic abnormality and this may link the Bartter’s syndrome with other diseased states characterized by chloride loss, such as the syndrome of habitual vomiting and chronic treatment with loop diuretics. Key-words: renin-angiotensin system ; angiotensin responsiveness; indomethacin ; aspirin; hypokalemia Aoa Rudin, M . D . , Section of Endocrinology, Department of Medicine, II, Sahlgretiska sjukhuset, S-413 45 Goteborg, Sweden
The observation of Fichman et a/. [9] that the prostaglandin inhibitor indomethacin almost cured a patient with Bartter’s syndrome indicated a new treatment for this disease. They 0036-55 I3/79/1000-0.543$02.00
0 1979 Medisinsk Fysiologisk Forenings Forlag
showed that the hypokalaemia, alkalosis, hyperreninaemia and angiotensin unresponsiveness, which characterize this syndrome, all reverted towards normal in a patient afflicted by the disease. Other workers have confirmed the effectiveness of indomethacin and other inhibi-
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tors of prostaglandin synthesis for normalising the hyperreninaemia and the responsiveness of thevascular bed to angiotensin [3, 4, 12, 13, 15, 20, 26, 30, 311. The effect on the potassium balance is unclear, however, as hypokalaemia has not been corrected in all patients [9, 12, 13, 20, 26, 311 and the period of observation in other studies is too short for an appraisal of the effectiveness of the new treatment [3, 151. The etiology of the syndrome is still not established. Unresponsiveness of the vascular bed to angiotensin was initially postulated to be the primary defect [2]. We have recently observed three patients suffering from Bartter’s syndrome and studied this aspect by using the angiotensin blocking agent Saralasin (sarl-alas-angiotensin 11) before and after treatment with indomethacin or aspirin. This paper reports the findings obtained.
MATERIAL AND METHODS The patients were studied in a metabolic ward and received a diet containing fixed amounts of sodium ( 1 50-1 75 mmol/day) and potassium (75 mmol/day). Except for supplementary KC1, no medication was allowed. Spironolactone was withdrawn 2 weeks prior to the present study in case 3. After a control period of 3 days, 100 mg of acetylsalicylic acid per kg BW per day was given to patient no. 1, and 150 and 200 mg of indomethacin per day to patients no. 2 and 3, respectively, for 5-7 days. Serum electrolytes were determined during fasting. Urine was collected in 24 h portions and electrolytes were measured by flame photometry. Total potassium was estimated by means of a whole body counter. Plasma renin activity, plasma renin concentration and renin substrate were assessed in the control period and treatment period after 8 h in the supine position by radioimmunoassay for angiotensin I according to the method of Giese et al. [ll], as previously described in detail [l]. The angiotensin 11 concentration was estimated by the method described by G. Diisterdieck & G. McElwee [8]. Angiotensin infusion tests were performed before treatment and on the fourth day of the treatment period. Angiotensin I1 amide (Hypertensin, Ciba) was diluted in isotonic sodium chloride solution and given intravenously by
infusion at rates of from 2.5 to 85 ng/min/kg BW until a diastolic blood pressure rise of 20 mmHg was achieved. The tests were performed at 0900 hours, after about 8 h in the supine position and at least 60 min stabilization of blood pressure after introduction of indwelling catheters. Saralasin infusion tests were done on the same day, 1 h after the angiotensin tests, and with the patient still in the supine position. Sariala’-angio-tensin I1 (Norvich Pharmacal Co) in isotonic sodium chloride solution was given intravenously by infusion pump at rates of from 0.6 to 42 pg/min/kg BW. Saralasin testing was done in exactly the same way on both occasions in each subject. Blood pressure was measured every minute using a mercury manometer. No cross-reaction between angiotensin I and saralasin was found in the assay system within the range of 5-500 ng/ml. A slight crossreaction between angiotensin 11 and saralasin was observed, indicating that a saralasin concentration of 500 ng/ml, which might be obtained during infusion of saralasin in the present experiments [17, 211, would indicate an apparent plasma angiotensin I1 concentration of at most 80 pglml. Case-reports Case I*. A boy, aged 14 years at the time of the present investigation, was first admitted to hospital with gastroenteritis at the age of 4, when a serum potassium level of 1.8 mmol/l was found. One year later he was more extensively studied because of persistent hypokalaemia. Blood pressure was 90/60 mmHg, s-K 2.8, s-Na 139 mmol/l, blood pH 7.49. Creatinine clearance and intravenous pyelography were normal. Plasma renin activity was markedly elevated and urinary aldosterone excretion slightly elevated. A renal biopsy specimen showed pronounced juxtaglomerular hyperplasia. The diagnosis of Bartter’s syndrome was made. KC1, 4 g/day, was prescribed and the serum potassium level has since been 2.5-3.3 mmolll on that regime. His development has been normal and he denies symptoms of any kind. Case 2*. This boy, aged 13 years, and a *Details are also found in a previous publication; Berglund, G . , Hood, B., Lindholm, B., Sigstrom, L. & Vikgren, P. Two brothers with hypokalaemia-Bartter’s syndrome. Lukarridningen 65, 5031. 1968.
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Blood pressure and renin in Bartter’s syndrome brother to case 1, developed alarming weakness and cerebral symptoms in connection with gastroenteritis at the age of 3. Persistent hypokalaemia in the range of 2.1-3.0 mmol/l was observed. Blood pressure was 110/75 mmHg, s-Na 134 mmolil and blood pH 7.44. Creatinine clearance and intravenous pyelography were normal. Urinary maximal concentration ability was 843 mosmikg. Plasma renin activity was extremely elevated and urinary aldosterone excretion moderately elevated. A renal biopsy specimen showed hyperplasia and hypergranularity of the juxtaglomerular cells. The diagnosis of Bartter’s syndrome was made and treatment with KCl, 3 giday, instituted, after which serum potassium stabilized at 2.2-2.9 mmol/l. His physical and mental development have been normal and he complains of no symptoms. Case 3. This patient was a 34 year-old woman in whom hypokalamia was discovered 3 years earlier, when serum electrolytes were assessed in connection with a gall-bladder operation. There were no symptoms which could be referred to hypokalaemia. Blood pressure was 100/70 mmHg. S-K ranged between 2.4 and 3.0 mmol/l. Blood pH was 7.49, s-creatinine 0.8 mg% and urine osmolarity 660 mosm/l. Intravenous pyelography was normal. Plasma renin activity was high and urine aldosterone excretion increased. Kidney biopsy was not performed. Other known causes of hypokalaemia associated with high renin concentration and normal blood pressure, such as abuse of diuretics or laxatives, diarrhoea and secret vomiting were as far as possible excluded. Frequent urinary screenings for diuretic agents were negative. Urinary chloride excretion was normal. The patient was therefore diagnosed as having Bartter’s syndrome. Treatment with spironolactone, 200 mgiday, and KCI, 8g/day, was instituted, whereafter s-K has been in the range 3.2-3.4 mmol/l. No symptoms have developed during the observation period of 3 years.
RESULTS Blood pressure, serum potassium and total potassium remained unchanged during the control and treatment period in all three patients. In patient no. 3 a slight weight gain (0.5 kg) was observed during the treatment period, while in the other two body weight remained
545
unaltered. Excretion of sodium and potassium is shown in Fig. 1 . I n patient no. 1 the sodium balance became slightly negative and potassium balance slightly positive during treatment with aspirin. In the other two patients, treated with indomethacin, the sodium and potassium balance were unchanged in one (patient no. 2), and in the other (patient no. 3) a minor retention of sodium and potassium was observed during the first few days of treatment, which cleared within a few days when the treatment was stopped. Data on the renin-angiotensin system are given in Table I. Plasma renin activity (PRA), plasma renin concentration (PRC), angiotensin I1 concentration, renin substrate and the responsiveness to the pressor action of angiotensin 11, before and after treatment, are given in the table. PRA and PRC were increased while the angiotensin I1 concentration was almost within normal limits during conditions of strict overnight bedrest before plasma samples were taken. Renin substrate was decreased. Angiotensin unresponsiveness was prominent in all patients. No change during treatment was observed in patient no. 1, treated with acetylsalicylic acid. The other two patients were treated with indomethacin, which produced a marked reduction in PRA, PRC and angiotensin I1 concentration, while renin substrate increased by 36 and 38%, respectively. Angiotensin responsiveness increased and normalized in one patient and almost normalized in the other. The effect of the angiotensin blocking agent, saralasin, on blood pressure in the control and treatment periods is presented in Fig. 2. In patient no. 1 a marked blood pressure fall was elicted by saralasin in the control period and, but for a lower initial diastolic pressure, the response was identical after aspirin treatment. In patients no. 2 and 3 a moderate blood pressure fall was produced by saralasin in the control period. After treatment with indomethacin the response was different. A blood pressure rise was obtained in patient no. 2 and the blood pressure was unchanged in patient no. 3. Renin and angiotensin I1 concentrations were measured immediately before and after (1-2 min) the saralasin infusions. As shown in Table 11, angiotensin blockade resulted in a very marked increase in renin and angiotensin I1
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Patient 1
Patient 3 150 100
50
-
-
0
200
100
50
0
.
,
l
'
l
,
l
,
l
l
I
-
1
L
-
-1ndornetacin 1
0
1
1
2
1
4
1
6
1
B
1
,
1
I
0
I
i
2
Time (days)
1. Sodium and potassium excretion and intake in three patients with Bartter's syndrome, before and during treatment with aspirin (patient no. 1) and indomethacin (patients no. 2 and and 3).
FIG.
concentrations in the control period in all three patients. Aspirin did not change that response, but after indomethacin the increase was greatly reduced.
DISCUSSJON
Defective conservation of potassium, with ensuing hypokalaemia, is a cardinal feature of
Blood pressure and renin in Barttev's syndrome
547
TABLE I. Plasma renin activity (PRA), plasma renin concentration (PRC), angiotensin I1 concentration (AII), renin substrate and rate of angiotensin infusion producing a 20 nimHg diastolic blood pressure rise, before and after treatment with aspirin (patient no. I ) and indomethacin (patients no. 2 and 3) in Bartter's syndrome.
Renin PRA PRC All substrate A 11-infusion (ngAII/min.kg/BW) (ng Al/ml) Patient (ng Al/ml/h) (jcCU/ml) (p&/mU Control Treatnienr Control Treatment no. Control Treatment Control Treatment Control Treatment
Normal range
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7.0 1.1 1.8
8.1 3.9 7.8
I 2 3
326 I43 244
0.3-2 .0
32 25 62
274 43 73
6-60
E
I
a m
41 9 17
528 627 715
527 850 990
8OO--I ,160
5-30
36 30 85
36 10 25
7-10
8
70 6
a
10
Patient 3 S"SI0IIC
__ Aeforr Afte!
S a r a l a s i n pg m l n ' k q -5
0
5
10
15
20
~w-1
P5
Time (rninl
FIG.2. Saralasin-tests in three patients with Bartter's syndrome before and after treatment with aspirin and - - - - - after treatment. (patient no.. 1) indomethacin (patients no. 2 and 3). *-before,
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Bartter’s syndrome. Unresponsiveness of the vascular bed to angiotensin, initially postulated to be the primary defect in this condition [2], would explain not only the constant hyperreninaemia and high production of angiotensin, but also the deficit of potassium as a consequence of angiotensin-stimulated aldosteronism. Other reports have suggested that, at least in some of the patients, a defective renal sodium conservation might be the basic abnormality, which, through subtle volume depletion, causes secondary aldosteronism [7, 141. Doubts have been expressed, however, as to whether aldosteronism is a main cause of potassium loss in Bartter’s syndrome. Thus, adrenalectomy did not prevent continuing losses of potassium in a few reported cases [27, 281, and treatment with spironolactone [2, 14, 191, aminoglutethimide [14] or potassium sparing agents [26] is notoriously ineffective in Bartter’s syndrome. As to the hypothetical role of hypovolaemia for the stimulation of the renin-angiotensin system, volume expansion, using saline [19] or albumin [5, 6, 141, did not normalize overproduction of renin and/or aldosterone in several other studies. As renal prostaglandins are involved in the release of renin and are also actually overproproduced in Bartter’s syndrome [12, 151, considerable interest has been focused on the significance of this finding. Treatment with inhibitors of prostaglandin synthesis has been observed to reduce plasma renin activity and urinary prostaglandin excretion at the same time to increase the responsiveness to exogenous angiotensin I1 [9, 12, 15, 20, 30, 311. The present
study adds support to these reports by showing that indomethacin, an effective inhibitor of prostaglandin synthesis, can markedly attenuate or normalize the hyperactivity of the reninangiotensin system in Bartter’s syndrome (Table I ) . It also shows that this abnormality was probably not the cause of potassium loss in our patients, as the potassium balance did not become positive during treatment (Fig. I ) . A hypotensive response to another angiotensin analogue, sarl-ile*-angiotensin IT, has previously been demonstrated in two patients afflicted with Bartter’s syndrome [23, 331. In contrast, normal subjects are insensitive to saralasin on an ordinary salt intake or show an increase in blood pressure [16, 221. This dependency of blood pressure maintenance on the renin-angiotensin system now found in Bartter’s syndrome is shared by other patients with a high activity of the system [21, 221. When prostaglandin production (although not measured in our patients) was inhibited during indomethacin treatment, blood pressure was maintained in the supine position (Fig. 2), without participation of the renin-angiotensin system and-equally important-without prior volume expansion, as indicated by the absence of sodium retention or weight gain (Fig. I). I n other studies, however, sodium retention and weight gain occurred during the first few days of indomethacin treatment [3, 9, 12, 15, 30, 311. The cause of the different pattern of behaviour of our patients in this respect is not known. The results show, however, that sodium retention in our patients was not a prerequisite for normalization of the hyperactivity of the renin-angio-
TABLE11. Renin concentration and angiotensin I1 concentration immediately before and after Saralasin-infusion in the control and treatment period in three patients with Bartter’s syndrome. PRC Patient no.
Angiotensin
(PGUiml)
11
(pgml)
Before 326 214
After 3.920 1.840
Before 38 40
After 800
2 Control Treatment (indomethacin)
143 43
940 36
24 5
195 19
3 Control Treatment (indomethacin)
244 13
2.032 118
54 19
840 115
1 Control
Treatment (aspirin)
800
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Blood pressure and renin in Bartter’s syndrome tensin system during treatment with indomethacin. The marked release of renin and production of angiotensin I 1 elicited by saralasin before treatment with indomethacin should be noted (Table IT). This response is presumably mainly due to an interruption of the negative feed-back control of renin release [29] as the blood pressure reduction was only moderate (Fig. 2). It can be hypothesized that increased local production of prostaglandins makes the vascular bed less sensitive to angiotensin 11, as well as to noradrenaline, as this abnormality is abolished during treatment with inhibitors of prostaglandin synthesis [3, 9, 15, 251. In our two patients a few days’ treatment with indomethacin normalized the blood pressure response to angiotensin I1 (Table I). Hypokalaemia persisted, however, in spite of a daily intake of 115-195 mmol of potassium. Even long-term treatment with indomethacin, although effective in depressing prostaglandin production and normalizing the responsiveness to angiotensin 11, has lately been reported not to correct the hypokalaemia [4]. These findings argue strongly against prostaglandin overproduction or angiotensin unresponsiveness of the vascular bed as primary causes of Bartter’s syndrome. They are consistent with the view that potassium loss is an event nearer the initial or primary abnormality in Bartter’s syndrome [31]. Increased synthesis of prostaglandins has recently been linked to several other hypokalaemic conditions. Thus, it has been documented in patients with habitual vomiting [13, 311, a condition characterized by alkalosis and renal losses of potassium [24] but caused by gastric drainage. The induction of potassium deficiency in dogs has also been shown to increase prostaglandin synthesis and plasma renin activity as well as to decrease the blood pressure responsiveness to angiotensin 11, changes which could be reversed by indomethacin [lo]. Furthermore, the so-called loop diuretics also stimulate renal prostaglandin synthesis [32]. Indeed, a basic abnormality in Bartter’s syndrome may be a defect in chloride reabsorption in the ascending loop of Henle, promoting potassium loss by enhancing distal tubular flow [13, 181. Indomethacin and acetylsalicyclic acid are both known to inhibit prostaglandin synthesis. Successful depression of plasma renin activity has been reported [20]. In this study aspirin
549
failed to suppress the plasma renin activity in patient no. 1 , while suppression was achieved with indomethacin in patients no. 2 and 3. Failure of medication was excluded by measurement of the plasma concentration of acetylsalicylic acid in patient no. 1 (34 mg/100 ml). As patients no. 1 and 2 are brothers, it seems justified to assume they have the same kind of basic abnormality. The reason for this difference in response is obscure. The obvious thing to do is of course to repeat the study in the reverse order i.e. to give patient no. 1 indomethacin and patient no. 2 aspirin. However, the brothers have refused further studies for the time being, but this differing response to aspirin and indomethacin obviously deserves further investigation. In summary, indomethacin normalized the hyperactivity of the renin-angiotensin system as well as the responsiveness to angiotensin I1 in two cases of Bartter’s syndrome but did not induce retention of sodium or potassium. These results are consistent with other reports indicating that unresponsiveness to angiotensin I1 is not a primary abnormality in Bartter’s syndrome, but probably a result of increased prostaglandin synthesis. Neither the abnormality nor the secondary aldosteronism explain the central phenomenon of the syndrome, the hypokalaemia, which is probably closer to the primary defect of the syndrome than any other abnormality so far observed. The cause of the increased production of prostaglandins in Bartter’s syndrome is unknown, but its relation to potassium deficiency must be a subject of further study.
ACKNOWLEDGMENT This work was supported by a grant from the Swedish Medical Research Council (B79-19x05230). REFERENCES 1 Aurell, M., Berglund, G. & Pettersson, M. Reninangiotensin system in essential hypertension. Lancet ii, 342, 1975. 2 Bartter, F.C., Pronove, P. Gill, J.R. & MacCardle,
R.C. Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. An?. J . Med. 33, 811, 1962. 3 Bartter, F.C., Gill, J.R., Frolich, J.C., Bowden, R.E., Hollifield, J.W., Radfar, N., Keiser, H.R.,
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Oates, J.A., Seyherth, H . & Taylor, A.A. Prostaglandins are overproduced by the kidney and mediate hyper reninemia i n Bartter’s syndronie. Tr. Ass. A m . Phys. 89, 77, 1976. 4 Bowden, R.E., Gill, J.R., Radfar, N., Taylor, A.A. & Keiser, H . R . Prostaglandin synthetase inhibitors i n Bartter’s syndrome-effect o n imrnunoreactive prostaglandin-E excretion. J A M A 233, 117, 1978. 5 Brackett,N.C., Koppel, M., Randall, F..E. & Nixon, W.P. Hyperplasia o f the juxtaglomerular complex with secondary aldosteronism without hypertension (Bartter’s syndrome). A m . J . Met/. 44, 803, 1968. h Bravo, E. & Bartter, F.C. The syndrome of juxtaglomerular hyperplasia and hyperaldosteronism without hypertension; studies on pathophysiological mechanisms. Clin. Rrs. 16, 263, 1968. 7 Chaimowitz, C., Levi, Y . , Better, O.S., Oslander, L. & Benderli, A . Studies on the site of renal salt loss in a patient with Bartter’s syndrome. f e d . Res. 7, 89, 1973. 8 Dusterdieck, G . & McElwee, G . Estimation of angiotensin 11 concentration in human plasma by radioimmunoassay. Some applications t o physiological and clinical states. Em-. J . d i n . Invest. 2, 32, 1971. 9 Fichman, M.P., Telfer, N . Zia, P., Speckart, P., Goluh, M . & Rude, M. Role of prostaglandins in the pathogenesis of Bartter’s syndrome. A m . J . M c 4 . 60, 785, 1976. 10 Galvez, O.G., Bay, W.H.. Roberts, B.W. & Ferris, T.F. The hemodynamic effect of potassium deficiency in the dog. Circ. Res., Suppl, I, 40, 1-1 I, 1977. 1 1 Giese, J., Jorgensen, M., Nielsen, M.D., Lund, J.O. & Munck, 0. Plasma renin measured by use of fadioimmunoassay for angiotensin 1. Scund J. d i n . Lah. Jnwst. 26, 455, 1970. 12 Gill, J.R., Frolich, J.C., Bowdens R.E.. Taylor, A.A., Keiser, H.R., Seyberth, H.W., Oates, J.A. & Bartter, F.C. Bartter’s syndrome: A disorder characterized by high urinary prostaglandins and a dependency of hyperreninemia on prostaglandin synthcsis. A , J . M r d . 61, 43, 1976. 13 Gill, J.R., Dartter, F.C., Taylor, A.A. & Radfar, N. Impaired tubular chloride reahsorption as a proximal cause of Bartter’s syndrome. Clin. Res. 25, 562 A, 1977. 14 Goodmans, A.D., Vagnucci, A.H. & Hartroft. P.M. Pathogenesis of Bartter‘s syndrome. N . Engl. J . Mcd. 281, 1435, 1969. 15 Halushka, P.V., Wohltmann, H., Printern, P.J., Huswitz, G . & Margolius, H.S. Bartter’s syndrome: Urinary prostaglandin-E like material and kallikrein. Indometacine elrects. A m . I n / . M e d . 87, 281, 1977. 16 Hollenberg, N.K., Williams, G.H., Burger, €3.. Ishikawa, I . & Adams, D.F. Blockade a n d stimulation of renal, adrenal and vascular angiotensin 11 receptors with I-sar, 8-ala angiotensin I I in normal man. J . d i n . Invest. 57, 39, 1976. 17 Kappelgaard, A.M., Ibsen., H., Nielsen, M.D. & Giese, J . Radioimmunoassay for saralasin by means of anti-angiotensin I1 sera. Clin. Chem. Actu, 83, 25, 1978. 18 Khuri, R.N., Wiederholt. M . , Stredos, N . & Giebisch. G. Effects of flow rate and potassium
intake on distal tubular potassium transfer. A m . J . Physiol. 228, 1249, 1975. 19 Modlinger, R.S., Nicolis, G.L., Krakoff, L.R. & Gahrilore. J . L . Some observations of the Dathogenesis of Bartter’s syndrome. N . Engl. J . Meh. 289, 1022 1977 -- - - - - - /
20 Norhy, L. & Flamenbaum. W. Prostaglandins a n d aspirin therapy i n Bartter’s syndrome. Lancet. ii, 604, 1976. 21 Pettinger, W.A., Keeton, K. & Tdnaka, K. T h e rddioimniunoassay and pharmacokinetics of saralasin in the rat and hypertensive man. Clin. Phtirmac. Ther. 17, 146, 1975. 22 Posternak. L., Brunner, H.R., Gavas. H. & Brunner. D. Angiotensin I[ blockade in normal man. Interaction of renin a n d sodium in maintaining blood pressure. Kidney Int. 11, 197, 1977. 23 Sasaki, H., Okumura, M., Ikeda, M., Kawasaki, T . & Fukivma. K . Hvootensive resoonse t o aneiotensin I I analogue. in Ba%er’s syndrome. N.Engl-J. Med. 294, 611, 1976. 24 Schwartz, W.B., van Ypersele de Strihou, C. & Kassirer, J . Role of anions in metabolic alkalosis a n d potassium deficiency. N . &ng/. J. Med. 279, 630, 1968. 25 Silverberg, A.B., Mennes, P.A. & Cryer, P.E. Kesistence to endogenous norepinephrine in Bartter’s syndrome. A m . J. Med. 64, 231. 1978. 26 Simatupang, T.A., Rado, J.P., Boer, P., Geyskes, G.G., Ves, J . & Dorhout Mees, E.J. Pharmacologic studies in Bartter’s syndrome: Opposite effects of treatment with anti-kaliuretic a n d anti-prostaglandin drugs. I n / . J . d i n . Phurmoc. 16, 14, 1978. 27 Takayashu, H . , Aso, Y., Nakauchi, K . & Kawabe, K . A case of Bartter’s syndrome with surgical treatment followed for 4 years. J. din. Endorr. Metoh 32, 842, 1971. 28 Trygstad, C.W., Mangos, J.A. & Bloodworth, J.M.B. A sibship with Bartter’s syndrome: failure of total adrenalectomy t o correct the potassium wasting. Prtliritrks. 44, 234, 1969. 29 Vander, A.C. & Goelhood, G.W. Inhibition of renin secretion by angiotensin II. Proc. Soc. e x p / . bid. M t d . 120, 399, 1965. 30 Verbercknioes, R., van Damme, B., Clement, J . , Amery, A. & Michielsen, P. Bartter’s syndrome with hyperplasia o f renomedullary cells: Successful treatment with indomethacin Kidney Int. 9, 302, 1976. 3 1 Vinci, J.M., Gill, J.R. Jr, Bowden, R.E.. Pisano, J.J., Izzo, J.L. Jr, Radfar, M.,Taylor, A.A.. Zusman, R.M., Bartter, F.C. & Keiser, H.R. T h e kallikrein and its respome t o prostaglandin synthetase inhibition. J. d i n . Inr>est.61, 1671, 1978. 32 Weher, P.C., Scherer, B. & Larsson, C. Increase of free arachidonic acid by fuoresmide in m a n as t h e cause of prostaglandin in renin release. Eur. J. Pharmac. 41, 329, 1911. 33 Yamamoto, T.. Doi, K., Ogihara, T., Ichihara, K., Hata, T. & Kumahara, M. Drugs affecting the renin-angiotensin-aldosteronesystem. f r o g . biochem. Phamac. 12, 174. 1975.
Received 7 November 1978 Accepted 16 February 1979
