Acta physiol. scand. 1976. 98. 272-274 From the Institute of Medical Physiology C, University of Copenhagen, Denmark
Sodium Excretion and Sodium-Free Volume Expansion in Dogs: Effect of Inhibition of Aldosterone Activity by Canrenoate BY
PETER BIE
Whereas an iso-osmolar expansion of the extracellular fluid volume has frequently been reported to evoke an increase in the rate of urinary sodium excretion (e.g. de Wardener 1973) no alteration (Schrier et al. 1968) or a decrease (Blythe and Welt 1963) has been observed following hypo-osmolar expansion in dogs. It was recently shown (Bie 1976 a) that i.v. infusion of moderate amounts of a hypo-osmolar solution of glucose and urea is followed by a considerable decrease in the rate of excretion of sodium. In the present experiments the effect of the aldosterone inhibitor canrenoate (Soldactonea) on this antinatriuretic response has been investigated. Potassium canrenoate is a water soluble substance which is converted in uivo to a compound (canrenone) identical to the major, active metabolite of spirolactone (Hofmann, Polk and Maibach 1975). Beagle bitches weighing approximately 10 kg were used. Except for the administration of canrenoate the experiments were performed as previously described (Bie 1976 a): During chloralose anesthesia the body weight was increased by 2.0% within a 60 min period and kept (within F0.1Yo) at this elevated level for an additional period of 120 min by i.v. infusion of a solution of glucose (40 mM) and urea (25 mM). In each experiment canrenoate was given i.v. approximately I20 min and 60 min before the start of the infusion period. Two series of experiments were performed in which the total doses of canrenoate were 10 and 30 mg/kg b.wt. Plasma (2 ml) and urine samples were analyzed as described earlier (Bie 1976 h). The activity of renin in mixed venous plasma was determined according to Poulsen and Jplrgensen (1974).
The rates of excretion of sodium and water in the two series of expts. are shown in Fig. 1 in which the results of similar experiments on dogs not treated with canrenoate (Bie 1976 a) are included. It is apparent that in the canrenoate-treated dogs the rate of excretion of sodium after hypo-osmolar, sodium-free volume expansion (SFVE) was not different from pre-expansion values. The transient increase in the sodium excretion rate which appeared in all series was associated with rapid increases in diuresis and may be due to wash-out from the dead space of the lower urinary tract and the artificial drainage system. The effects of SFVE on the measured plasma variables were similar to those obtained earlier (Bie 1976 a) i.e. a decrease of some 3 4 % in the osmolality and in the sodium concentration together with an increase of similar relative magnitude in the potassium concentration. Measurement of the plasma renin activity 5 and 120 min after SFVE gave values (3.46 i0.72 and 4.84 L0.78 ng Ang. I/ml- h, respectively) which were not different from the preinfusion level (4.01 20.52, mean kS.E., n =7). In plasma obtained before anesthesia was induced renin activity was found to be 2.71 i0.60 ng Ang. I/ml*h.
2 72
273
VOLUME EXPANSION BY SODIUM-FREE SOLUTION l”f”SlO”
uNo
( pmollrninl
Diuresis
I mi I m i n l
0.5-
Fig. 1. Diuresis ( 0 i: ) and rates of excretion of sodium (0+ ) in 2 series of expts. Doses of canrenoate were 10 mg/kg b.wt. in 6 expts. (00) and 30 mg/kg b.wt. in 7 expts. ( x 3.). Values from identical expts. on dogs not pretreated with canrenoate (Bie 1976 a) are indicated by interrupted lines. Results are m e a n t S . E .
02-
0.1 -
0.070
’
60
’
’
’
120 I80 Time t min I
’
2LO
In 4 control expts. in dogs not treated with canrenoate a delay (60 min) of the SFVE was associated with an equivalent delay in the decline of the rate of excretion of sodium. Discussion. The results of previous expts. (Bie 1976 a) demonstrated that an appreciable but not excessive volume expansion by sodium-free solution elicits a considerable decrease in the rate of excretion of sodium. In addition, a concomitant increase in the rate of excretion of potassium was found. The present finding that these effects are abolished by canrenoate -whereas the diuretic response is not affected-suggests that the antinatriuretic and kaliuretic effects normally elicited are brought about by aldosterone. This conclusion obviously rests upon the assumption that the observed effects of canrenoate are due to an inhibition of the activity of aldosterone. It is possible-but it seems less likely-that the effects may be due to some other property of canrenoate. Accepting the view that canrenoate exerts the said effects by inhibiting the activity of aldosterone the antinatriuretic (and kaliuretic) response to hypo-osmolar volume expansion must be due to either an increasc in the rate of secretion of aldosterone, to a decrease i n the rate of aldosterone catabolism, or to an increased sensitivity of the tubular epithelium to aldosterone. The present studies do not allow a distinction between these possibilities. As regards the first possibility it is difficult from our present knowledge to indicate a stimulus for an increase in aldosterone secretion. Renin must be excluded since no alteration in the renin activity in plasma was produced by the hydration procedure. Decrease in plasma
274
PETER BIE
sodium concentration and increase in plasma potassium concentration have been classified as direct mediators of aldosterone secretion (Laragh and Sealey 1973), but the general opinion seems to be that greater alterations are required than those of minus 6-9 mM and 0.12-0.20 mM, respectively, encountered in the present studies. It is suggested, however, that during sodium-free volume expansion deviations in the concentration of sodium and/or potassium in plasma elicit an augmentation in the renal effect of aldosterone by a mechanism which is independent of plasma renin activity. The determinations of plasma renin activity were kindly performed by Dr. K. Poulsen, Institute of Experimental Medicine, University of Copenhagen. This work was supported by a grant from Nordisk Insulinfond. The author is indebted to Kirsten Poppe for her technical assistance. Canrenoate was a gift from G.D. Searle AS, Copenhagen. The author was supported by a grant from J. and H. Weimann’s legacy.
References BIE, P., Effects on renal water and sodium excretion of infusions of either iso-osmolar saline or a hypoosmolar solution of non-electrolytes. Arta physiol. srand. 1976 a. 96. 319-323. BIE, P., Studies of cerebral osmoreceptors in anesthetized dogs: The effect of intravenous and intracarotid infusion of hyper-osmolar sodium chloride solutions during sustained water diuresis. Acfaphysiol. scand. 1976 b. 96. 306-318. BLYTHE, W. B. and L. G. WELT,Plasma sodium concentrations and urinary sodium excretion. Trans. Ass. Amer. Phycns 1965. 78. 9Ck96. HOFMANN, L. M., R. C. POLKand H. 1. MAIBACH, Renal clearance of canrenoate in normal man. Clin. Pharmacol. Ther. 1975. 18. 748-756. LARAGH,J. H. and J. E. SEALEY, The renin-angiotensin-aldosteronehormonal system and regulation of sodium, potassium and blood pressure homeostasis. Renal Physiology. Handbook of Physiology, sect. 8. Washington: American Physiological Society 1973. p. 881. POULSEN, K. and J. JBRGENSEN, An easy radioimmunological microassay of renin activity, concentration and substrate in human and animal plasma and tissues based o n angiotensin I trapping by antibody. J. clin. Endocr. 1974. 39. 816-825. SCHRIER, R. W., K. M. MCDONALD, R. A. MARSHALL and D. P. LAULER, Absence of natriuretic response to acute hypotonic intravascular volume expansion in dogs. Clin. Sci. 1968. 34. 57-72. WARDENER, H. E. de, The control of sodium excretion. Renal Physiology. Handbook of Physiology, sect. 8. Washington: American Physiological Society. 1973. p. 714.
Sodium Excretion and Sodium-Free Volume Expansion in Dogs: Effect of Inhibition of Aldosterone Activity by Canrenoate BY
PETER BIE
Whereas an iso-osmolar expansion of the extracellular fluid volume has frequently been reported to evoke an increase in the rate of urinary sodium excretion (e.g. de Wardener 1973) no alteration (Schrier et al. 1968) or a decrease (Blythe and Welt 1963) has been observed following hypo-osmolar expansion in dogs. It was recently shown (Bie 1976 a) that i.v. infusion of moderate amounts of a hypo-osmolar solution of glucose and urea is followed by a considerable decrease in the rate of excretion of sodium. In the present experiments the effect of the aldosterone inhibitor canrenoate (Soldactonea) on this antinatriuretic response has been investigated. Potassium canrenoate is a water soluble substance which is converted in uivo to a compound (canrenone) identical to the major, active metabolite of spirolactone (Hofmann, Polk and Maibach 1975). Beagle bitches weighing approximately 10 kg were used. Except for the administration of canrenoate the experiments were performed as previously described (Bie 1976 a): During chloralose anesthesia the body weight was increased by 2.0% within a 60 min period and kept (within F0.1Yo) at this elevated level for an additional period of 120 min by i.v. infusion of a solution of glucose (40 mM) and urea (25 mM). In each experiment canrenoate was given i.v. approximately I20 min and 60 min before the start of the infusion period. Two series of experiments were performed in which the total doses of canrenoate were 10 and 30 mg/kg b.wt. Plasma (2 ml) and urine samples were analyzed as described earlier (Bie 1976 h). The activity of renin in mixed venous plasma was determined according to Poulsen and Jplrgensen (1974).
The rates of excretion of sodium and water in the two series of expts. are shown in Fig. 1 in which the results of similar experiments on dogs not treated with canrenoate (Bie 1976 a) are included. It is apparent that in the canrenoate-treated dogs the rate of excretion of sodium after hypo-osmolar, sodium-free volume expansion (SFVE) was not different from pre-expansion values. The transient increase in the sodium excretion rate which appeared in all series was associated with rapid increases in diuresis and may be due to wash-out from the dead space of the lower urinary tract and the artificial drainage system. The effects of SFVE on the measured plasma variables were similar to those obtained earlier (Bie 1976 a) i.e. a decrease of some 3 4 % in the osmolality and in the sodium concentration together with an increase of similar relative magnitude in the potassium concentration. Measurement of the plasma renin activity 5 and 120 min after SFVE gave values (3.46 i0.72 and 4.84 L0.78 ng Ang. I/ml- h, respectively) which were not different from the preinfusion level (4.01 20.52, mean kS.E., n =7). In plasma obtained before anesthesia was induced renin activity was found to be 2.71 i0.60 ng Ang. I/ml*h.
2 72
273
VOLUME EXPANSION BY SODIUM-FREE SOLUTION l”f”SlO”
uNo
( pmollrninl
Diuresis
I mi I m i n l
0.5-
Fig. 1. Diuresis ( 0 i: ) and rates of excretion of sodium (0+ ) in 2 series of expts. Doses of canrenoate were 10 mg/kg b.wt. in 6 expts. (00) and 30 mg/kg b.wt. in 7 expts. ( x 3.). Values from identical expts. on dogs not pretreated with canrenoate (Bie 1976 a) are indicated by interrupted lines. Results are m e a n t S . E .
02-
0.1 -
0.070
’
60
’
’
’
120 I80 Time t min I
’
2LO
In 4 control expts. in dogs not treated with canrenoate a delay (60 min) of the SFVE was associated with an equivalent delay in the decline of the rate of excretion of sodium. Discussion. The results of previous expts. (Bie 1976 a) demonstrated that an appreciable but not excessive volume expansion by sodium-free solution elicits a considerable decrease in the rate of excretion of sodium. In addition, a concomitant increase in the rate of excretion of potassium was found. The present finding that these effects are abolished by canrenoate -whereas the diuretic response is not affected-suggests that the antinatriuretic and kaliuretic effects normally elicited are brought about by aldosterone. This conclusion obviously rests upon the assumption that the observed effects of canrenoate are due to an inhibition of the activity of aldosterone. It is possible-but it seems less likely-that the effects may be due to some other property of canrenoate. Accepting the view that canrenoate exerts the said effects by inhibiting the activity of aldosterone the antinatriuretic (and kaliuretic) response to hypo-osmolar volume expansion must be due to either an increasc in the rate of secretion of aldosterone, to a decrease i n the rate of aldosterone catabolism, or to an increased sensitivity of the tubular epithelium to aldosterone. The present studies do not allow a distinction between these possibilities. As regards the first possibility it is difficult from our present knowledge to indicate a stimulus for an increase in aldosterone secretion. Renin must be excluded since no alteration in the renin activity in plasma was produced by the hydration procedure. Decrease in plasma
274
PETER BIE
sodium concentration and increase in plasma potassium concentration have been classified as direct mediators of aldosterone secretion (Laragh and Sealey 1973), but the general opinion seems to be that greater alterations are required than those of minus 6-9 mM and 0.12-0.20 mM, respectively, encountered in the present studies. It is suggested, however, that during sodium-free volume expansion deviations in the concentration of sodium and/or potassium in plasma elicit an augmentation in the renal effect of aldosterone by a mechanism which is independent of plasma renin activity. The determinations of plasma renin activity were kindly performed by Dr. K. Poulsen, Institute of Experimental Medicine, University of Copenhagen. This work was supported by a grant from Nordisk Insulinfond. The author is indebted to Kirsten Poppe for her technical assistance. Canrenoate was a gift from G.D. Searle AS, Copenhagen. The author was supported by a grant from J. and H. Weimann’s legacy.
References BIE, P., Effects on renal water and sodium excretion of infusions of either iso-osmolar saline or a hypoosmolar solution of non-electrolytes. Arta physiol. srand. 1976 a. 96. 319-323. BIE, P., Studies of cerebral osmoreceptors in anesthetized dogs: The effect of intravenous and intracarotid infusion of hyper-osmolar sodium chloride solutions during sustained water diuresis. Acfaphysiol. scand. 1976 b. 96. 306-318. BLYTHE, W. B. and L. G. WELT,Plasma sodium concentrations and urinary sodium excretion. Trans. Ass. Amer. Phycns 1965. 78. 9Ck96. HOFMANN, L. M., R. C. POLKand H. 1. MAIBACH, Renal clearance of canrenoate in normal man. Clin. Pharmacol. Ther. 1975. 18. 748-756. LARAGH,J. H. and J. E. SEALEY, The renin-angiotensin-aldosteronehormonal system and regulation of sodium, potassium and blood pressure homeostasis. Renal Physiology. Handbook of Physiology, sect. 8. Washington: American Physiological Society 1973. p. 881. POULSEN, K. and J. JBRGENSEN, An easy radioimmunological microassay of renin activity, concentration and substrate in human and animal plasma and tissues based o n angiotensin I trapping by antibody. J. clin. Endocr. 1974. 39. 816-825. SCHRIER, R. W., K. M. MCDONALD, R. A. MARSHALL and D. P. LAULER, Absence of natriuretic response to acute hypotonic intravascular volume expansion in dogs. Clin. Sci. 1968. 34. 57-72. WARDENER, H. E. de, The control of sodium excretion. Renal Physiology. Handbook of Physiology, sect. 8. Washington: American Physiological Society. 1973. p. 714.
