Eur J Clin Pharmacol (1992) 43:185-187 European,Journal
of { ~ [ ~ : ~ ( ~ @ ~
© Springer-Verlag 1992
Short communications
A low molecular weight heparin decreases plasma aldosterone in patients with primary hyperaldosteronism N. Cailleux 1, N. Moore 2, H. Levesque 3, H. Courtois 3, and M. Godin 1 Departments of 1Nephrology, 2Pharmacology and 3Internal Medicine, CHU de Rouen, Boisguillaume, France Received: October 11,1991/Accepted in revised form: February 3, 1992
Summary. Four patients with primary hyperaldosteronism were treated with nadroparin 4100 or 6150 antiXa I U daily for 4 days. Plasma and urine sodium and potassium, and plasma aldosterone and renin were monitored before, during and after the study. After four days of treatment, and for the following two days, plasma aldosterone was decreased (by a m e a n of 49 % on D a y 6), and urinary Na/K was increased (3.7fold). T h e direction of the changes was reversed on D a y 8. The study has confirmed the effect of low molecular weight heparin on aldosterone, and m a k e s it unlikely that it is related to inhibition of angiotensin II stimulation in these patients, as renin could not be detected in their plasma. Key words: Primary hyperaldosteronism; plasma aldosterone, low molecular weight heparin In a previous study [1], the low molecular weight heparins ( L M W H ) enoxaparin and nadroparin (fraxiparine) were shown to reduce plasma aldosterone and to increase serum potassium in elderly patients with normal plasma aldosterone. The serum potassium was increased above the u p p e r limit of normal in a few patients. Aldosterone was also decreased in two patients with diuretic-related hyperaldosteronism. This observation led us to wonder whether the effect would also be found in patients with primary hyperaldosteronism, as had b e e n shown long ago with heparin and another heparinoid, RO1-8307 [2, 3].
not changed during the study. Patients ate a standard hospital diet containing NaC13 g/day. The patients received nadroparin 0.4 or 0.6 ml/day (4100 or 6150 antiXa IU) SC, according to body weight, in the morning from Day 1 (after the initial blood and urine samples) to Day 4 (after collecting the samples). Plasma aldosterone and renin were measured in blood samples collected after the patients had rested supine for 12 h, as well as serum and urine sodium and potassium, on entry (Day 1), and on Days 2, 4, 6, and 8. Because patients were admitted on the evening before Day 1, 24 h urine samples for Day 1 could not be obtained and it was not possible to calculate the 24-h excretion of sodium and potassium on that day; the results for Day 1 are given therefore in mmol/1.The urinary Na/K ratio was computed on all days. Assays for aldosterone and renin used standard radio-immunoassay kits (respectively CIS bio international, and IRMA Pasteur, France); serum and urine sodium and potassium were assayed by standard flame spectrometry with an automated apparatus. Statistical analysis employed paired t-tests after analysis of variance for repeated measures (Systat ®, on a Macintosh ®microcomputer)
Results The results (Table 1, Fig. 1) show a decrease in supine plasma aldosterone (P < 0.05 on D a y 6), with an increase in the urinary N a / K ratio (P < 0.05 on D a y 6) and of serum 4.5
Urinary Na/K
4 3.53
2.5
Materials and method Four patients with primary hyperaldosteronism were studied two had an adenoma and the other two had bilateral hyperplasia of the adrenal glands. The patients, three women and one man, mean age 64.5 y, were hospitalised for one week in the Nephrology unit. All treatments that could directly influence aldosterone production or its effects, i.e., angiotensin converting enzyme inhibitors and diuretics, were stopped at least two months before the study. The other treatments, comprising calcium antagonists (nicardipine in two patients, and nifedipine and diltiazem in one patient), and/or alpha blockers (urapidil in one patient, and prazosin in one patient), were
2 1.5 1
•
0.5
I
I
I
I clays
Time
Fig,1. Changes in the individual urinary Na/K ratio. The arrows indicate low molecular weight heparin injections, which were given in the morning after the corresponding blood and urine samples had been collected. Pt: patient
186 Table 1, Effects of the low-molecular weight heparin nadroparin (fraxiparine) from Days 1 to 4 on blood and urine parameters in 4 patients with primary hyperaldosteronism (mean with SD). Data for Day 1 represent pre-treatment values Aldosterone, supine (pmol/1) Serum K (retool/l) SerumNa (retool/l) Serum Na/K Urinary K (mmol/24 h) UrinaryNa (mmol/24 h) Urinary Na/K
Day 1 1155
(351)
Day 2 902 (221)
Day 4 953 (485)
3.10 (0.56)
3.13 (0.52)
3.25 (0.66)
143.3 (1.7)
143.5 (1.3)
47.5 (9.6) 51.0 (37.4)a
46.9 (8.4) 61.0 (12.2)
48.7 (29.1)a
87.0 (24.8)
1.16 (0.62)
1.42 (0.31)
143.5 (2.1) 45.4 (8.4) 63.0 (19.8) 126
(40.4)
2.00 (0.12)
Day 6 615 (315)* 3.43 (0.39) 144.0 (1.2) 42.5 (5.0) 50.8 (27.4) 184
(91.6)
3.68 (0.68)*
Day 8 1032
(321)
3.33 (0.43) 144.0 (0.8) 43.9 (6.22) 57.0 (17.8) 132
(68.9)
2.41 (1.06)
*P < 0.05, Student's paired t-test after repeated-measures ANOVA; "Urine Na and K on Day 1 are given in mmol/1
potassium during and shortly after treatment, the maximal change being observed on Day 6, i.e. 48 h after the last dose of nadroparin. On Day 8, the values had begun to revert towards the initial values. The changes in the urinary Na/K ratio were parallel in all the patients (Fig. i), and were perhaps more related to increased sodium excretion than to decreased potassium excretion. The urinary Na/K ratio was highly correlated with the supine plasma aldosterone (r = - 0.52 to - 0.96, not shown). The changes in plasma renin were difficult to evaluate: in all patients plasma renin values were initially at or below the sensitivity limit (5 ng/1). However, three out of four patients were above this limit on Day 6, and but renin again was undetectable on Day 8.
Discussion Low molecular weight heparins ( L M W H ) can decrease aldosterone production, modify the urinary sodium to potassium ratio and increase serum potassium, even in patients with primary hyperaldosteronism. The differences reached significance for aldosterone and the urinary Na/K ratio on Day 6. The observed changes in serum potassium were small and never reached significance, but the trial was short, and, considering the profile of the effect found, it is possible that the effect would have been greater had L M W H been given for a longer period. The observed effect could have been due to chance, but it was consistent with other results found with heparin and L M W H [1-5], and the changes tended to turn to the pretreatment values after stopping the heparin. The results confirm the effect of heparinoids on aldosterone production and that this effect occurs, even in primary hyperaldosteronism. The mechanism of this effect of heparinoids on aldosterone is not known. Presumably it is due to a direct action on aldosterone synthesis, although a decrease in aldosterone production due to a decrease in the sensitivity to angiotensin II has also been suggested [6-8]. In the present cases, there cannot have been an effect on renin or on the sensitivity to renin, since renin was
so low as to be more or less undetectable, and, if anything, it tended to increase during treatment. Although not verified here, a previous study [1] did not reveal an effect on the synthesis of cortisol, so there is no effect on steroidogenesis as a whole. If the mechanism by which heparin reduces the synthesis or liberation of aldosterone were elucidated, it could open the way to new treatments of primary or secondary hyperaldosteronism. From a more practical point of view, if patients are treated with other drugs that increase potassium, either potassium sparing diuretics or potassium supplements, there is a potential for an interaction with heparin. Hyperkalaemia is not likely to occur in patients with primary hyperaldosteronism, but it could be a problem in patients with normal aldosterone, or with secondary hyperaldosteronism [9-12]. Physicians should be aware of this potential interaction and closely monitor serum potassium in these patients.
References 1. Levesque H, Verdier S, Cailleux N et al. 0990) Low molecular weight heparins and hypoaldosteronism. Br Med J 300: 14371438 2. Ford HC, B alley RE (1966) The effect of heparin on aldosterone secretion and metabolism in primary hyperaldosteronism. Steroids 7:30-40 3. Corm JW, Rovner DR, Cohen EL, Anderson JE, Jr (1966) Inhibition by heparinoid of aldosterone biosynthesis in man. J Clin Endocr 26:527-532 4. Sherman RA, Ruddy MC (1986) Suppression of aldosterone by low-dose heparin. Am J Nephrol 6:165-168 5. O'Kelly R, Magee F, McKenna TJ (1983) Routine heparin therapy inhibits adrenal aldosterone production. J Clin Endocr Metab 56:108-112 6. Azukizawa S, Iwasaki I, Kigoshi T, Uchida K, Morimoto S (1988) Effects of heparin treatment in vivo and in vitro on adrenal angiotensin II induced aldosterone production in rats. Acta Endocrinol (Copenh) 119:367-372 7. Uchida K, Azukizawa S, Imaizumi N, Kigoshi T, Yamamoto I, Hosojima H, Morimoto S (1986) Effect of angiotensin II on aldosterone and its precursor steroid production in adrenal zona
187 glomerulosa cells from heparin-treated rats. Acta Endocrinol (Copenh) 111:222-227 8. Azukizawa S, Uchida K, Imaizumi N, Hosojima H, Morimoto S (1986) Direct effects of heparin on basal and stimulated aldosterone production in rat adrenal glomerulosa cells. J Steroid Biochem 25:455-457 9. Aull L, Chao H, Coy K (1990) Heparin-induced hyperkalemia. DICP 24:244-246 10. Edes TE, Sunderrajan EV (1985) Heparin-induced hyperkalemia. Arch Intern Med 145:1070-1072 11. Monreal M, Lafoz E, Salvador R, Roncales J, Navarro A (1989): Adverse effects of three different forms of heparin therapy:
thrombocytopenia, increased transaminases, and hyperkalemia. Eur J Clin Pharmaco137:415-418 12. Pone HR Jennings AE, Madias NE, Harrington JT (1985) Druginduced hyperkalemia. Medicine 64:357-370
Dr. N. Moore Department of Pharmacology CHU de Rouen BP 100 F-76233 Boisguillaume Cedex, France
of { ~ [ ~ : ~ ( ~ @ ~
© Springer-Verlag 1992
Short communications
A low molecular weight heparin decreases plasma aldosterone in patients with primary hyperaldosteronism N. Cailleux 1, N. Moore 2, H. Levesque 3, H. Courtois 3, and M. Godin 1 Departments of 1Nephrology, 2Pharmacology and 3Internal Medicine, CHU de Rouen, Boisguillaume, France Received: October 11,1991/Accepted in revised form: February 3, 1992
Summary. Four patients with primary hyperaldosteronism were treated with nadroparin 4100 or 6150 antiXa I U daily for 4 days. Plasma and urine sodium and potassium, and plasma aldosterone and renin were monitored before, during and after the study. After four days of treatment, and for the following two days, plasma aldosterone was decreased (by a m e a n of 49 % on D a y 6), and urinary Na/K was increased (3.7fold). T h e direction of the changes was reversed on D a y 8. The study has confirmed the effect of low molecular weight heparin on aldosterone, and m a k e s it unlikely that it is related to inhibition of angiotensin II stimulation in these patients, as renin could not be detected in their plasma. Key words: Primary hyperaldosteronism; plasma aldosterone, low molecular weight heparin In a previous study [1], the low molecular weight heparins ( L M W H ) enoxaparin and nadroparin (fraxiparine) were shown to reduce plasma aldosterone and to increase serum potassium in elderly patients with normal plasma aldosterone. The serum potassium was increased above the u p p e r limit of normal in a few patients. Aldosterone was also decreased in two patients with diuretic-related hyperaldosteronism. This observation led us to wonder whether the effect would also be found in patients with primary hyperaldosteronism, as had b e e n shown long ago with heparin and another heparinoid, RO1-8307 [2, 3].
not changed during the study. Patients ate a standard hospital diet containing NaC13 g/day. The patients received nadroparin 0.4 or 0.6 ml/day (4100 or 6150 antiXa IU) SC, according to body weight, in the morning from Day 1 (after the initial blood and urine samples) to Day 4 (after collecting the samples). Plasma aldosterone and renin were measured in blood samples collected after the patients had rested supine for 12 h, as well as serum and urine sodium and potassium, on entry (Day 1), and on Days 2, 4, 6, and 8. Because patients were admitted on the evening before Day 1, 24 h urine samples for Day 1 could not be obtained and it was not possible to calculate the 24-h excretion of sodium and potassium on that day; the results for Day 1 are given therefore in mmol/1.The urinary Na/K ratio was computed on all days. Assays for aldosterone and renin used standard radio-immunoassay kits (respectively CIS bio international, and IRMA Pasteur, France); serum and urine sodium and potassium were assayed by standard flame spectrometry with an automated apparatus. Statistical analysis employed paired t-tests after analysis of variance for repeated measures (Systat ®, on a Macintosh ®microcomputer)
Results The results (Table 1, Fig. 1) show a decrease in supine plasma aldosterone (P < 0.05 on D a y 6), with an increase in the urinary N a / K ratio (P < 0.05 on D a y 6) and of serum 4.5
Urinary Na/K
4 3.53
2.5
Materials and method Four patients with primary hyperaldosteronism were studied two had an adenoma and the other two had bilateral hyperplasia of the adrenal glands. The patients, three women and one man, mean age 64.5 y, were hospitalised for one week in the Nephrology unit. All treatments that could directly influence aldosterone production or its effects, i.e., angiotensin converting enzyme inhibitors and diuretics, were stopped at least two months before the study. The other treatments, comprising calcium antagonists (nicardipine in two patients, and nifedipine and diltiazem in one patient), and/or alpha blockers (urapidil in one patient, and prazosin in one patient), were
2 1.5 1
•
0.5
I
I
I
I clays
Time
Fig,1. Changes in the individual urinary Na/K ratio. The arrows indicate low molecular weight heparin injections, which were given in the morning after the corresponding blood and urine samples had been collected. Pt: patient
186 Table 1, Effects of the low-molecular weight heparin nadroparin (fraxiparine) from Days 1 to 4 on blood and urine parameters in 4 patients with primary hyperaldosteronism (mean with SD). Data for Day 1 represent pre-treatment values Aldosterone, supine (pmol/1) Serum K (retool/l) SerumNa (retool/l) Serum Na/K Urinary K (mmol/24 h) UrinaryNa (mmol/24 h) Urinary Na/K
Day 1 1155
(351)
Day 2 902 (221)
Day 4 953 (485)
3.10 (0.56)
3.13 (0.52)
3.25 (0.66)
143.3 (1.7)
143.5 (1.3)
47.5 (9.6) 51.0 (37.4)a
46.9 (8.4) 61.0 (12.2)
48.7 (29.1)a
87.0 (24.8)
1.16 (0.62)
1.42 (0.31)
143.5 (2.1) 45.4 (8.4) 63.0 (19.8) 126
(40.4)
2.00 (0.12)
Day 6 615 (315)* 3.43 (0.39) 144.0 (1.2) 42.5 (5.0) 50.8 (27.4) 184
(91.6)
3.68 (0.68)*
Day 8 1032
(321)
3.33 (0.43) 144.0 (0.8) 43.9 (6.22) 57.0 (17.8) 132
(68.9)
2.41 (1.06)
*P < 0.05, Student's paired t-test after repeated-measures ANOVA; "Urine Na and K on Day 1 are given in mmol/1
potassium during and shortly after treatment, the maximal change being observed on Day 6, i.e. 48 h after the last dose of nadroparin. On Day 8, the values had begun to revert towards the initial values. The changes in the urinary Na/K ratio were parallel in all the patients (Fig. i), and were perhaps more related to increased sodium excretion than to decreased potassium excretion. The urinary Na/K ratio was highly correlated with the supine plasma aldosterone (r = - 0.52 to - 0.96, not shown). The changes in plasma renin were difficult to evaluate: in all patients plasma renin values were initially at or below the sensitivity limit (5 ng/1). However, three out of four patients were above this limit on Day 6, and but renin again was undetectable on Day 8.
Discussion Low molecular weight heparins ( L M W H ) can decrease aldosterone production, modify the urinary sodium to potassium ratio and increase serum potassium, even in patients with primary hyperaldosteronism. The differences reached significance for aldosterone and the urinary Na/K ratio on Day 6. The observed changes in serum potassium were small and never reached significance, but the trial was short, and, considering the profile of the effect found, it is possible that the effect would have been greater had L M W H been given for a longer period. The observed effect could have been due to chance, but it was consistent with other results found with heparin and L M W H [1-5], and the changes tended to turn to the pretreatment values after stopping the heparin. The results confirm the effect of heparinoids on aldosterone production and that this effect occurs, even in primary hyperaldosteronism. The mechanism of this effect of heparinoids on aldosterone is not known. Presumably it is due to a direct action on aldosterone synthesis, although a decrease in aldosterone production due to a decrease in the sensitivity to angiotensin II has also been suggested [6-8]. In the present cases, there cannot have been an effect on renin or on the sensitivity to renin, since renin was
so low as to be more or less undetectable, and, if anything, it tended to increase during treatment. Although not verified here, a previous study [1] did not reveal an effect on the synthesis of cortisol, so there is no effect on steroidogenesis as a whole. If the mechanism by which heparin reduces the synthesis or liberation of aldosterone were elucidated, it could open the way to new treatments of primary or secondary hyperaldosteronism. From a more practical point of view, if patients are treated with other drugs that increase potassium, either potassium sparing diuretics or potassium supplements, there is a potential for an interaction with heparin. Hyperkalaemia is not likely to occur in patients with primary hyperaldosteronism, but it could be a problem in patients with normal aldosterone, or with secondary hyperaldosteronism [9-12]. Physicians should be aware of this potential interaction and closely monitor serum potassium in these patients.
References 1. Levesque H, Verdier S, Cailleux N et al. 0990) Low molecular weight heparins and hypoaldosteronism. Br Med J 300: 14371438 2. Ford HC, B alley RE (1966) The effect of heparin on aldosterone secretion and metabolism in primary hyperaldosteronism. Steroids 7:30-40 3. Corm JW, Rovner DR, Cohen EL, Anderson JE, Jr (1966) Inhibition by heparinoid of aldosterone biosynthesis in man. J Clin Endocr 26:527-532 4. Sherman RA, Ruddy MC (1986) Suppression of aldosterone by low-dose heparin. Am J Nephrol 6:165-168 5. O'Kelly R, Magee F, McKenna TJ (1983) Routine heparin therapy inhibits adrenal aldosterone production. J Clin Endocr Metab 56:108-112 6. Azukizawa S, Iwasaki I, Kigoshi T, Uchida K, Morimoto S (1988) Effects of heparin treatment in vivo and in vitro on adrenal angiotensin II induced aldosterone production in rats. Acta Endocrinol (Copenh) 119:367-372 7. Uchida K, Azukizawa S, Imaizumi N, Kigoshi T, Yamamoto I, Hosojima H, Morimoto S (1986) Effect of angiotensin II on aldosterone and its precursor steroid production in adrenal zona
187 glomerulosa cells from heparin-treated rats. Acta Endocrinol (Copenh) 111:222-227 8. Azukizawa S, Uchida K, Imaizumi N, Hosojima H, Morimoto S (1986) Direct effects of heparin on basal and stimulated aldosterone production in rat adrenal glomerulosa cells. J Steroid Biochem 25:455-457 9. Aull L, Chao H, Coy K (1990) Heparin-induced hyperkalemia. DICP 24:244-246 10. Edes TE, Sunderrajan EV (1985) Heparin-induced hyperkalemia. Arch Intern Med 145:1070-1072 11. Monreal M, Lafoz E, Salvador R, Roncales J, Navarro A (1989): Adverse effects of three different forms of heparin therapy:
thrombocytopenia, increased transaminases, and hyperkalemia. Eur J Clin Pharmaco137:415-418 12. Pone HR Jennings AE, Madias NE, Harrington JT (1985) Druginduced hyperkalemia. Medicine 64:357-370
Dr. N. Moore Department of Pharmacology CHU de Rouen BP 100 F-76233 Boisguillaume Cedex, France
