(Hypertension. 1995;25:823-827.)
© 1995 American Heart Association, Inc.
Articles |
Effects of Kinin Blockade on the Blood Pressure of Salt-Loaded Pregnant Rats
From the Clinica Medica and Farmacologia, Sassari (Italy) University.
Correspondence to Paolo Madeddu, MD, Clinica Medica, University of Sassari, Viale S. Pietro 8, 07100 Sassari, Italy.
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Abstract |
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Abstract We evaluated whether chronic inhibition of bradykinin B2 receptors by the long-acting antagonist D-Arg,[Hyp3,Thi5,D-Tic7,Oic8]-bradykinin (Hoe 140) affects blood pressure of salt-loaded pregnant rats. Pairs of rats fed a high sodium diet (0.84 mmol sodium per gram chow) were mated at 14 weeks of age. Infusion of vehicle or Hoe 140 (300 nmol/d per kilogram body weight) was performed throughout each dam's pregnancy by use of an Alzet osmotic pump implanted in the abdominal cavity. In both groups, no significant change in systolic pressure (tail-cuff plethysmography) or renal blood flow (Doppler flowmeter) was observed from that in the unmated state to that at midterm pregnancy. In the control group, systolic pressure decreased at the 21st day of pregnancy (from 126±2 to 97±2 mm Hg, P<.01), and renal blood flow increased (from 6.1±0.1 to 7.5±0.2 kHz, P<.01). These changes were nullified by the administration of Hoe 140 (systolic pressure changing from 124±2 to 118±4 mm Hg, P=NS; renal blood flow changing from 6.3±0.2 to 6.2±0.1 kHz, P=NS). In the group given Hoe 140, placental weight was greater (0.50±0.01 versus 0.43±0.01 g in controls, P<.01) and the fetal/placental weight ratio was reduced (4.53±0.09 versus 5.31±0.17 in controls, P<.01). A separate set of experiments was performed in the progeny of vehicle- and antagonist-treated dams to evaluate the effect of early postnatal administration of Hoe 140 combined with high sodium intake on survival rate. In the offspring of vehicle-treated rats, survival rate was reduced by chronic postnatal administration of Hoe 140 (at 70 days, 34% versus 62% in controls given vehicle). An earlier and more pronounced fall in survival rate was observed in the offspring of Hoe 140–treated rats maintained on antagonist or vehicle treatment during the postnatal period (0% and 18%, respectively, at 70 days). These results indicate that the kallikrein-kinin system plays a role in the regulation of blood pressure in pregnant rats exposed to a high sodium diet. The mechanism responsible for the increased early mortality in the progeny of Hoe 140–treated rats remains unknown. The possibility that it is related to blockade of kinin receptors may suggest a protective effect of endogenous kinins against the deleterious consequences of a dietary excess of sodium.
Key Words: hypertension, pregnancy-induced • blood pressure • kallikrein-kinin system • sodium, dietary
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Introduction |
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Normal pregnancy, both in humans and in rats, is characterized by systemic and renal vasodilatation, increased cardiac output, and blood volume expansion, all these changes resulting in a decrease in arterial blood pressure.1 2 3 The blood pressure–lowering effect of pregnancy has been also documented in rats with preexisting hypertension.4 5 6 Pregnancy-induced hypertension, a condition in which hypertension appears late during gestation in a previously normotensive subject, is probably the consequence of the loss of balance between vasoconstricting and vasodilating factors.7 8 9 Together, these findings suggest that the activities of the endocrine and paracrine vasodilating systems are enhanced during normal pregnancy. Consistent with this possibility is the observation that the fall in blood pressure that normally occurs in pregnant rats is nullified by chronic inhibition of endothelium-derived relaxing factor (EDRF) synthase.10 11 Kinins, derived from the enzymatic action of kallikrein on kininogen, could also participate in the regulation of blood pressure and renal function during pregnancy, because they act as paracrine vasodilating and natriuretic hormones by stimulating the release of EDRFs and prostaglandins.12 Renal kallikrein synthesis is upregulated by estrogen and progesterone13 and is increased early during normal pregnancy in the rat.14 By contrast, decreased renal synthesis and excretion of kallikrein14 15 16 17 and enhanced excretion of kallistatin (a potent tissue kallikrein inhibitor) occur in pregnancy-induced hypertension in humans.18 In addition, the presence of a kallikrein-like enzyme in myometrium, placenta, and amniotic fluid19 20 provides an anatomic basis for the hypothesis that kinins might play a role in the implantation process and in the maintenance of uteroplacental blood flow.21 22
Recently we observed that the administration of a newly synthesized, potent, and long-lasting antagonist of bradykinin B2 receptors, D-Arg,[Hyp3,Thi5,D-Tic7,Oic8]-bradykinin (Hoe 140), does not alter the blood pressure fall that occurs during pregnancy in rats on normal sodium intake.23 Because antagonism of endogenous kinins does not suffice to alter the normal gestational blood pressure pattern, the present study was designed to evaluate the alternative possibility that kinins become important in conditions of sodium repletion. Therefore, we examined the effect of combined chronic sodium loading and kinin-receptor blockade on the blood pressure and renal blood flow of pregnant rats. In addition, experiments were performed to determine whether kinin-receptor blockade combined with the above conditions results in increased mortality of offspring.
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Methods |
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The experimental protocol was approved by the local animal care and use committee. All procedures complied with the standards for the care and use of animals as stated in Guide for the Care and Use of Laboratory Animals.24 All surgical procedures were performed with rats under ether anesthesia; disappearance of the corneal reflex was used to assess and adjust the depth of anesthesia. Wistar rats (Morini Co) were housed at a constant room temperature (24±1°C) and humidity (60±3%) with a 12-hour light/dark cycle. They had free access to rat chow (0.84 mmol sodium per gram) and tap water for the duration of the experiment.
Hemodynamic Measurements
Systolic blood pressure (SBP) was measured by the
tail-cuff plethysmography method (Recorder 8002, Ugo Basile, Biological
Research Apparatus) in unanesthetized rats prewarmed for 10 minutes at
35°C. Each pressure value was obtained by averaging 8 to 10
individual readings. Direct measurement of mean blood pressure (MBP)
was performed in unanesthetized rats with a Statham transducer (Gould).
To measure renal blood flow (RBF), a pulsed Doppler flowmeter
(Pulse-Doppler, University of Iowa) was positioned on the left renal
artery, as described previously.25 The Doppler RBF
was recorded with a Kipp and Zonen recorder.
Experiment 1
Pairs of rats were mated at 14 weeks of age. Hoe 140 (a generous
gift from Hoechst AG) at a dose of 75 nmol/d (corresponding to 300
nmol/d per kilogram body weight) or vehicle was infused throughout the
duration of pregnancy by Alzet osmotic pumps (Alza Co) that were
implanted in the abdominal cavities of female rats (n=8, each group) 2
days before the rats were mated. At the same time, a Doppler flowmeter
was positioned on the left renal artery. Previous studies have shown
that the dose of antagonist indicated above is able to block the
vasodepressor effect induced by the intra-arterial injection of
exogenous bradykinin.26
Day 1 of pregnancy was the day on which sperm were seen in vaginal smears. SBP and RBF were determined before the rats were mated and on days 5, 10, and 21 of pregnancy. In addition, pregnant rats were observed carefully up to end-gestation to determine the exact birth date for the pups. Within 10 hours after birth, litters were culled to reduce the size of each litter to eight pups. On the following day, litters were randomly allocated to the following four groups (n=32 rats in each), according to the treatments received during the fetal and postnatal periods. Group 1 (offspring of vehicle-treated rats) received vehicle during postnatal life; group 2 (offspring of vehicle-treated rats) received Hoe 140 instead of vehicle; group 3 (offspring of Hoe 140–treated rats) received vehicle during postnatal life; and group 4 (offspring of Hoe 140–treated rats) received Hoe 140 instead of vehicle. Because the size of the pups made implantation of osmotic pumps impossible during the first weeks of life, a syringe injection technique was used until the 7th week. Hoe 140 or vehicle was injected subcutaneously every 6 hours during the day with a 100-µL Hamilton syringe. Both the daily dose of antagonist (300 nmol/d per kilogram body weight) and the timing of administration were decided on the basis of previous experiments showing the effectiveness of bradykinin-receptor blockade by repeated subcutaneous injections.27 At 7 weeks of age, infusion of Hoe 140 (300 nmol/d per kilogram body weight) or vehicle was performed with Alzet osmotic pumps implanted in the rats' abdomens. The rats were fed a high sodium diet (0.84 mmol/g) throughout the study. SBP was measured at the 7th and 9th weeks of age and survival rate was recorded until the 10th week of age.
Experiment 2
Pairs of rats were mated at 14 weeks of age. Infusions of Hoe
140 (300 nmol/d per kilogram body weight) or vehicle were performed
during gestation with Alzet osmotic pumps, as in experiment 1. On day
20 of pregnancy, dams (n=4 in each group) were anesthesized. A
polyethylene catheter (PE-50, Clay Adams) was inserted into the left
carotid artery and advanced into the descending aorta. The free end of
the catheter was connected to a Statham transducer to measure MBP. The
uterus was then dissected and the placentas were enucleated from the
uterine wall. Umbilical vessels and membranes were dissected at the
start from the placental disk. The placentas and fetuses were weighed
immediately to avoid dehydration. At the end of this procedure dams
were killed with an excess of anesthesia.
Statistical Analysis
All data are expressed as mean±SEM. Multivariate
repeatedmeasures ANOVA was performed to test for interaction
between time and grouping factor. Univariate ANOVA was then used to
test for differences among groups and over time. Differences within or
between groups were determined by use of paired or unpaired Student's
t test, respectively, with the Bonferroni multiple
comparison adjustment. Mathematical and statistical analyses were
performed with a STATVIEW II package (Brain Power) on an
Apple Macintosh IICX computer. A value of P<.05 was
significant.
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Results |
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Experiment 1
As shown in Fig 1, the SBP and RBF of sodium-loaded rats did not change from the unmated state to midterm pregnancy. During the late phase of pregnancy, SBP of vehicle-treated rats decreased (from 126±2 to 97±2 mm Hg at day 21, P<.01) and Doppler RBF increased (from 6.1±0.1 to 7.5±0.2 kHz at day 21, P<.01). These changes did not occur in Hoe 140–treated pregnant rats (SBP being 124±2 before mating and 118±4 mm Hg at day 21 of pregnancy and Doppler RBF being 6.3±0.2 and 6.2±0.1 kHz, respectively; P=NS for both comparisons).
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As shown in Fig 2, a high perinatal mortality was observed in the offspring of Hoe 140–treated rats (30% versus 5% in controls). In the offspring of vehicle-treated rats, survival rate was reduced by chronic postnatal administration of Hoe 140 (at 70 days, 34% versus 62% in controls given vehicle). However, the worst outcome was observed in the offspring of Hoe 140–treated rats, particularly if the administration of the antagonist was continued during postnatal life (at 70 days, 0% versus 18% in controls given vehicle). A severe retardation in body weight growth was observed in the offspring of Hoe 140–treated rats maintained on Hoe 140 (at 7 weeks, 35±4 g in group 4 versus 78±3, 76±2, and 72±4 g in groups 1, 2, and 3, respectively; P<.01). SBP was significantly higher in Hoe 140–treated rats than in controls at 7 weeks of age; however, no significant difference was observed at 9 weeks.
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Experiment 2
At day 20 of pregnancy, MBP was higher in rats given Hoe 140
compared with controls (96±3 versus 78±2 mm Hg, respectively;
P<.05). No significant difference in litter size between
groups was observed (14±2 in rats given Hoe 140 versus 14±2 in
controls, P=NS) or fetal weight (2.25±0.04 versus
2.20±0.04 g, P<.01), whereas placental weight was greater
in the Hoe 140–treated group (0.50±0.01 versus 0.43±0.01 g,
P<.01). As a consequence, the fetal/placental weight ratio
was reduced in the group given the antagonist (4.53±0.09 versus
5.31±0.17, P<.01).
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Discussion |
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The fact that normal pregnancy is characterized by decreased systemic and renal vascular resistances suggests a predominance of vasodilating factors in this condition. By contrast, in pregnancy-induced hypertension an altered activity of paracrine vasodilating systems could leave vasopressor factors unbalanced, thus increasing peripheral resistances. This alteration could be consequent to a generalized endothelial dysfunction, as indicated by studies showing elevated levels of endothelin-1 and reduced EDRF release.28 29 30
Our finding that chronic blockade of bradykinin receptors prevents the late gestational fall in blood pressure and the increase in RBF suggests that kinins participate in the regulation of systemic and renal hemodynamics during pregnancy. Kinins exert their vasodilating action through the stimulation of various intermediaries, namely EDRF and eicosanoids.31 Thus, it is conceivable that the effects of Hoe 140 on blood pressure and RBF are mediated by inhibition of EDRF and prostacyclin release. Consistent with this possibility is the observation that inhibition of EDRF synthase also prevents the fall in blood pressure and the increase in glomerular filtration rate and RBF that occur in late pregnancy.10 11 At high doses, inhibitors of EDRF synthase also induce severe hypertension and proteinuria, thus reproducing a condition similar to preeclampsia. Therefore, the difference between overt preeclampsia and milder forms of the disease may depend on the severity of endothelial dysfunction.
Sodium loading is necessary for Hoe 140 to produce cardiovascular effects, because the kinin antagonist does not alter the blood pressure change that occurs during pregnancy in rats on normal sodium intake.23 Manipulation of nutrition proved to be important in experimental models of gestational hypertension caused by uteroplacental ischemia. Indeed, reduction of uteroplacental blood flow increases blood pressure when associated with sodium chloride supplementation in late-pregnant sheep, but it is ineffective in sheep receiving a low sodium diet.32 It is possible that body fluid volume expansion, a typical pattern of normal pregnancy, is exaggerated in conditions of a dietary excess of sodium. It is not surprising, therefore, that concomitant blockade of endogenous kinins results in alterations of systemic and renal hemodynamics.
As in studies on chronic EDRF inhibition,10 11 our finding was that administration of Hoe 140 is able to worsen fetal outcome. Again, this effect is observed only when the kinin antagonist is given in combination with high sodium; administration in pregnant rats fed a normal sodium diet has no consequence for the fetus.23 Some cautiousness is recommended when interpreting the increased mortality of the offspring of Hoe 140–treated rats. In particular, a direct proof that kinins protect against the deleterious effect of sodium is not provided by the present study, particularly in consideration of the fact that we examined only bradykinin antagonism, not agonism. Because pharmacokinetic studies indicate that Hoe 140 is able to pass the placental barrier in Wistar rats (K. J. Wirth et al, unpublished data, 1994), increased perinatal mortality could be related to an altered placentation, possibly secondary to interference of the antagonist with angiogenesis and uteroplacental blood flow.21 In this regard, a puzzling aspect of our results is that placental weight was increased in the group given Hoe 140, but fetal weight was not affected. Although hypoplacentosis is the usual pattern associated with pregnancy-induced hypertension, hyperplacentosis also reflects placental dysfunction, responsible for poor fetal outcome.33
During suckling, dietary sodium influences the offspring primarily through hormonal and behavioral changes in the mother,34 and at weaning sodium excess exerts direct effects on the pups. The mortality observed after weaning in our salt-loaded rats may indicate a particular sensitivity to sodium chloride. Indeed, the high salt diet used in our experiments contains half the level of salt reported to be toxic in previous studies.34
Renal maturation is characterized by enhanced expression of kallikrein, kininogen, and bradykinin B2 receptor genes within the rat kidney.35 Recently we found that rats fed a normal sodium diet and treated with Hoe 140 since early life have blood pressure levels higher than those of controls given only vehicle. The increased blood pressure was associated with elevated sodium levels in serum and erythrocytes and reduced hematocrit.23 Together, these results suggest that the renal kallikrein-kinin system plays an important physiological role in the developing kidney in the rat, namely, in the regulation of excretory function. Therefore, it is tempting to speculate that in rats exposed since early life to salt load and kinin antagonism, the excretory ability of the immature kidney is overwhelmed, leaving the animals more susceptible to the deleterious consequences of chronic sodium excess. A limitation of the present study is that blood pressure was not measured until 7 weeks of age. Thus, we cannot say whether the excess of mortality that occurred in Hoe 140–treated rats was in some way related to the development of arterial hypertension. Blood pressure levels were higher in Hoe 140–treated rats than in controls at 7 weeks of age, but this difference was lost at 9 weeks, when a further decline in survival rate was observed.
In conclusion, the present study indicates that bradykinin receptor antagonism disrupts an intrinsic control system that normally compensates blood pressure downward in pregnant salt-loaded rats. Although the mechanism responsible for the increased early mortality in the progeny of Hoe 140–treated rats remains unknown, one possibility is that it might be related to blockade of kinin receptors, thus suggesting a protective effect of endogenous kinins against the deleterious consequences of a dietary excess of sodium.
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Acknowledgments |
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This work was supported in part by a grant of the Ministry of University and Scientific Research and research grant 91.00173.41 from the National Research Council (CNR)–Targeted Projects, "Prevention and Control of Disease Factors."
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References |
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