Klinische Wochenschrift
KEn. Wschr. 54, 661-663 (1976)
© by Springer-Verlag 1976
Originalien The Effect of Saralasin (1-Sar-8-Ala-Angiotensin lI) on Blood Pressure in Patients with Cushing's Syndrome W. Vetter, * H. Vetter, 3 R. Beckerhoff, 1 B. Redlich, 3 p. Cottier 2 and W. Siegenthaler 1 1 Departmentof Medicine, Kantonsspital,Universityof Ztirich 2 MedizinischeAbteilung, RegionalspitalInterlaken, Switzerland 3 MedizinischePoliklinik,Universityof Bonn, Federal Republicof Germany
Der Effekt yon Saralasin (1-Sar-8-Ala-Angiotensin II) auf den Blutdruck bei Patienten mit Cushing-Syndrom Zusammenfassung. Um die Bedeutung des Renin-Angiotensin Systems in der Pathogenese der Hypertonie bei Cushing-Syndrom zu untersuchen, wurden bei 2 Patienten mit Hyperkortizismus 20 mg Saralasin (1Sar-8-Ala-Angiotensin II) fiber einen Zeitraum yon 30 min unter st~indiger Blutdruckkontrolle infundiert. Zus/itzlich diente ein Patient mit primfirem Aldosteronismus, einer etablierten Form yon Mineralokortikoidhochdruck, als Kontrolle. Weder bei den 2 Patienten mit Cushing-Syndrom noch bei dem Patienten mit primfirem Aldosteronismus liel3 sich ein blutdrucksenkender Effekt des Saralasins nachweisen. Die beiden Patienten mit Hyperkortizismus zeigten unter Saralasin sowohl einen Anstieg der Renin-Aktivitfit als auch des Plasmaaldosterons. Bei dem Patienten mit primfirem Aldosteronismus liel3 sich nur ein geringgradiger Anstieg der Plasmaaldosteronkonzentration nachweisen. Diese Ergebnisse sprechen gegen eine wichtige Rolle des Renin-Angiotensin Systems in der Pathogenese der Hypertonie bei Cushing-Syndrom. Die Unbeeinflul3barkeit des Hochdrucks durch Saralasin bei den beiden Patienten mit Hyperkortizismus und dem Patienten mit primS.rein Aldosteronismus stfitzen indirekt die Annahme, dab bei Patienten mit CushingSyndrom eine erh6hte Mineralokortikoidaktivitfit der Hauptfaktor in der Pathogenese der Hypertonie ist. SchliisselwiJrter: Cushing-Syndrom - Hypertonie Renin-Aktivit~it, - Aldosteronismus. Summary. To investigate the role of the renin angiotensin system in the pathogenesis of hypertension in Cushing's syndrome two patients with hypercorticism were infused with 20 mg saralasin (1-sar-8-alaangiotensin II) over a period of 30 minutes under constant blood pressure control. In addition, one pa-
tient with primary aldosteronism, an established form of mineralocorticoid hypertension, served as control. Neither in the two patients with Cushing's syndrome nor in the patient with primary aldosteronism could a blood pressure lowering effect of saralasin be observed. In the two patients with hypercorticism both renin activity and plasma aldosterone increased during saralasin infusion. The patient with primary aldosteronism only showed a weak increase in plasma aldostetone concentration. These results seem to exclude an important role of the renin angiotensin system in the pathogenesis of hypertension in Cushing's syndrome. The unresponsiveness of elevated blood pressure to saralasin in the two patients with hypercorticism and in the patient with primary aldosteronism indirectly supports the assumption that in patients with Cushing's syndrome increased mineralocorticoid activity may be the main factor in the pathogenesis of hypertension.
Key words: Cushing's syndrome - Hypertension Renin activity - Aldosteronism.
Recently it has been suggested that the renin angiotensin system may play an important role in the pathogenesis of hypertension in Cushing's syndrome [3]. If this assumption is valid a significant reduction in blood pressure should be achieved in patients with Cushing's syndrome by infusion of saralasin (1-sar-8ala-angiotensin II) which is known to be a specific inhibitor of the vascular action of angiotensin II [5-7]. Thus, in the present study two patients with hypercorticism were infused with saralasin. In addition, one patient with primary aldosteronism, an established form of mineralocorticoid hypertension, served as control.
662
W. Vetter et al. : Saralasin in Cushing's Syndrome
Patients and Methods Three female patients (M.L., V.J. and B.M.) were investigated. Two patients (M.L. and V.J.) suffered from hypercorticism and one patient (B.M.) had primary aldosteronism. In patient M.L. the diagnosis of a cortisol producing adenoma of the left adrenal gland was confirmed by surgery. Patient V.J. showed no suppression of abnormally high (free) cortisol excretion rates by 2 mg dexamethasone/day whereas 8 mg dexamethasone/day produced a marked fall in urinary cortisol excretion. Thus, in this patient hypercorticism of hypothalamic-pituitary origin was assumed. This diagnosis was confirmed by a fall of urinary cortisol excretion to a very low value (5 gg/24 h; normal range 20-120 gg/24 h) shortly after hypophysectomy. In patient B.M. the diagnosis of primary aldosteronism was made by the combination of persistent hypokalemia ( < 3 maeq/1) with relatively low (supine) plasma renin activity ( < 1 ng/ml. 3 h) and abnormally high (supine) plasma aldosterone ( > 200 pg/ml). In this patient an aldosterone producing adenoma of the left adrenal gland was predicted because plasma aldosterone concentration was abnormally high in the left adrenal vein (3,500 pg/ml) and within normal range in the right adrenal vein (1,000 pg/ml). In all patients antihypertensive therapy was withdrawn 4 days before start of the study. Patients V.J. and B.M. received 80 mg furosemide orally the evening before start of the saralasin infusion. Patient M.L. received no diuretic drug prior to the study.
200-
150-
~:i::!:~:i::::~!i!i!)~ - ~iiiil.ii:i)::i;i!i}iii!::ill ~ . !i!ii!ii!!!iii!!i!iiiiii!iiii!! .
Blood pressure was measured by an arteriosonde (Roche) in patient V.J. whereas in patients M.L. and B.M. conventional mercury manometer was used to determine blood pressure values. Diastolic and systolic blood pressure were determined at short-time intervals starting two hours before and ending two hours after saralasin infusion. During saralasin infusion blood pressure values were obtained every 5 min. Plasma renin activity and plasma aldosterone were determined immediately before and shortly after infusion of saralasin. Renin activity and plasma aldosterone were measured by radioimmunoassay procedures [1, 9]. Saralasin (1-sar-8-ala-angiotensin II) was obtained from R6hm-Pharma. 20 mg of the peptide were dissolved in 30 ml of 5% glucose and infused intravenously by a constant rate (1 ml/min) over a period of 30 min through an indwelling catheter.
Results
Effect of saralasin on blood pressure All three patients showed markedly elevated blood pressure before the start of the saralasin infusion (Fig. 1). This elevation in blood pressure levels was especially seen in diastolic blood pressure. In all patients infusion of 20 mg saralasin over a period of 30 rain had no detectable significant effect on diastolic and systolic blood pressure values. After saralasin infusion only minor fluctuations in systolic and diastolic blood pressure occurred in all patients. These blood pressure values were not significantly different from those observed before or during infusion of saralasin.
100' 200"
Effect of saralasin on renin activity and on plasma aldosterone
P R E S S U R E 150 m m Hg
In the two patients with hypercorticism (M.L. and V.J.) both plasma renin activity and plasma aldosterone markedly increased in response to 20 mg saralasin (Table 1). In the patient with an aldosterone producing adenoma of the left adrenal gland plasma renin activity remained unchanged during saralasin (Ta-
BLOOD
100 200
Tablel. Effect of 20mg saralasin (1-sar-8-ala-angiotensin II) on plasma renin activity and on plasma aldosterone in two patients with Cushing's syndrome (M.L. and V.J.) and in one patient with primary aldosteronism (B.M.)
150
I00-
-120-(~0
,F 0
15
.#
Patients
30 60 1~'0 rain.
Fig. 1. Effect of a 30 min infusion of 20 mg saralasin (1-sar-8-alaangiotensin II) on systolic and diastolic blood pressure in two patients with Cushing's syndrome (M.L. and V.J.) and in one patient with primary aldosteronism (B.M.). Systolic and diastolic blood pressure levels were recorded at short-time intervals starting 2 h before and ending 2 h after saralasin infusion. During saralasin infusion blood pressure was determined every 5 min
M.L, V.J. B.M.
Renin activity (ng/ml. 3 h)
Aldosterone (pg/ml)
before saralsin
after
before after saralasin
1.6 0.4 1.2
2.5 0.9 1.3
18 14 264
136 140 292
W. Vetter et al. : Saralasin in Cushing's Syndrome
ble 1). In this patient plasma aldosterone which was markedly elevated above normal before saralasin (264 pg/ml; normal range 20-120 pg/ml) increased slightly after saralasin to a value of 292 pg/ml.
Discussion
In patients with Cushing's syndrome excess production of cortisol is known to increase the formation of renin substrate in the liver [2]. This mechanism in turn may lead to elevated plasma concentrations of the vasoactive angiotensin II. Furthermore, in patients with hypercorticism the pressor response to vasopressive substances is markedly enhanced [4]. On the basis of these two findings Krakoff et al. [3] have postulated a renin-dependent hypertension in patients with Cushing's syndrome although abnormally high mineralocorticoid activity seems to be more accepted as the causative factor in the pathogenesis of hypertension in this disease. The present study shows that infusion of saralasin (1-sar-8-ala-angiotensin II) which is known to be a specific inhibitor of the vascular action of angiotensin II [5-7] does not significantly lower elevated blood pressure levels in two patients with hypercorticism. Therefore, an important role of the renin angiotensin system in the pathogenesis of hypertension in Cushing's syndrome can be excluded whereas indirect support is given to the more accepted theory that abnormally high mineralocorticoid activity may be the important pathogenic factor. The latter assumption is also strengthened by our observation that no effect of saralasin on elevated blood pressure was seen in the patient with primary aldosteronism, the classical form of mineralocorticoid hypertension. Our results are in good agreement with the findings of Pals et al. [5] who were unable to lower blood pressure by saralasin in experimental animals with DOC-induced hypertension. The increase in plasma renin activity observed in the two patients with hypercorticism during saralasin
Addendum. We have meanwhile obtained similar results in one patient with a cortisol producing carcinoma of the right adrenal gland and in two patients with primary aldosteronism.
663
is well known [8]. The rise in plasma aldosterone concentration in the two patients with Cushing's syndrome and in the patient with primary aldosteronism after saralasin may be caused by an angiotensin II-like activity of the peptide at the adrenal cortex. This increase can also be observed in normal subjects (unpublished observation). We thank Dr. K.D. V61ger of R6hm-Pharma, Darmstadt for generously supplying saralasin.
References l. Haber, E., Koerner, T., Page, L.J., Kliman, B., Purnode, A.: Application of a radioimmunoassay for angiotensin I to the physiologic measurements of plasma renin activity in normal human subjects. J. clin. Endocr. 29, 1349 (1969) 2. Krakoff, L.R.: Measurement of plasma renin substrate by radioimmunoassay of angiotensin I: Concentration in syndromes associated with steroid excess. J. clin. Endocr. 37, i10 (1973) 3. Krakoff, L., Nicolis,G., Amsel, B. : Pathogenesis of hypertension in Cushing's syndrome. Amer. J. Med. 58, 216 (1975) 4. Mendlowitz, M., Gitlow, S., Naftchi, N. : Work of digital vasoconstriction produced by infused norepinephrine in Cushing's syndrome. J. appl. Physiol. 13, 252 (1958) 5. Pals, D.T., Masucci, F.D., Denning, G.S., Sipos, F., Fessler, D.C. : Role of the pressor action of angiotensin II in experimental hypertension. Circulat. Res. 29, 673 (1971) 6. Pals, D.T., Masucci, F.D. : Plasma renin and the antihypertensive effect of 1-sar-8-ala-angiotensin II. Europ. J. Pharmacol. 23, 115 (1973) 7. Pals, D.T., Fulton, R.W.: Mechanism of the antihypertensive effect of 1-sar-8-ala-angiotensin II during the acute phase of experimental renal hypertension. Arch. int. Pharmacodyn. 204, 20 (1973) 8. Pettinger, W.A., Keeton, K., Tanaka, K.: Radioimmunoassay and pharmacokinetics of saralasin in the rat and hypertensive patients. Clin. Pharmacol. Ther. 17, 146 (1975) 9. Vetter, W., Vetter, H., Siegenthaler, W.: Radioimmunoassay of aldosterone without chromatography. 2. Determination of plasma aldosterone. Acta endocr. (Kbh) 74, 558 (1973) Dr. W. Vetter Kantonsspital Departement f/Jr Innere Medizin CH-8091 Ztirich, Schweiz
KEn. Wschr. 54, 661-663 (1976)
© by Springer-Verlag 1976
Originalien The Effect of Saralasin (1-Sar-8-Ala-Angiotensin lI) on Blood Pressure in Patients with Cushing's Syndrome W. Vetter, * H. Vetter, 3 R. Beckerhoff, 1 B. Redlich, 3 p. Cottier 2 and W. Siegenthaler 1 1 Departmentof Medicine, Kantonsspital,Universityof Ztirich 2 MedizinischeAbteilung, RegionalspitalInterlaken, Switzerland 3 MedizinischePoliklinik,Universityof Bonn, Federal Republicof Germany
Der Effekt yon Saralasin (1-Sar-8-Ala-Angiotensin II) auf den Blutdruck bei Patienten mit Cushing-Syndrom Zusammenfassung. Um die Bedeutung des Renin-Angiotensin Systems in der Pathogenese der Hypertonie bei Cushing-Syndrom zu untersuchen, wurden bei 2 Patienten mit Hyperkortizismus 20 mg Saralasin (1Sar-8-Ala-Angiotensin II) fiber einen Zeitraum yon 30 min unter st~indiger Blutdruckkontrolle infundiert. Zus/itzlich diente ein Patient mit primfirem Aldosteronismus, einer etablierten Form yon Mineralokortikoidhochdruck, als Kontrolle. Weder bei den 2 Patienten mit Cushing-Syndrom noch bei dem Patienten mit primfirem Aldosteronismus liel3 sich ein blutdrucksenkender Effekt des Saralasins nachweisen. Die beiden Patienten mit Hyperkortizismus zeigten unter Saralasin sowohl einen Anstieg der Renin-Aktivitfit als auch des Plasmaaldosterons. Bei dem Patienten mit primfirem Aldosteronismus liel3 sich nur ein geringgradiger Anstieg der Plasmaaldosteronkonzentration nachweisen. Diese Ergebnisse sprechen gegen eine wichtige Rolle des Renin-Angiotensin Systems in der Pathogenese der Hypertonie bei Cushing-Syndrom. Die Unbeeinflul3barkeit des Hochdrucks durch Saralasin bei den beiden Patienten mit Hyperkortizismus und dem Patienten mit primS.rein Aldosteronismus stfitzen indirekt die Annahme, dab bei Patienten mit CushingSyndrom eine erh6hte Mineralokortikoidaktivitfit der Hauptfaktor in der Pathogenese der Hypertonie ist. SchliisselwiJrter: Cushing-Syndrom - Hypertonie Renin-Aktivit~it, - Aldosteronismus. Summary. To investigate the role of the renin angiotensin system in the pathogenesis of hypertension in Cushing's syndrome two patients with hypercorticism were infused with 20 mg saralasin (1-sar-8-alaangiotensin II) over a period of 30 minutes under constant blood pressure control. In addition, one pa-
tient with primary aldosteronism, an established form of mineralocorticoid hypertension, served as control. Neither in the two patients with Cushing's syndrome nor in the patient with primary aldosteronism could a blood pressure lowering effect of saralasin be observed. In the two patients with hypercorticism both renin activity and plasma aldosterone increased during saralasin infusion. The patient with primary aldosteronism only showed a weak increase in plasma aldostetone concentration. These results seem to exclude an important role of the renin angiotensin system in the pathogenesis of hypertension in Cushing's syndrome. The unresponsiveness of elevated blood pressure to saralasin in the two patients with hypercorticism and in the patient with primary aldosteronism indirectly supports the assumption that in patients with Cushing's syndrome increased mineralocorticoid activity may be the main factor in the pathogenesis of hypertension.
Key words: Cushing's syndrome - Hypertension Renin activity - Aldosteronism.
Recently it has been suggested that the renin angiotensin system may play an important role in the pathogenesis of hypertension in Cushing's syndrome [3]. If this assumption is valid a significant reduction in blood pressure should be achieved in patients with Cushing's syndrome by infusion of saralasin (1-sar-8ala-angiotensin II) which is known to be a specific inhibitor of the vascular action of angiotensin II [5-7]. Thus, in the present study two patients with hypercorticism were infused with saralasin. In addition, one patient with primary aldosteronism, an established form of mineralocorticoid hypertension, served as control.
662
W. Vetter et al. : Saralasin in Cushing's Syndrome
Patients and Methods Three female patients (M.L., V.J. and B.M.) were investigated. Two patients (M.L. and V.J.) suffered from hypercorticism and one patient (B.M.) had primary aldosteronism. In patient M.L. the diagnosis of a cortisol producing adenoma of the left adrenal gland was confirmed by surgery. Patient V.J. showed no suppression of abnormally high (free) cortisol excretion rates by 2 mg dexamethasone/day whereas 8 mg dexamethasone/day produced a marked fall in urinary cortisol excretion. Thus, in this patient hypercorticism of hypothalamic-pituitary origin was assumed. This diagnosis was confirmed by a fall of urinary cortisol excretion to a very low value (5 gg/24 h; normal range 20-120 gg/24 h) shortly after hypophysectomy. In patient B.M. the diagnosis of primary aldosteronism was made by the combination of persistent hypokalemia ( < 3 maeq/1) with relatively low (supine) plasma renin activity ( < 1 ng/ml. 3 h) and abnormally high (supine) plasma aldosterone ( > 200 pg/ml). In this patient an aldosterone producing adenoma of the left adrenal gland was predicted because plasma aldosterone concentration was abnormally high in the left adrenal vein (3,500 pg/ml) and within normal range in the right adrenal vein (1,000 pg/ml). In all patients antihypertensive therapy was withdrawn 4 days before start of the study. Patients V.J. and B.M. received 80 mg furosemide orally the evening before start of the saralasin infusion. Patient M.L. received no diuretic drug prior to the study.
200-
150-
~:i::!:~:i::::~!i!i!)~ - ~iiiil.ii:i)::i;i!i}iii!::ill ~ . !i!ii!ii!!!iii!!i!iiiiii!iiii!! .
Blood pressure was measured by an arteriosonde (Roche) in patient V.J. whereas in patients M.L. and B.M. conventional mercury manometer was used to determine blood pressure values. Diastolic and systolic blood pressure were determined at short-time intervals starting two hours before and ending two hours after saralasin infusion. During saralasin infusion blood pressure values were obtained every 5 min. Plasma renin activity and plasma aldosterone were determined immediately before and shortly after infusion of saralasin. Renin activity and plasma aldosterone were measured by radioimmunoassay procedures [1, 9]. Saralasin (1-sar-8-ala-angiotensin II) was obtained from R6hm-Pharma. 20 mg of the peptide were dissolved in 30 ml of 5% glucose and infused intravenously by a constant rate (1 ml/min) over a period of 30 min through an indwelling catheter.
Results
Effect of saralasin on blood pressure All three patients showed markedly elevated blood pressure before the start of the saralasin infusion (Fig. 1). This elevation in blood pressure levels was especially seen in diastolic blood pressure. In all patients infusion of 20 mg saralasin over a period of 30 rain had no detectable significant effect on diastolic and systolic blood pressure values. After saralasin infusion only minor fluctuations in systolic and diastolic blood pressure occurred in all patients. These blood pressure values were not significantly different from those observed before or during infusion of saralasin.
100' 200"
Effect of saralasin on renin activity and on plasma aldosterone
P R E S S U R E 150 m m Hg
In the two patients with hypercorticism (M.L. and V.J.) both plasma renin activity and plasma aldosterone markedly increased in response to 20 mg saralasin (Table 1). In the patient with an aldosterone producing adenoma of the left adrenal gland plasma renin activity remained unchanged during saralasin (Ta-
BLOOD
100 200
Tablel. Effect of 20mg saralasin (1-sar-8-ala-angiotensin II) on plasma renin activity and on plasma aldosterone in two patients with Cushing's syndrome (M.L. and V.J.) and in one patient with primary aldosteronism (B.M.)
150
I00-
-120-(~0
,F 0
15
.#
Patients
30 60 1~'0 rain.
Fig. 1. Effect of a 30 min infusion of 20 mg saralasin (1-sar-8-alaangiotensin II) on systolic and diastolic blood pressure in two patients with Cushing's syndrome (M.L. and V.J.) and in one patient with primary aldosteronism (B.M.). Systolic and diastolic blood pressure levels were recorded at short-time intervals starting 2 h before and ending 2 h after saralasin infusion. During saralasin infusion blood pressure was determined every 5 min
M.L, V.J. B.M.
Renin activity (ng/ml. 3 h)
Aldosterone (pg/ml)
before saralsin
after
before after saralasin
1.6 0.4 1.2
2.5 0.9 1.3
18 14 264
136 140 292
W. Vetter et al. : Saralasin in Cushing's Syndrome
ble 1). In this patient plasma aldosterone which was markedly elevated above normal before saralasin (264 pg/ml; normal range 20-120 pg/ml) increased slightly after saralasin to a value of 292 pg/ml.
Discussion
In patients with Cushing's syndrome excess production of cortisol is known to increase the formation of renin substrate in the liver [2]. This mechanism in turn may lead to elevated plasma concentrations of the vasoactive angiotensin II. Furthermore, in patients with hypercorticism the pressor response to vasopressive substances is markedly enhanced [4]. On the basis of these two findings Krakoff et al. [3] have postulated a renin-dependent hypertension in patients with Cushing's syndrome although abnormally high mineralocorticoid activity seems to be more accepted as the causative factor in the pathogenesis of hypertension in this disease. The present study shows that infusion of saralasin (1-sar-8-ala-angiotensin II) which is known to be a specific inhibitor of the vascular action of angiotensin II [5-7] does not significantly lower elevated blood pressure levels in two patients with hypercorticism. Therefore, an important role of the renin angiotensin system in the pathogenesis of hypertension in Cushing's syndrome can be excluded whereas indirect support is given to the more accepted theory that abnormally high mineralocorticoid activity may be the important pathogenic factor. The latter assumption is also strengthened by our observation that no effect of saralasin on elevated blood pressure was seen in the patient with primary aldosteronism, the classical form of mineralocorticoid hypertension. Our results are in good agreement with the findings of Pals et al. [5] who were unable to lower blood pressure by saralasin in experimental animals with DOC-induced hypertension. The increase in plasma renin activity observed in the two patients with hypercorticism during saralasin
Addendum. We have meanwhile obtained similar results in one patient with a cortisol producing carcinoma of the right adrenal gland and in two patients with primary aldosteronism.
663
is well known [8]. The rise in plasma aldosterone concentration in the two patients with Cushing's syndrome and in the patient with primary aldosteronism after saralasin may be caused by an angiotensin II-like activity of the peptide at the adrenal cortex. This increase can also be observed in normal subjects (unpublished observation). We thank Dr. K.D. V61ger of R6hm-Pharma, Darmstadt for generously supplying saralasin.
References l. Haber, E., Koerner, T., Page, L.J., Kliman, B., Purnode, A.: Application of a radioimmunoassay for angiotensin I to the physiologic measurements of plasma renin activity in normal human subjects. J. clin. Endocr. 29, 1349 (1969) 2. Krakoff, L.R.: Measurement of plasma renin substrate by radioimmunoassay of angiotensin I: Concentration in syndromes associated with steroid excess. J. clin. Endocr. 37, i10 (1973) 3. Krakoff, L., Nicolis,G., Amsel, B. : Pathogenesis of hypertension in Cushing's syndrome. Amer. J. Med. 58, 216 (1975) 4. Mendlowitz, M., Gitlow, S., Naftchi, N. : Work of digital vasoconstriction produced by infused norepinephrine in Cushing's syndrome. J. appl. Physiol. 13, 252 (1958) 5. Pals, D.T., Masucci, F.D., Denning, G.S., Sipos, F., Fessler, D.C. : Role of the pressor action of angiotensin II in experimental hypertension. Circulat. Res. 29, 673 (1971) 6. Pals, D.T., Masucci, F.D. : Plasma renin and the antihypertensive effect of 1-sar-8-ala-angiotensin II. Europ. J. Pharmacol. 23, 115 (1973) 7. Pals, D.T., Fulton, R.W.: Mechanism of the antihypertensive effect of 1-sar-8-ala-angiotensin II during the acute phase of experimental renal hypertension. Arch. int. Pharmacodyn. 204, 20 (1973) 8. Pettinger, W.A., Keeton, K., Tanaka, K.: Radioimmunoassay and pharmacokinetics of saralasin in the rat and hypertensive patients. Clin. Pharmacol. Ther. 17, 146 (1975) 9. Vetter, W., Vetter, H., Siegenthaler, W.: Radioimmunoassay of aldosterone without chromatography. 2. Determination of plasma aldosterone. Acta endocr. (Kbh) 74, 558 (1973) Dr. W. Vetter Kantonsspital Departement f/Jr Innere Medizin CH-8091 Ztirich, Schweiz
