(Hypertension. 1997;30:580.)
© 1997 American Heart Association, Inc.
Articles |
Reduced Sensitivity of the Renal Circulation to Angiotensin II in Pregnant Rats
From the Department of Physiology and Biophysics, University of Mississippi Medical Center (Jackson).
Correspondence to Joey P. Granger, PhD, Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 N State St, Jackson, MS 39216-4505.
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Abstract |
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Abstract The renal circulation undergoes significant changes during pregnancy and pregnancy-induced hypertension. Although numerous studies indicate that the pressor response to angiotensin II (Ang II) is reduced during pregnancy, it is unclear as to whether this altered sensitivity to Ang II occurs in the renal circulation. The first aim of this study was to determine whether the renal vascular responsiveness to exogenous Ang II is altered in the midterm pregnant rat. All rats were pretreated with an intravenous infusion of the converting-enzyme inhibitor captopril (20 µg · kg-1 · min-1) to block endogenous Ang II formation. Following a control period, Ang II was infused at a dose of 10 ng · kg-1 · min-1 for 50 minutes into the renal arteries via a suprarenal aortic catheter. In anesthetized virgin rats, Ang II markedly decreased renal plasma flow (RPF) by 39% (5.0±0.4 to 3.1±0.4 mL/min), glomerular filtration rate (GFR) by 39% (1.9±0.1 to 1.16±0.2 mL/min), and urine flow by 47% (22.1±5.6 to 12.3±4.8 µL/min). In contrast, Ang II had no significant effect on RPF, GFR, and urine flow in the anesthetized pregnant rats. Since nitric oxide (NO) has been previously reported to modulate the renal vascular actions of Ang II in normal animals and NO synthesis is thought to be elevated in pregnancy, this study examined the role of NO in the attenuated renal response to Ang II. In pregnant rats pretreated with L-NAME, the arterial pressure was higher and RPF was lower than in the control pregnant rats. However, the renal response to Ang II in the L-NAME–pretreated pregnant rats was similar to control pregnant rats. These data indicate that the renal circulation has a reduced sensitivity to Ang II during pregnancy. We also found that NO synthesis inhibition does not alter the attenuated renal response to Ang II in the anesthetized pregnant rats.
Key Words: pregnancy • angiotensin II • rats
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Introduction |
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During pregnancy a number of physiological changes occur in the maternal circulation to accommodate the growing fetus. These changes usually include an increase in cardiac output and decreases in arterial blood pressure and total peripheral resistance.1 2 3 4 5 However, in patients with preeclampsia or pregnancy-induced hypertension, arterial pressure increases during the later stages of pregnancy and is accompanied by proteinuria, both of which remit after delivery of the placenta.6 7 Pregnancy-induced hypertension is one of the leading causes of fetal and maternal death; however, little is known about the etiology of the disease.
In preeclamptic patients, not only is the blood pressure higher but the pressor sensitivity to Ang II is significantly greater compared with normal pregnant patients.8 This increased responsiveness to endogenous vasoconstrictors could contribute to the pathophysiology of the disease. The exact mechanism for the altered vascular sensitivity during pregnancy and preeclampsia is still being debated.
Like most organ systems in the body, the kidney undergoes significant physiological changes during pregnancy. RBF and GFR have been shown to be increased early in pregnancy and remain elevated throughout the pregnancy but return to prepregnant values postpartum in a variety of species.2 9 One possible mechanism for the renal hyperemia and hyperfiltration during pregnancy is a reduction in the sensitivity of the renal circulation to vasoconstrictors such as Ang II. Although numerous studies indicate that the pressor response to Ang II is reduced during pregnancy,10 11 12 13 14 15 16 there is limited evidence to suggest that the renal circulation has a reduced sensitivity to exogenous Ang II.
The purpose of this study was to determine whether there is a reduced renal responsiveness to Ang II in the pregnant rat and the possible mechanism for this attenuated response. The decreased renal responsiveness may result from increased production of some endogenous vasodilator substance or substances. Due to the vasodilator properties of NO, it is a possible mediator of the decreased responsiveness to vasoconstrictors during pregnancy. NO is known to modulate the renal actions of Ang II in nonpregnant animals.17 18 In addition, some investigators have found that urinary excretion of NO and cGMP are increased during gestation in rats.19 Therefore, NO may be a mediator of the decreased responsiveness to Ang II. In the present study, we compared the acute renal hemodynamic and excretory responses to Ang II in anesthetized virgin and pregnant rats who were pretreated with the NO synthesis inhibitor L-NAME. Since endogenous levels of Ang II can alter the response to exogenous Ang II, all experiments were performed under conditions in which endogenous formation of Ang II was inhibited by Ang II–converting enzyme inhibition.
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Methods |
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All experiments were performed in female Sprague-Dawley rats. The rats were obtained from Harlan Sprague-Dawley, Inc (Indianapolis, Ind) and fed standard rat chow. The rats were allowed free access to tap water. Surgery and care of the rats were conducted in accordance with National Institutes of Health guidelines using protocols as approved by the Animal Care and Use Committee of the University of Mississippi Medical Center.
The rats were divided into four groups. The rats in two of the groups (groups III and IV) were mated with male Sprague-Dawley rats. Presence of sperm on a vaginal smear slide was considered day 1 of pregnancy. The experimental protocol was performed during the end of the second trimester of pregnancy (day 12 to 14). The rats in the other two groups (groups I and II) were not mated and served as the virgin controls.
All rats were fed a high sodium diet (8% NaCl) for 2 to 3 days before the acute experiment to reduce the blood pressure–lowering effects of captopril in anesthetized rats. On the day of the experiment, rats were anesthetized with thiobutabarbital sodium (Inactin, Promonto GMBH) (100 mg/kg body wt IP) and placed on a thermostatically controlled warming table to maintain body temperature at 37°C. A tracheotomy was performed, and PE-240 tubing 3 cm long was inserted into the trachea to maintain an open airway. The left femoral vein was cannulated with PE-50 tubing for continuous intravenous infusion. The left carotid artery was also cannulated with PE-50 tubing for blood sampling and continuous arterial pressure monitoring. The carotid artery catheter was connected to a model P23DC strain gauge and mean arterial pressure was recorded on a Grass recorder. A small midline incision was made, and the bladder was cannulated for urine collection using a flare-tipped PE-90 tubing. The right common iliac was cannulated with pulled PE-50, and the catheter was advanced into the aorta above the kidneys for suprarenal infusion of Ang II.
After surgery, saline containing 125I-iothalamate (Isotex), 131I-iodohippurate, and captopril (20 µg · kg-1 · min-1) was infused into the femoral vein at a rate of 2.5 mL/h (Syringe Infusion Pump 22, Harvard Apparatus) for groups I and III. In groups II and IV the NO synthesis inhibitor L-NAME was also added to the infusion at a dose of 5 µg · kg-1 · min-1. Saline was infused into the suprarenal catheter at a rate of 1 mL/h. After a 60-minute stabilization period, two 15-minute urine collections and steady state measurements of arterial pressure were obtained. A 500-µL blood sample was collected at the end of the control clearances. Ang II was then infused through the suprarenal catheter at a dose of 10 ng · kg-1 · min-1 for 15 minutes followed by two 15-minute urine collections and a 750-µL blood sample. At the end of the protocol, the rats were killed with an intravenous injection of concentrated potassium chloride. The kidneys were removed and weighed. Sodium and potassium concentrations in plasma and urine were measured by flame photometry (IL-943, Instrumentation Laboratory). GFR, RPF, as well as urinary excretion of sodium and potassium, were calculated from determination of the concentration of sodium, potassium, and radioactivities of 125I and 131I in plasma and urine.
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Results |
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As is shown is Fig 1A, the RPF significantly decreased in the virgin rats during infusion of Ang II. In the virgin rats (group I), RPF decreased from the baseline of 5.04±0.25 to 3.39±0.42 mL/min during infusion of Ang II (P<.05). Similarly, in virgin rats treated with the NO synthesis inhibitor L-NAME (group II), effective RPF significantly decreased. In this group as is shown in Fig 2A, RPF decreased from a baseline of 3.95±0.49 to 2.48±0.41 mL/min during the Ang II infusion. By contrast, in the pregnant rats, effective RPF did not significantly decrease during Ang II infusion. As is shown in Fig 1A, in the control pregnant animals (group III) the baseline RPF was 5.67±0.38 mL/min while the RPF during infusion of Ang II was 4.95±0.65 mL/min, which was not significantly different from baseline. In the pregnant rats which were also treated with L-NAME (group IV), the RPF response to Ang II was also attenuated. As is shown in Fig 2A, RPF did not significantly decrease in this group. The baseline RPF was 4.58±0.46 mL/min, and the RPF during infusion of Ang II was 4.19±0.55 mL/min.
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Figs 1B and 2B show the GFR response to Ang II in pregnant and virgin rats with and without treatment with L-NAME. As is shown in Fig 1B, in virgin rats GFR significantly decreased from 1.81±0.12 to 1.22±0.12 mL/min during infusion of Ang II (P<.05). Similarly in the virgin L-NAME group (group II), GFR decreased from 1.43±0.14 to 1.09±0.17 mL/min (P<.05, Fig 2B). In the pregnant rats and pregnant rats with L-NAME there were no significant changes in GFR. As is shown in Fig 1B in the pregnant rats (group III), baseline GFR was 1.44±0.13 and 1.48±0.13 mL/min during infusion of Ang II. In group IV (pregnant rats+L-NAME), the GFR was 1.49±0.12 mL/min under baseline conditions and 1.46±0.09 mL/min during Ang II infusion (Fig 2B).
Figs 3A and 4A illustrate the urine flow data for virgin and pregnant rats with and without treatment with L-NAME. As is shown in Fig 3A, urine flow significantly decreased in the group I (virgin rats) during infusion of Ang II. The baseline urine flow rate was 23.1±5.7 µL/min and decreased to 14.5±4.3 µL/min (P<.05). In the virgins treated with L-NAME (group II), Fig 4A shows that the urine flow tended to decrease but it did not reach statistical significance. Urine flow decreased from 29±5.5 µL/min under basal conditions to 16.8±4.3 µL/min during Ang II infusion. In pregnant rats with and without L-NAME treatment urine flow tended to increase, but it did not reach statistical significance during infusion of Ang II. As is shown in Fig 3A, urine flow under basal conditions was 11.7±2.8 and 19.4±7.1 µL/min during Ang II infusion. As is shown in Fig 4A, in the pregnant rats treated with L-NAME, urine flow under basal conditions was 33±4.7 and 37.2±9.4 µL/min during infusion of Ang II.
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Figs 3B and 4B illustrate the sodium excretion data for the pregnant and virgin groups with and without NO synthesis inhibition with L-NAME. In the virgin rats (groups I and II), sodium excretion tended to decrease; however, only in the L-NAME–treated virgins was this difference statistically significant. In group I (virgin rats), sodium excretion fell from 4.48±0.78 at baseline to 3.20±0.64 µEq/min (Fig 3B). In group II (virgin treated with L-NAME), sodium excretion decreased from 5.73±0.90 to 3.7±0.60 µEq/min (P<.05, Fig 4B). By contrast, in pregnant rats with and without L-NAME treatment, sodium excretion tended to increase. As is shown in Fig 3B, in group III sodium excretion increased from a baseline of 1.90±0.64 to 4.79±1.7 µEq/min during infusion of Ang II. In the L-NAME–treated pregnant rats (Fig 4B), sodium excretion increased from 6.72±1.5 to 7.68±2.1 µEq/min during infusion of Ang II.
Fig 5A and 5B shows the MAP response to suprarenal aortic infusion of Ang II. Ang II did not induce any significant changes in MAP in any of the groups (I through IV). In group I (virgin), MAP under basal condition was 111±4.4 and 112±4.5 mm Hg during Ang II infusion (Fig 5A). In the L-NAME–treated virgins MAP was 117±6 mm Hg under basal conditions and 122±5 mm Hg during Ang II infusion (Fig 5B). As is shown in Fig 5A, the pregnant rats (group III) tended to have lower MAPs than the virgins (group I), but there was also no significant effect of Ang II on MAP. MAP under basal conditions was 103±5 and 104±5 mm Hg during the Ang II infusion. As is shown in Fig 5B, in the L-NAME pregnant rats the MAP was similar to that in the virgins (120±3.5 baseline and 124±0.7 mm Hg during Ang II infusion), and there was no significant change during Ang II infusion.
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Discussion |
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Normal pregnancy is typically associated with significant cardiovascular alterations that include increases in cardiac output and decreases in arterial blood pressure and total peripheral resistance in humans1 2 3 as well as in rats.4 5 Another common feature of pregnancy is a reduction in the pressor responsiveness to exogenous vasoconstrictors such as Ang II. The blunted systemic pressor response to Ang II has been observed in gravid humans and in a variety of animal models of pregnancy.10 11 12 13 14 15 16 Although numerous studies indicate that the systemic pressor response to Ang II is reduced during pregnancy, there are limited data as to whether this altered sensitivity to Ang II occurs in the renal circulation. Since the kidneys play a central role in the long-term regulation of arterial pressure, a reduction in the renal vascular and tubular responsiveness to Ang II could be an important mechanism for the reduction in blood pressure associated with pregnancy. To determine whether the renal vascular responsiveness to exogenous Ang II is altered in the pregnant rat, we compared the effects of Ang II on renal hemodynamics and water and electrolyte excretion between virgin and pregnant rats. Since changes in systemic arterial pressure could potentially influence the renal hemodynamic and excretory response to Ang II, we infused Ang II suprarenally at a dose that did not affect renal perfusion pressure. Furthermore, since differences in the concentration of endogenous Ang II could also influence the effects of exogenously administered Ang II, all rats were pretreated with an intravenous infusion of the converting-enzyme inhibitor captopril to block endogenous Ang II formation. Under these conditions, we found that Ang II in virgin rats markedly decreased RPF and GFR by approximately 40% and decreased urine flow and sodium excretion by 47% and 30%, respectively. In sharp contrast, Ang II had no significant effects on RPF, GFR, and sodium and water excretion in pregnant rats. These findings clearly indicate that the renal hemodynamic and excretory effects of exogenous Ang II are significantly attenuated in pregnant rats.
One of potential mediators of the attenuated renal response to Ang II during pregnancy is NO. In fact, Conrad and colleagues19 have shown that during gestation in the rat there are significant increases in both urinary excretion of nitrate, a metabolite of NO, and cGMP. The role of NO in pregnancy has also been studied through the use of arginine analogues as inhibitors of NO synthesis. Danielson and Conrad20 have also reported that pregnant rats are more responsive to NO synthesis inhibition than age-matched virgin controls and that NO may be a mediator of the pregnancy-induced renal hyperfiltration. In addition, rats treated with NO synthase inhibitor L-NAME show symptoms similar to those observed in preeclamptic patients.21 Although there is good evidence that NO mediates, in part, the renal hyperemia and hyperfiltration observed during pregnancy, it is unclear whether NO mediates the altered renal responsiveness to Ang II. Supporting a potential role for NO are studies demonstrating that the NO synthesis inhibitor L-NAME potentiates the systemic pressor response to vasoconstrictors such as Ang II.12 13 15 17 22 23 For example, Molnar and Hertelendy12 found that NO synthesis inhibition restored the systemic pressor response to Ang II, norepinephrine, and vasopressin in pregnant rats. We have also demonstrated that the renal hemodynamic and excretory responsiveness to Ang II were enhanced in nonpregnant animals pretreated with an NO inhibitor.17 Although others have shown that NO plays an important role in modulating basal renal hemodynamics in pregnant rats, our results indicate that it does not appear to play a major role in mediating the reduced renal responsiveness to Ang II in our anesthetized rat model pretreated with captopril.
Another possible mechanism for the decreased responsiveness to Ang II involves the Ang II receptor. During pregnancy, the receptor could be occupied by endogenous Ang II, downregulated or dysfunctional. In the present study, captopril was administered to remove the effects of endogenous Ang II. Paller14 has reported that captopril had no effect on the MAP response to Ang II, which suggests that previous occupancy of the receptor was not responsible for the attenuated Ang II response during pregnancy. Ang II receptors in the glomeruli and mesenteric artery of rats have been reported to be downregulated during gestation in the rabbit24 ; however, the same group has shown that the receptors are not downregulated in the preglomerular vessels.25 Alterations in the receptor are a potential mechanism for the reduced responsiveness to Ang II; however, the evidence for this hypothesis is not clear. Furthermore, other investigators have reported that the responses to norepinephrine and vasopressin are also attenuated in pregnant animals.12 14 This seems to support the hypothesis that the attenuation of the vasoconstrictor response is related to post-receptor signaling, but further studies are needed in this area.
Another possible mediator of the reduced renal responsiveness to Ang II in our anesthetized pregnant rats could be renal prostaglandins. The decreased pressor responsiveness to Ang II in pregnant rabbits was altered by prostaglandin synthesis inhibition.26 Moreover, the attenuated RBF responses to Ang II in rabbits were significantly modified by meclofenamate pretreatment.26 Although some studies indicate a potential role for renal prostaglandins in modulating the vasoconstrictor responses during pregnancy, other studies have found that prostaglandins do not play a role in modulating the systemic and renal hemodynamic responses during pregnancy.10 15 22 In isolated blood vessels from pregnant rats, the vasoconstrictor response to phenylephrine is not altered by treatment with indomethacin.22 Furthermore, Conrad and Colpoys15 report that the blunted renal pressor responsiveness to Ang II is not restored by indomethacin. Thus, the importance of renal prostaglandins in modulating the renal hemodynamic and excretory responses to Ang II in the present study remains to be determined.
In summary, we found that Ang II produced significant reductions in renal plasma flow, GFR, and water and sodium excretion in anesthetized virgin rats pretreated with a converting-enzyme inhibitor. In sharp contrast, Ang II had no significant effect on renal hemodynamics or water and electrolyte excretion in anesthetized pregnant rats pretreated with captopril. We also found that L-NAME did not affect the attenuated renal response to Ang II in pregnant rats. We conclude from these findings that the renal circulation has a reduced sensitivity to Ang II during pregnancy and that the attenuated the renal response to Ang II does not appear to be mediated by NO.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported in part by National Institutes of Health grants HL-38499 and HL-51971. Jacqueline Novak is a recipient of a National Research Service Award (HL-09373) from the National Institutes of Health. We thank Brett Tucker and Todd Miller for their excellent technical support.
Received March 18, 1997; first decision April 21, 1997; accepted May 6, 1997.
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References |
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