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Renal responses of pregnant and nonpregnant women to isopressor doses of angiotensin II
CURRENT INVESTIGATION
Renal responses of pregnant and nonpregnant women to isopressor doses of angiotensin II L E 0 N C . CHESLEY, Ph.D . Brooklyn, New York
R E c E N T evidence, reviewed by Davis, 1 indi<:ates that the renin-angiotensin system is a major humoral regulator of aldosterone secretion. In addition, angiotensin, itself, has a profound effect upon the kidney and, although it is the most potent pressor substance known, doses too small to affect the blood pressure will markedly reduce sodium and water excretion. 2 Whether the spectacular hyperaldosteronism of normal pregnancy depends upon the renin-angiotensin system is not known, but the perennial interest in the question of salt retention during pregnancy justifies a study of the effects of angiotensin. Chesley, Wynn, and Silverman 3 reported that the infusion of 0.5 meg. per minute of angiotensin II reduced the inulin clearance (glomerular filtration rate) an average of about 25 per cent in nonpregnant women; the urine flow and sodium and chloride excretion fell about 75 per cent from control
levels. Pregnant women at term showed about the same reduction in filtration, but the water and electrolyte excretion fell only 40 per cent (a statistically significant differ· ence) . Responses in women at 30 ± 5 weeks of gestation were significantly different from those at term, in regard to electrolyte excretion, for in some there were actual increases, in some there was no change, and in some there were slight decreases. The pressor responses of the pregnant women not only were smaller, but also often were not maintained during the continuing infusion of angiotensin. Abdul-Karim and Assali, 4 who found smaller pressor responses to single injections of 5 meg. of angiotensin in pregnant than in nonpregnant women, or in the same woman after delivery, cited Page's" report that plasma angiotensinase increases progressively during pregnancy. Khairallah, and co-workers6 infused tritiated angiotensin into rats and found that the uterus took up large amounts of radioactivity. On these bases, one might suspect that the resistance of pregnant women to angiotensin depends upon rapid inactivation by the enzyme, fixation in the uterine muscle, or by both. The fact that
From the Department of Obstetrics and Gynecology, State University of New York Downstate Medical Center. Supported by United States Public Health Service Grant HE-OJ 837.
410
Volume 87 'lumber 3
411
Current investigation
Table I. The distribution of pressor responses to infusions of angiotensin Rise in diastolic pressure (mm. Hg) ········-------········--
Pregnancy status ~onpregnant
5-9
10-14
15-19
4
8 8
5
4
I
20-24 6 6
5
I
25-29
I
2 2
30-34
35+
3 1
2
Table II. Average percentage changes in urine volume and sodium excretion in relation to pressor responses to angiotensin infusions in pregnant and nonpregnant women Diastolic rise less than 20 mm. Hg No. of cases Percentage decrease in urine volume Percentage decrease in sodium excretion
Diastolic rise more than 20 mm. Hg
Pregnant
Nonpregnant
Pregnant
Nonpregnant
17
17
11
12
29
65
29
75
63
45
76
29
~-~-~------~---
~
---~
the resistance seems to decrease during the last weeks of pregnancy and that the effect on inulin clearance is not different in pregnant women from its effect in nonpregnant women would contradict the hypothesis. The purpose of this paper is to compare the effect of angiotensin on the kidneys in pregnant and nonpregnant women who were infused with "isopressor" doses. That is, the infusion rates were adjusted to give comparable pressor reactions which were taken to mean that at least roughly equivalent effective doses of angiotensin were in the bloodstream. Material and methods
Twenty-eight normotensive, afebrile women with no recognized extrapelvic disease, from the gynecologic wards, and 27 "normal" women in the twenty-fifth to fortysecond week of gestation were studied. These 57 women included the 10 nonpregnant and 20 pregnant women of a previous study, 3 all of whom were infused with angiotensin at a constant rate of 0.5 meg. per minute. The other 27 were infused at rates adjusted to give desired pressor responses. Conventional clearance methods, with variations described elsewhere/ were used. After 3 control peri-
~
~-----
ods, angiotensin II* was infused for from 45 to 90 minutes, during which time 2 clearance periods were run. Results
Pressor responses. In order to match the pressor responses of the 20 pregnant women in the original study, nonpregnant women were infused with angiotensin at rates varying from 0.1 to 0.4 meg. per minute. Seven additional pregnant women were infused at rates greater than the 0.5 meg. per minute that was used originally. These increased rates initially varied from 1.0 to 2.5 meg. per minute, in a constant volume. Because of the tendency of the blood pressure to fall back toward control levels, the infusion rate was accelerated as necessary in order to maintain the desired blood pressure levels. Table I shows that the distribution of pressor responses is about the same in the pregnant and nonpregnant women, and that a comparison of renal effects at isopressor doses of angiotensin can be made.
*Hypertensin-Ciba, l·L·asparaginyi·5·L-valyl angiotensin octapeptide, supplied by Frank A. Travers, M.D., and William E. Wagner, M.D., of the Ciba Pharmaceutical Products Company.
412
Chesley
Renal responses. The average percentage decreases in urine flow and sodium excretion, in relation to pressor responses and pregnancy status, are listed in Table II. When the rises in diastolic pressure were less than 20 mm. Hg, the urine volume fell 65 per cent in nonpregnant and 29 per cent in pregnant women; sodium excretion levels fell by 63 and 29 per cent, respectively. The differences are statistically significant, with p < 0.0 1. * With diastolic pressure rises of 20 mm. Hg or greater, the urine volume fell 75 per cent in nonpregnant and 29 per cent in pregnant women; the decreases in sodium excretion were 76 and 45 per cent, respectively. The differences are statistically significant (p<0.01). An even more rigorous test can be made by comparing pregnant women with diastolic increases of more than 20 mm. Hg to nonpregnant women with increases of less than 20. The difference in the effect upon urine flow is significant, but the difference in effect upon sodium excretion is not quite significant (p = 0.02). Comment
Women in th.e last trimester of pregnancy have a relatively high tolerance for angiotensin. In subjects infused with 0.5 meg. per minute, the mean rise in blood pressure in nonpregnant women was 31 mm. Hg in the systolic and 27 mm. Hg in the diastolic pressure; the corresponding values in pregnant women were just about half as high ( 18 and 14, respectively) at their maxima, but the pressures usually fell from their peaks even as the infusions went on. 3 In order to get blood pressure rises in pregnant women that
REFERENCES
1. Davis, J. 0.: The Physiologist 5: 65, 1962. 2. Peart, W. S.: In Bock, K. D., and Cottier, P. T., editors: Essential Hypertension; an 1960, Berlin, Symposium, International Springer-Verlag, p. 112. 3. Chesley, L. C., Wynn, R. M., and Silverman, N. 1.: Circulation Res. (In press.)
*Student's t test was used in the statistical evaluations.
Am.
J.
October 1, 1963 Obst. & Gyner..
covered the same range as those induced in nonpregnant subjects, the infusion rates had to be adjusted over a wide range, so that the dose for many pregnant women was from 5 to 30 times that used to get comparable pressor responses in nonpregnant subjects. The dissociation of renal from pressor responses was an unexpected finding. Table II clearly shows that the effect of angiotensin upon sodium and water excretion is far less in pregnant than in nonpregnant women with the same pressor responses. Moreover, the dissociation can be seen within each group. In the pregnant women the urine flow decreased an average of 29 per cent whether the diastolic blood pressure rise was less or more than 20 mm. Hg, and the depressions in sodium excretion were not significantly different (p = 0.05). In the nonpregnant women the average decreases in sodium and water excretion were somewhat greater with higher pressor responses, but the differences are not statistically significant. Conclusion Pregnant women are resistant to the pressor and renal effects of angiotensin. When they are infused with relatively large amounts in order to induce blood pressure increases comparable to those elicited in nonpregnant subjects by small doses, angiotensin still has far less effect upon their renal excretion of sodium and water than it has in nonpregnant women. I wish to acknowledge my gratitude to the resident staff, especially Carl Pauerstein, M. D., for making patients available for study.
4. Abdul-Karim, R., and Assali, N. S.: AM . .J. 0BST. & GYNEC. 82: 246, 1961. 5. Page, E. W.: Am. J. M. Sc. 213: 715, 1947. 6. Khairallah, P. A., Page, I. H., Bumpus, F. M., and Smeby, R. R.: Science 138: 523, 1962. 450 Clarkson Ave. Brooklyn 3. New York
Renal responses of pregnant and nonpregnant women to isopressor doses of angiotensin II L E 0 N C . CHESLEY, Ph.D . Brooklyn, New York
R E c E N T evidence, reviewed by Davis, 1 indi<:ates that the renin-angiotensin system is a major humoral regulator of aldosterone secretion. In addition, angiotensin, itself, has a profound effect upon the kidney and, although it is the most potent pressor substance known, doses too small to affect the blood pressure will markedly reduce sodium and water excretion. 2 Whether the spectacular hyperaldosteronism of normal pregnancy depends upon the renin-angiotensin system is not known, but the perennial interest in the question of salt retention during pregnancy justifies a study of the effects of angiotensin. Chesley, Wynn, and Silverman 3 reported that the infusion of 0.5 meg. per minute of angiotensin II reduced the inulin clearance (glomerular filtration rate) an average of about 25 per cent in nonpregnant women; the urine flow and sodium and chloride excretion fell about 75 per cent from control
levels. Pregnant women at term showed about the same reduction in filtration, but the water and electrolyte excretion fell only 40 per cent (a statistically significant differ· ence) . Responses in women at 30 ± 5 weeks of gestation were significantly different from those at term, in regard to electrolyte excretion, for in some there were actual increases, in some there was no change, and in some there were slight decreases. The pressor responses of the pregnant women not only were smaller, but also often were not maintained during the continuing infusion of angiotensin. Abdul-Karim and Assali, 4 who found smaller pressor responses to single injections of 5 meg. of angiotensin in pregnant than in nonpregnant women, or in the same woman after delivery, cited Page's" report that plasma angiotensinase increases progressively during pregnancy. Khairallah, and co-workers6 infused tritiated angiotensin into rats and found that the uterus took up large amounts of radioactivity. On these bases, one might suspect that the resistance of pregnant women to angiotensin depends upon rapid inactivation by the enzyme, fixation in the uterine muscle, or by both. The fact that
From the Department of Obstetrics and Gynecology, State University of New York Downstate Medical Center. Supported by United States Public Health Service Grant HE-OJ 837.
410
Volume 87 'lumber 3
411
Current investigation
Table I. The distribution of pressor responses to infusions of angiotensin Rise in diastolic pressure (mm. Hg) ········-------········--
Pregnancy status ~onpregnant
5-9
10-14
15-19
4
8 8
5
4
I
20-24 6 6
5
I
25-29
I
2 2
30-34
35+
3 1
2
Table II. Average percentage changes in urine volume and sodium excretion in relation to pressor responses to angiotensin infusions in pregnant and nonpregnant women Diastolic rise less than 20 mm. Hg No. of cases Percentage decrease in urine volume Percentage decrease in sodium excretion
Diastolic rise more than 20 mm. Hg
Pregnant
Nonpregnant
Pregnant
Nonpregnant
17
17
11
12
29
65
29
75
63
45
76
29
~-~-~------~---
~
---~
the resistance seems to decrease during the last weeks of pregnancy and that the effect on inulin clearance is not different in pregnant women from its effect in nonpregnant women would contradict the hypothesis. The purpose of this paper is to compare the effect of angiotensin on the kidneys in pregnant and nonpregnant women who were infused with "isopressor" doses. That is, the infusion rates were adjusted to give comparable pressor reactions which were taken to mean that at least roughly equivalent effective doses of angiotensin were in the bloodstream. Material and methods
Twenty-eight normotensive, afebrile women with no recognized extrapelvic disease, from the gynecologic wards, and 27 "normal" women in the twenty-fifth to fortysecond week of gestation were studied. These 57 women included the 10 nonpregnant and 20 pregnant women of a previous study, 3 all of whom were infused with angiotensin at a constant rate of 0.5 meg. per minute. The other 27 were infused at rates adjusted to give desired pressor responses. Conventional clearance methods, with variations described elsewhere/ were used. After 3 control peri-
~
~-----
ods, angiotensin II* was infused for from 45 to 90 minutes, during which time 2 clearance periods were run. Results
Pressor responses. In order to match the pressor responses of the 20 pregnant women in the original study, nonpregnant women were infused with angiotensin at rates varying from 0.1 to 0.4 meg. per minute. Seven additional pregnant women were infused at rates greater than the 0.5 meg. per minute that was used originally. These increased rates initially varied from 1.0 to 2.5 meg. per minute, in a constant volume. Because of the tendency of the blood pressure to fall back toward control levels, the infusion rate was accelerated as necessary in order to maintain the desired blood pressure levels. Table I shows that the distribution of pressor responses is about the same in the pregnant and nonpregnant women, and that a comparison of renal effects at isopressor doses of angiotensin can be made.
*Hypertensin-Ciba, l·L·asparaginyi·5·L-valyl angiotensin octapeptide, supplied by Frank A. Travers, M.D., and William E. Wagner, M.D., of the Ciba Pharmaceutical Products Company.
412
Chesley
Renal responses. The average percentage decreases in urine flow and sodium excretion, in relation to pressor responses and pregnancy status, are listed in Table II. When the rises in diastolic pressure were less than 20 mm. Hg, the urine volume fell 65 per cent in nonpregnant and 29 per cent in pregnant women; sodium excretion levels fell by 63 and 29 per cent, respectively. The differences are statistically significant, with p < 0.0 1. * With diastolic pressure rises of 20 mm. Hg or greater, the urine volume fell 75 per cent in nonpregnant and 29 per cent in pregnant women; the decreases in sodium excretion were 76 and 45 per cent, respectively. The differences are statistically significant (p<0.01). An even more rigorous test can be made by comparing pregnant women with diastolic increases of more than 20 mm. Hg to nonpregnant women with increases of less than 20. The difference in the effect upon urine flow is significant, but the difference in effect upon sodium excretion is not quite significant (p = 0.02). Comment
Women in th.e last trimester of pregnancy have a relatively high tolerance for angiotensin. In subjects infused with 0.5 meg. per minute, the mean rise in blood pressure in nonpregnant women was 31 mm. Hg in the systolic and 27 mm. Hg in the diastolic pressure; the corresponding values in pregnant women were just about half as high ( 18 and 14, respectively) at their maxima, but the pressures usually fell from their peaks even as the infusions went on. 3 In order to get blood pressure rises in pregnant women that
REFERENCES
1. Davis, J. 0.: The Physiologist 5: 65, 1962. 2. Peart, W. S.: In Bock, K. D., and Cottier, P. T., editors: Essential Hypertension; an 1960, Berlin, Symposium, International Springer-Verlag, p. 112. 3. Chesley, L. C., Wynn, R. M., and Silverman, N. 1.: Circulation Res. (In press.)
*Student's t test was used in the statistical evaluations.
Am.
J.
October 1, 1963 Obst. & Gyner..
covered the same range as those induced in nonpregnant subjects, the infusion rates had to be adjusted over a wide range, so that the dose for many pregnant women was from 5 to 30 times that used to get comparable pressor responses in nonpregnant subjects. The dissociation of renal from pressor responses was an unexpected finding. Table II clearly shows that the effect of angiotensin upon sodium and water excretion is far less in pregnant than in nonpregnant women with the same pressor responses. Moreover, the dissociation can be seen within each group. In the pregnant women the urine flow decreased an average of 29 per cent whether the diastolic blood pressure rise was less or more than 20 mm. Hg, and the depressions in sodium excretion were not significantly different (p = 0.05). In the nonpregnant women the average decreases in sodium and water excretion were somewhat greater with higher pressor responses, but the differences are not statistically significant. Conclusion Pregnant women are resistant to the pressor and renal effects of angiotensin. When they are infused with relatively large amounts in order to induce blood pressure increases comparable to those elicited in nonpregnant subjects by small doses, angiotensin still has far less effect upon their renal excretion of sodium and water than it has in nonpregnant women. I wish to acknowledge my gratitude to the resident staff, especially Carl Pauerstein, M. D., for making patients available for study.
4. Abdul-Karim, R., and Assali, N. S.: AM . .J. 0BST. & GYNEC. 82: 246, 1961. 5. Page, E. W.: Am. J. M. Sc. 213: 715, 1947. 6. Khairallah, P. A., Page, I. H., Bumpus, F. M., and Smeby, R. R.: Science 138: 523, 1962. 450 Clarkson Ave. Brooklyn 3. New York