(Hypertension. 1995;25:453-459.)
© 1995 American Heart Association, Inc.
Articles |
Early Blockade of Bradykinin B2-Receptors Alters the Adult Cardiovascular Phenotype in Rats
From the Clinica Medica and Farmacologia, Sassari (Italy) University.
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Abstract We evaluated whether long-term inhibition of bradykinin B2-receptors by the long-acting antagonist Hoe 140 (D-Arg,[Hyp3,Thi5,D-Tic7,Oic8]-bradykinin) affects the blood pressure of normotensive rats. Neither Hoe 140 (at 75 nmol/d for 8 weeks) nor its vehicle altered systolic pressure of adult rats on a normal or high sodium intake. In further experiments, pairs of Hoe 140–treated rats were mated and their offspring maintained on Hoe 140 and a normal sodium diet. Controls were given vehicle instead of Hoe 140. At 9 weeks of age, rats given Hoe 140 during prenatal and postnatal phases of life showed greater systolic pressures, heart rates, and body weights than controls (122±1 versus 113±1 mm Hg, 444±6 versus 395±8 beats per minute, 258±7 versus 213±3 g, respectively, P<.01), whereas urinary creatinine excretion was reduced (1.13±0.05 versus 1.36±0.04 µmol/100 g body wt in controls, P<.05). The difference in blood pressure (confirmed by direct intra-arterial measurement) persisted after 20 days of dietary sodium loading, whereas it was nullified by sodium restriction. In additional experiments, the offspring of untreated rats received Hoe 140 or vehicle from 2 days to 11 weeks of age. At this stage, systolic pressure and body weight were significantly greater in Hoe 140–treated rats compared with controls, and heart rate was similar. In addition, Hoe 140–treated rats showed higher sodium levels in serum and erythrocytes and a greater ratio of heart weight to body weight compared with controls; hematocrit and the ratio of kidney weight to body weight were lower. In conclusion, long-term blockade of bradykinin receptors by Hoe 140 alters the adult cardiovascular phenotype, provided that the antagonist is given since the early phases of life. Our data suggest that endogenous kinins may play a role in the regulation of cardiovascular function by influencing renal function and the activity of the sympathetic nervous system during development.
Key Words: bradykinin • kallikrein-kinin system • kidney • blood pressure • phenotype
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Introduction |
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Tissue (glandular) kallikrein is a serine protease able to cleave bradykinin and Lys-bradykinin from kininogen. Kinins thus generated act as vasodilating local hormones by stimulating the release of endothelium-derived relaxing factors and prostaglandins.1 In addition, they could play a role in the regulation of systemic blood pressure (BP) either by influencing renal excretory function directly or by interacting with other endocrine2 3 and paracrine4 systems.
Recently, the hypothesis that defective generation of kinins may contribute to the pathogenesis of arterial hypertension has been challenged by the use of the new potent and long-lasting antagonist of bradykinin B2-receptors, D-Arg,[Hyp3,Thi5,D-Tic7,Oic8]-bradykinin (Hoe 140).5 6 Long-term blockade of B2-receptors, which mediate most cardiovascular and renal effects of bradykinin,7 increases BP in deoxycorticosterone-treated rats and enhances the slow pressor effect induced by moderate increases in circulating angiotensin II levels.8 9 10 These results were confirmed by studies showing an enhanced pressor response to long-term administration of angiotensin II or deoxycorticosterone in Brown Norway Katholiek rats, which are genetically deficient in kininogen.11 12 Thus, endogenous kinins could be part of a homeostatic response that minimizes the BP effect induced by a chronic excess of vasoconstrictor and sodium-retaining hormones. On the other hand, the finding that Hoe 140 fails to alter BP in rats on a normal or high sodium intake8 13 14 does not favor a major role of kinins in basal conditions or during alterations in sodium balance. Alternatively, one may speculate that once humoral and neural regulatory systems have reached full maturation, the effects induced by kinin inhibition could be compensated by a series of feedback responses able to maintain cardiovascular homeostasis unaltered. The case is different in the early phases of the life, which are crucial to the expression of genes involved in the regulation of cardiovascular and renal function.15 16 17 18 Indeed, there is evidence that environmental and pharmacological interference with regulatory mechanisms during prenatal and early postnatal development can alter the adult BP phenotype and the response to later challenges. For instance, a window of sensitivity for the modulation of BP by high dietary sodium has been demonstrated during the early phases of life.19 20 Another example is provided by studies showing that sustained hypertension occurs in adult rats exposed to mineralocorticoids during the weaning period,21 a phase of maturation in which renal Na+,K+-ATPase expression is particularly sensitive to mineralocorticoids.22 23 Furthermore, hypertension development in rats genetically predisposed to this disease can be completely prevented by antagonists of angiotensin-converting enzyme (ACE), a protease that generates angiotensin II and also degrades bradykinin,24 provided that these antihypertensive agents are given early in life25 when the expression of cardiovascular and renal ACE is upregulated.26
If manipulation of vasopressor and sodium-retaining mechanisms during maturation is able to alter the adult BP phenotype, one might speculate that cardiovascular and renal functions of the adult organism could also be altered as a consequence of the early exposure to environmental and pharmacological factors affecting vasodilator systems. Relevant to this aspect is the finding that the expressions of kallikrein, kininogen, and ACE are upregulated in the vascular and renal tissue during the first weeks of postnatal life.26 27 In addition, studies on the spatial and temporal expressions of kallikrein and its mRNA in the developing rat kidney have suggested a trophic role of bradykinin in postnatal nephrogenesis and blood flow redistribution from the inner to the outer renal cortex.28
These important observations prompted us to evaluate the possibility that kinins play a role in the regulation of cardiovascular function during perinatal development. In particular, we wished to answer the following questions: (1) Can early inhibition of bradykinin B2-receptors by the antagonist Hoe 140 alter the adult BP phenotype? (2) Does the antagonist affect sodium homeostasis and renal excretory function? (3) Can the altered BP phenotype be passed on to progeny?
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Wistar rats (Morini, Como, Italy) 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 (sodium, 0.12 mmol/g; Mucedola) and tap water for the duration of the experiments unless specified otherwise.
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 the Guide for the Care and Use of Laboratory Animals (Institute of Laboratory Animal Resources, National Academy of Science, Bethesda, Md). All surgical procedures were performed with rats under ether anesthesia using disappearance of the corneal reflex to adjust the depth of anesthesia.
BP Measurements
Unanesthetized rats were warmed for 10 minutes at 35°C in a
thermostatically controlled heating cabinet. Systolic BP (SBP) and
heart rate (HR) then were measured by tail-cuff plethysmography
(recorder 8002, Ugo Basile, Biological Research Apparatus) with the rat
gently wrapped in a cotton hand towel. Each pressure value was obtained
by averaging 8 to 10 individual readings. Mean BP (MBP) was measured
directly in unanesthetized rats with a Statham transducer (Gould
Instruments).
Experiment 1. Hoe 140 Administration in Adult Rats: Effects on BP
During Alterations in Sodium Balance
Male 7-week-old Wistar rats were randomly allocated to four
groups (n=8 each). Group 1 received a continuous infusion of
physiological saline (vehicle) at the rate of 60 µL/d, and group 2
received Hoe 140 (a generous gift from Hoechst AG, Frankfurt, Germany)
at the rate of 75 nmol/d. Both groups were maintained on their initial
diet (sodium content: 0.12 mmol/g chow) during the experiment. Groups 3
and 4 were similar to groups 1 and 2, respectively, except that during
the experimental period their diet (Mucedola) was enriched with sodium
chloride (sodium content: 0.84 mmol/g chow); the concentration of the
other nutrients was not modified. Infusions were performed for 8 weeks
using Alzet osmotic pumps (Alza Corp), which were implanted into the
abdominal cavity through a midline incision.
SBP, HR, and body weight were measured every 2 weeks. At the end of the experimental period, a polyethylene catheter (PE-10 Clay Adams) was inserted through the left femoral artery and advanced into the abdominal aorta of anesthetized rats; a PE-50 catheter was inserted into the left carotid artery and advanced into the descending aorta. Both catheters were tunneled under the skin and exteriorized at the back of the neck. Twenty-four hours later, MBP of the rats (free to move in their own cages) was measured by connecting a Statham transducer to the femoral catheter. After 20 minutes of stabilization, the inhibitory activity of Hoe 140 was tested by comparing the vasodepressor effects of bradykinin (Peninsula Laboratories) in groups given vehicle or antagonist. A dose of 0.85 nmol/kg body wt was injected via the carotid catheter.
Experiment 2. Early (Prenatal and Postnatal) Hoe 140
Administration: Effects on the Adult BP Phenotype
Pairs of Hoe 140–treated rats were mated at 14 weeks of age.
Control breeders were given normal saline (vehicle) instead of Hoe 140.
Infusions of vehicle or Hoe 140 (75 nmol/d) were performed throughout
pregnancy using Alzet osmotic pumps that were implanted into the
abdominal cavity 2 days before mating. Day 1 of pregnancy was the day
on which sperm were seen in vaginal smears. SBP was measured in the
virgin state and then on days 10 and 21 during pregnancy. Pregnant rats
were observed carefully up to the end of gestation for determination of
the exact birth date for the pups (second generation, 2ndG). Two days
after birth, the mother was carefully handled, and the pups were
weighed and sexed; only males were then injected with vehicle or Hoe
140 (300 nmol/kg body wt per day SC, divided in four administrations)
using a 100-µL Hamilton syringe until 7 weeks of age. Then the
administration of Hoe 140 (75 nmol/d) or vehicle (n=16 each group) was
continued throughout the study by intraperitoneal infusion using Alzet
osmotic pumps implanted into the abdomen.
At 9 weeks of age, both the vehicle- and Hoe 140–treated rats were randomly assigned to a low (0.02 mmol/g, n=8 each group) or a high (0.84 mmol/g, n=8 each group) sodium diet for the following 20 days. Twenty-four-hour urine collections were obtained before the start of the low or high sodium diet and over the first 5 days of the high sodium diet. During the collection periods, rats were maintained in individual metabolic cages, which allowed for a high degree of accuracy in the measurement of food and water intake by the inclusion of spill catches. The chow was ground and blended before use. At 12 weeks of age (after 20 days of the high or low sodium diet), both the vehicle- and Hoe 140–treated rats returned to the initial diet (sodium: 0.12 mmol/g chow) for 1 additional week.
SBP, HR, and body weight were measured weekly from 7 until 9 weeks of age and then every 5 days. At the end of the experiment, the rats were instrumented as described in experiment 1 for direct measurement of MBP.
Experiment 3. Early Postnatal Hoe 140 Administration:
Cardiovascular Effects in Adult Rats and Their Offspring
Pairs of rats were mated at 14 weeks of age. Pregnant rats were
observed carefully at the end of gestation to determine the exact birth
date for the pups. On the second day, the pups were weighed and sexed;
both males and females were then injected with vehicle or Hoe 140 (300
nmol/kg body wt per day SC, divided in four administrations) until 7
weeks of age. Then the administration of Hoe 140 (75 nmol/d) or vehicle
(n=25 rats [5 females] in each group) was continued throughout the
study using Alzet osmotic pumps implanted into the abdomen.
SBP, HR, and body weight were measured weekly starting at 7 weeks of age. At 11 weeks, a catheter was inserted into the left carotid artery as described in experiment 1 for direct measurement of MBP. The following day, MBP was recorded for 30 minutes. Blood was collected via the carotid catheter into plastic tubes without anticoagulant, left at room temperature for 2 hours, and then centrifuged at 2000g for 10 minutes to separate serum. Blood was also collected into tubes containing ice-chilled isosmotic lithium chloride solution for determination of the sodium concentration in erythrocytes. Rats were then killed with an excess of ether anesthesia, and the heart and both kidneys were removed, cleaned, washed three times in saline, blotted, and weighed.
In additional experiments, some Hoe 140–treated 2ndG rats (n=10, 5 females) had their treatment withdrawn at 11 weeks of age and then were mated. Vehicle-treated rats (n=10, 5 females) were also mated. The offspring (third generation, 3rdG) were maintained without any treatment. SBP, HR, and body weight were measured in 3rdG rats at 7, 8, and 9 weeks of age.
Analytical Procedures
Urine volume (UV) was determined gravimetrically. Sodium and
potassium concentrations in urine (UNaV and
UKV) and serum were determined by flame photometry. Urinary
creatinine was measured by an automatic analyzer (Hitachi 704).
Erythrocyte sodium concentration was determined by atomic absorption
spectrophotometry and expressed as millimoles per liter red blood
cells.
Statistical Analysis
All data are expressed as mean±SEM. Multivariate repeated
measures ANOVA was performed to test for interaction between time and
grouping factor. Univariate ANOVA then was used to test for differences
among groups and over time. Differences within or between groups were
determined using 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.
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Results |
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Experiment 1. Hoe 140 Administration in Adult Rats: Effects on BP During Alterations in Sodium Balance
Hoe 140 did not alter SBP of rats on a normal or high sodium intake (Table 1). These results were confirmed by direct measurement of MBP at the end of the study (normal sodium, 100±3 versus 99±2 mm Hg in controls; high sodium, 105±2 versus 104±2 mm Hg in controls; P=NS for both comparisons). Hoe 140 inhibited the vasodepressor effect of bradykinin in rats on a normal (0±1 versus 20±2 mm Hg in controls, P<.01) or high (0±2 versus 26±1 mm Hg in controls, P<.01) sodium intake. No significant difference in HR was observed between groups (normal sodium, 382±3 versus 386±7 beats per minute in controls; high sodium, 385±10 versus 390±8 beats per minute in controls; P=NS for both comparisons). Body weight gain during the study was similar among groups (data not shown).
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Experiment 2. Early (Prenatal and Postnatal) Hoe 140
Administration: Effects on the Adult BP Phenotype
SBP did not change from the virgin state to midterm pregnancy. It
was found significantly decreased at the 21st day of pregnancy in both
controls and Hoe 140–treated rats (from 112±2 to 102±3 and from
111±2 to 102±2 mm Hg, respectively, P<.01). All the
litters of vehicle- and Hoe 140–treated rats were carried to full
gestation without any complications. No significant group difference
was found as far as the litter size was concerned (13±2 versus 14±2
in controls, P=NS).
As shown in Fig 1, rats given Hoe 140 when in utero and then since the early phases of postnatal life showed greater SBP, HR, and body weight values than controls (122±1 versus 113±1 mm Hg, 444±6 versus 395±8 beats per minute, 258±7 versus 213±3 g at 9 weeks of age, respectively; P<.01 for each comparison). No significant differences between groups were observed at 9 weeks of age in daily intake of food and water (12.9±1.8 g and 25.6±1.2 mL versus 12.9±1.7 g and 28.7±1.3 mL in controls, respectively; P=NS), UV (23±2 versus 20±2 mL in controls, P=NS), UNaV (0.64±0.04 versus 0.65±0.05 mmol/100 g body wt in controls, P=NS), UKV (1.14±0.08 versus 1.24±0.08 mmol/100 g body wt in controls, P=NS), and the ratio of UNaV to UKV (0.54±0.04 versus 0.52±0.06 in controls, P=NS), whereas urinary creatinine excretion was lower in Hoe 140–treated rats (1.13±0.05 versus 1.36±0.04 µmol/100 g body wt in controls, P<.05).
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) or
Hoe 140 (
) during prenatal and postnatal life. Values are
mean±SEM. 
P<.01 vs vehicle-treated group.Fig 2 (left) shows that the effects of the antagonist on SBP, HR, and body weight remained unaltered after 20 days of a high sodium diet (SBP, 121±1 versus 112±2 mm Hg in controls; HR, 399±11 versus 362±4 beats per minute in controls; body weight, 349±5 versus 307±6 g in controls; P<.01 for each comparison). In addition, SBP was higher in Hoe 140–treated rats compared with controls on day 25 (5 days after the rats had returned to the normal sodium diet); this difference was confirmed by direct measurement of MBP at the end of the experiment (115±2 versus 99±2 mm Hg in controls, P<.01). No significant difference between groups was observed during the first 5 days of a high sodium intake regarding the cumulative intake of food and water (113±8 g and 432±45 mL versus 111±7 g and 396±29 mL in controls, respectively; P=NS) and cumulative UNaV and UKV (36.9±5.2 and 7.1±0.7 versus 37.7±5.4 and 7.2±0.6 nmol/100 g body wt in controls, respectively; P=NS).
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) or
Hoe 140 (
) during prenatal and postnatal life. Rats were given a
normal sodium diet until 9 weeks of age (time 0) and then were randomly
allocated to a high (left) or low (right) sodium diet for 20 days. Then
rats returned to the initial diet for an additional 7 days. Values are
mean±SEM. As shown in Table 2, UV and UNaV increased similarly in Hoe 140–treated rats and controls. Urinary creatinine excretion was significantly lower in Hoe 140–treated rats compared with controls on day 0 (basal) and on the first day of the high sodium diet, whereas no difference was detected between groups during the following days.
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As shown in Fig 2 (right), sodium restriction nullified the differences in SBP (116±2 versus 120±2 mm Hg in controls at day 20, P=NS) and body weight (310±9 versus 292±8 g in controls at day 20, P=NS), whereas it did not alter the higher HR of Hoe 140–treated rats (420±4 versus 390±5 beats per minute in controls at day 20, P<.01). At the end of the experiment, direct measurement of MBP did not reveal any difference between groups (98±2 versus 98±1 mm Hg, P=NS).
Experiment 3. Early Postnatal Hoe 140 Administration:
Cardiovascular Effects in Adult Rats and Their Offspring
As shown in Fig 3, rats given Hoe 140 since the
early phases of postnatal life showed greater SBP and body weight
values than controls, whereas HR was similar. Direct measurement of MBP
at the end of the experiment revealed higher values in Hoe 140–treated
rats (119±2 versus 98±2 mm Hg in controls, P<.01).
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Hoe 140–treated rats showed higher sodium levels in serum (144.3±0.3 versus 141.1±0.2 mmol/L in controls, P<.01) and erythrocytes (3.8±0.2 versus 2.8±0.1 mmol/L in controls, P<.01) and lower hematocrit values (0.42±0.01 versus 0.46±0.01 in controls, P<.01). The ratio of heart weight to body weight was significantly greater in Hoe 140–treated rats (300±4 versus 275±4 mg/100 g body wt in controls, P<.05), whereas the ratio of kidney weight to body weight was lower (323±4 versus 363±5 mg/100 g body wt in controls, P<.05).
No significant difference was found in 3rdG rats at 9 weeks of age between the offspring of vehicle- and Hoe 140–treated rats in SBP (114±2 versus 116±4 mm Hg, P=NS), HR (398±9 versus 402±10 beats per minute, P=NS), and body weight (215±6 versus 218±10 g, P=NS).
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Discussion |
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The present study demonstrates that the adult BP and HR phenotype can be altered by the early administration of a receptor antagonist of bradykinin B2-receptors.
Consistent with previous studies,8 9 13 14 long-term administration of Hoe 140, when limited to the adult life, did not alter the BP of our rats on a normal or high sodium intake. At variance with these results, Majima et al29 reported that Brown Norway Katholiek rats, which are genetically deficient in kininogen and devoid of kinin release in the urine but exhibit normal BP levels in basal conditions, become hypertensive with salt loading. They also found that subcutaneous infusion of a high dose of Hoe 140 (5 mmol/kg per day) increases SBP to hypertensive levels and decreases UNaV in normal Brown Norway Kitasato rats fed a 2% NaCl diet. Thus, very high doses of antagonist might be necessary in normal rats to reproduce the condition of increased sensitivity to salt found in kininogen-deficient rats. However, it is not clear why the effects of a lower dose of antagonist were not evaluated in the study of Majima et al, considering that 75 nmol Hoe 140 per day would suffice to exert a very potent and long-lasting inhibition of kinin receptor within the vasculature as well as at the interstitial and tubular sides of the nephron.8 14 In addition, although evidence has been provided that Hoe 140 at the dose used in the present study has no other action than that of blocking bradykinin receptors,8 14 we are not aware that specificity is preserved at very high doses. Unfortunately, in the study of Majima et al, the latter possibility was not evaluated, and the BP effect of 5 mmol Hoe 140 was not tested in the absence of sodium loading.
Apart from the inconsistency in the studies performed in salt-loaded adult rats, the assumption that the kallikrein-kinin system plays a role in the regulation of basal BP cannot be discarded solely because the blockade of kinin receptor by Hoe 140 or inability to generate kinins (as in Brown Norway Katholiek rats) is insufficient to cause hypertension. In the adult organism, cardiovascular homeostasis is maintained by a complex interaction of various humoral and neural systems. Inhibition of one component usually activates a series of feedback mechanisms able to buffer the effect of the initial manipulation. Therefore, it is reasonable to presume that pharmacological or environmental interventions leading to endogenous kinin inhibition can be counteracted by humoral and neuronal regulatory systems to maintain BP within the normal range. The other way around, the contribution of endogenous kinins to BP regulation is unmasked in experimental conditions characterized by an excess of vasoconstrictor hormones, as suggested by the finding that Hoe 140 enhances the long-term vasopressor effects of angiotensin II or deoxycorticosterone.9 10
Several examples show that prenatal and early postnatal exposure to pharmacological and environmental stimuli can modify the characteristics of the adult organism. For instance, perinatal exposure to a high sodium diet causes sustained increases in the BP of normotensive and hypertensive rats,19 20 whereas sodium loading exerts only minimal and temporary effects in the mature rat. This difference is explained by the fact that nephrogenesis is still incomplete in the newborn rat, and therefore, an excess of sodium at this stage could overcome the excretory ability of the immature kidney.
A similar explanation could account for our finding that blockade of kinin receptors by Hoe 140 increases the BP of adult rats provided that antagonist administration is started early in life. Postnatal renal maturation is associated with enhanced synthesis of active kallikrein, kininogen, and ACE, their mRNA expression increasing 10- to 20-fold from prenatal levels to weaning.26 27 28 In addition, the B2-receptor gene is overexpressed in the developing rat (S. El-Dahr, unpublished observations, 1994). These findings suggest that the kallikrein-kinin system plays an important physiological role in the developing rat kidney, namely, in the regulation of renal excretory function and renal blood flow. For instance, endogenous kinins could minimize the antinatriuretic effects of mineralocorticoids, whose full activity on sodium tubular reabsorption is also upregulated at weaning,21 22 23 and participate in the early postnatal redistribution of renal blood flow from the inner to the outer renal cortex.28 In the present study, the increase in BP induced by Hoe 140 may be consequent to inhibition of kinins generated within the developing kidney, thus leading to early sodium retention and body fluid volume expansion. Unfortunately, we cannot say whether these effects are consequent to alterations in renal hemodynamics, because we did not measure renal blood flow in the present study. The findings of increased body weight and sodium concentration in serum and erythrocytes together with decreased hematocrit suggest that sodium and fluid retention occurred in the body. The consequent increase in BP, although mild, would suffice to maintain UNaV within the normal range, as indicated by measurements of UV and UNaV at 9 weeks of age. At this stage, application of dietary sodium loading was able to induce a temporary increase in BP. This effect was similar in magnitude in Hoe 140–treated rats and controls so that the initial difference between groups remained unaffected. This suggests that in Hoe 140–treated rats, pressure natriuresis was efficient but shifted to higher BP levels. We cannot rule out the possibility that activation of compensatory mechanisms, as hypothesized above, could have contributed to prevent further increases in BP and body weight in Hoe 140–treated rats after exposure to an excess of salt. The observation that dietary sodium restriction nullifies the effects on BP and body weight also favors our previous hypothesis. However, we cannot say whether these effects were associated with a correction of body fluid volume expansion because water and sodium balances were not evaluated during sodium restriction.
Another intriguing possibility is that early kinin inhibition impaired renal excretory function by suppressing renal growth. Indeed, bradykinin is able to stimulate proliferation of cultured glomerular mesangial cells.30 Consistent with a trophic role of bradykinin in postnatal renal development is the observation that long-term blockade by Hoe 140 during the first 2 weeks of life suppresses renal growth, whereas similar treatment of adult rats does not.26 Similarly, we found that the ratio of kidney weight to body weight and urinary creatinine excretion was decreased in rats given an early administration of Hoe 140. Urinary excretion of creatinine returned to control levels after a few days of the high sodium diet, a result compatible with hyperfiltration induced by sodium loading.
The ratio of heart weight to body weight was higher in rats given an early administration of Hoe 140. Although this may be a consequence of the increased hemodynamic load, no significant correlation was observed between heart weight and BP or HR levels (data not shown). Recent studies have showed that a kallikrein-like enzyme is present in the cardiovascular tissue31 32 33 and that kallikrein and ACE activities are upregulated in the cardiovascular system at weaning.26 These observations raise the possibility that endogenous kinins regulate cardiovascular function, acting as paracrine hormones. Thus, the effects induced by Hoe 140 might represent a direct consequence of the early blockade of kinins generated in cardiovascular tissue.
Our data indicate that the early postnatal administration of Hoe 140 is sufficient to alter the adult BP phenotype in the rat. By contrast, the prenatal phase appears to be crucial in determining the accelerated HR of Hoe 140–treated rats, because the tachycardiac effect was absent in those rats that started the antagonist 2 days after birth. Inhibition of kinin receptors in the fetus could be directly responsible for the altered HR. Pharmacokinetic studies indicate that Hoe 140 is able to pass the placental barrier in Wistar rats. Indeed, concentrations in maternal blood and fetal body were similar (unpublished results from Hoechst AG, 1994). Alternatively, inhibition of kinins during pregnancy could have caused hormonal or behavioral changes in the mother, thus influencing the HR of the progeny indirectly. The accelerated HR found in rats given Hoe 140 since the prenatal phases of life suggests activation of the sympathetic nervous system. Consistent with this hypothesis is the observation that in these rats, ß-adrenergic blockade by propranolol induces an exaggerated bradycardic response without affecting BP (P.M., unpublished observation, 1994).
It seems unlikely that long-term administration of Hoe 140 increased BP by stimulating directly the sympathetic nervous system. Indeed, based on the ability of bradykinin to induce catecholamine release from sympathetic varicosities and the adrenal medulla via a B2-receptor–mediated mechanism,34 35 one would expect that Hoe 140 can reduce rather than increase sympathetic activity. As opposed to antagonists of the first generation (characterized by residual agonistic activity), Hoe 140 does not increase the release of catecholamines, histamine, or prostaglandins.14 34 36 Plasma renin activity is also unaffected during long-term infusion of Hoe 140.14 In addition, the antagonist proved to be specific because it did not alter the action of unrelated vasodilators.14 Therefore, the cardiovascular effects of Hoe 140 do not appear to be related to properties other than its kinin blocking ability.
Recently, the interesting possibility that early manipulation of the BP phenotype could be passed on to the subsequent generation was raised by Wu and Berecek.25 However, in the present study, the alteration of the BP phenotype induced by early administration of Hoe 140 was not transmitted to the offspring, which were never exposed to the antagonist.
Some caution is recommended when trying to extrapolate the pathophysiological implications of the present study. First, we want to emphasize that the increase in BP induced by the antagonist did not reach hypertensive levels. Second, we do not know whether any human condition exists in which kinin receptors can be blocked as in rats given Hoe 140. Third, nephrogenesis is completed at birth in humans,27 thus suggesting that important differences may also exist in the temporal expression of the renal and vascular kallikrein systems between species. Nevertheless, the demonstration that early pharmacological manipulation of this vasodilating system modifies the BP phenotype of the adult rat raises some hope that the development of arterial hypertension can be attenuated by the application of kallikrein gene therapy37 during this crucial stage of life.
In conclusion, the present study shows that the kallikrein-kinin system plays an important role in the development of the adult cardiovascular phenotype.
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Acknowledgments |
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This work was supported in part by a grant from the Minister of Universities and Scientific Research and a research grant from the National Research Council (CNR) targeted project "Prevention and Controls of Disease Factors" No. 91.001173.41.
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Footnotes |
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Reprint requests to Paolo Madeddu, MD, Clinica Medica, Viale S. Pietro 8, 07100 Sassari, Italy.
Received September 19, 1994; first decision October 26, 1994; accepted November 15, 1994.
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