(Hypertension. 1996;27:746-751.)
© 1996 American Heart Association, Inc.
Articles |
Sexual Dimorphism of Cardiovascular Responses to Early Blockade of Bradykinin Receptors
From the Clinica Medica (P.M., P.P.P., N.G.) and Farmacologia (V.A.), University of Sassari, Italy, and the Department of Biochemistry and Molecular Biology (C.C., C.W., J.C.), Medical University of South Carolina, Charleston.
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 To assess whether the cardiovascular effects induced by early blockade of bradykinin B2-receptors with Hoe 140 (D-Arg[Hyp3,Thi5,D-Tic7,Oic8]-bradykinin) are influenced by sex, Wistar rats of both sexes received the antagonist (300 nmol/d per kilogram body wt) or vehicle from 2 days to 7 weeks of age by subcutaneous injection and then by intraperitoneal infusion. Compared with control rats, Hoe 140–treated female rats showed higher systolic blood pressure levels at 7 and 9 weeks of age (125±2 versus 111±2 mm Hg and 132±3 versus 116±2 mm Hg, respectively, P<.05), whereas in male rats a difference was found at 7 weeks (122±4 versus 108±4 mm Hg, P<.05) but not at 9 weeks. At this stage, the mean blood pressure of Hoe 140–treated rats was higher than that of control animals, and this difference was more pronounced at 12 weeks in female rats (121±2 versus 100±3 mm Hg in control animals, P<.01) compared with males (116±3 versus 104±2 mm Hg in control rats, P<.05). After the first week of life, body weight gain was greater in Hoe 140–treated female rats than in control rats, whereas a group-difference was detected in male rats only after weaning. In Hoe 140–treated female rats, heart weight was already increased at 9 weeks (330±6 versus 305±5 mg/100 g body wt in control rats, P<.05), whereas it was necessary to prolong Hoe 140 administration in male rats to develop heart hypertrophy (300±4 versus 275±4 mg/100 g body wt in control rats at 12 weeks, P<.05). Tissue kallikrein mRNA levels were higher in the kidney of adult female rats, whereas no sex difference was detected in the heart. The finding of a sexual dimorphism in the cardiovascular response to early blockade of bradykinin receptor suggests that endogenous kinins play a role in the regulation of cardiovascular function in both sexes, but they may be functionally more important in the female rat.
Key Words: kallikrein • sex characteristics • receptor, bradykinin
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Tissue (glandular) kallikrein is a serine proteinase that is capable of releasing bradykinin or lys-bradykinin from kininogens. Kinins are vasodilating local hormones able to stimulate the release of endothelium-derived relaxing factors and prostaglandins.1 In addition, the tissue KKS could play a role in the regulation of systemic BP either by influencing renal excretory function directly or by interacting with other endocrine2 3 and paracrine systems.4
The activity of the KKS is modulated by mechanisms acting at the level of gene expression and the post-translational level.5 The possibility that sex hormones contribute to the regulation of kallikrein gene expression in the kidney is suggested by the observations that (1) human pancreatic/renal kallikrein gene has potential receptor binding sites for estrogen and progesterone5 ; (2) urinary kallikrein excretion is higher in women, decreases with aging, and peaks at the progestinic phase of the menstrual cycle; and (3) renal immunoreactive kallikrein and kallikrein mRNA levels are decreased by ovariectomy in the rat, with these alterations corrected by treatment with estrogen or progesterone.6
Activation of endothelium-dependent vasorelaxation by female sex hormones reportedly exerts a protective effect against the occurrence and progression of hypertension in female animals.7 8 9 10 11 12 13 Whether this concept is extensible to the activation of KKS observed in female rats remains to be elucidated. Recently, we found that early and lifelong administration of Hoe 140, a potent and long-lasting antagonist of bradykinin B2-receptors,14 is able to alter the adult cardiovascular phenotype,15 suggesting that endogenous kinins could play a role in the maturation of cardiovascular function. Taken together, these observations and the finding of a sexual dimorphism in the activity of the renal KKS6 prompted us to hypothesize that endogenous kinins may be functionally more important in female rats. Therefore, the present study was aimed to answer the following questions: (1) Is kallikrein gene expression increased in the kidney and heart of female normotensive rats? and (2) Can early blockade of bradykinin B2-receptors cause greater effects on the adult cardiovascular phenotype of female rats?
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Methods |
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Wistar rats (Morini, Como, Italy) were housed at a constant room temperature (24±1°C) and humidity (60%) 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 experiment unless specified otherwise. The experimental protocol was approved by the local animal care and use committee. All procedures were in compliance with the standards for the care and use of animals according to the Institute of Laboratory Animal Resources (National Academy of Science, Bethesda, Md). All surgical procedures were performed with rats anesthetized with ether, with disappearance of the corneal reflex used to adjust the depth of anesthesia.
Blood Pressure Measurements
Unanesthetized rats were warmed
for 10 minutes at
37°C in a thermostatically controlled heating cabinet. SBP was then
measured by tail-cuff plethysmography (model 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. MBP and heart rate (HR) were measured
directly in unanesthetized rats with a Statham transducer
(Gould Instruments).
Cardiovascular Effects of Early Postnatal Hoe
140 Administration
Pairs of rats were mated at 14 weeks of age. Day 1
of pregnancy
was the day on which sperm were seen in vaginal smears. 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 to eight pups (four females). Because
the size of the pups made implantation of osmotic pumps impossible
during the first weeks of life, a syringe injection technique was used
for administration of Hoe 140 (a generous gift from Hoechst AG,
Frankfurt, Germany) or vehicle. Starting 2 days after birth until 7
weeks of age, pups were injected subcutaneously with Hoe 140 or vehicle
(n=32 rats [16 females] in each group) every 6 hours during
the day
with a 100-µL syringe (Hamilton). Both the daily dose (300 nmol/d per
kilogram body wt) and the timing of administration were decided on the
basis of previous experiments showing the effectiveness of
bradykinin-receptor blockade by repeated subcutaneous
injections.16 At 7 weeks of age, infusion of Hoe 140 (300
nmol/d per kg body wt) or vehicle was performed with osmotic pumps
(Alza Corp) implanted in the abdomens of the rats. Body weight was
measured every 10 days, starting at 10 days of age. SBP was measured
weekly starting at 7 weeks of age.
At 9 weeks, a polyethylene catheter (model PE-10, Clay Adams) was inserted through the left femoral artery, advanced into the abdominal aorta, tunneled under the skin, and exteriorized at the back of the neck of anesthetized rats (n=16 [8 females] in each group). The following day, 24-hour urine collections were obtained from these rats; rats were maintained in individual metabolic cages with free access to tap water but deprived of food. At the end of the collection period, MBP and HR were measured for 30 minutes by connecting a Statham transducer to the femoral catheter. Rats were then killed with an excess of ether anesthesia, and the heart was removed, cleaned, washed three times in saline and then blotted and weighed. The remaining rats (n=16 [8 females] in each group) were studied at 12 weeks of age. A catheter was inserted into the left femoral artery as described above for direct measurement of MBP, which was performed on the following day. Rats were then killed, and the heart and both kidneys were removed and weighed.
Urinary volume was determined gravimetrically. Sodium and potassium concentration in urine was determined by flame photometry. Urinary creatinine was measured with an automatic analyzer (Hitachi 704). Albumin concentration in urine was determined by a colorimetric method.
Renal and Urinary Kallikrein Levels in Male and Female
Rats
Twenty-four–hour urine collections were obtained from
8-week-old Wistar rats (n=8, 4 females). The animals were then
killed and the kidneys were removed, washed with saline, weighed, and
homogenized. Immunoreactive intrarenal tissue kallikrein
and urinary kallikrein levels were measured by
radioimmunoassay.17 Similar experiments were performed in
7-month-old Wistar rats (n=8, 4 females).
In additional experiments, kallikrein activity was measured in urine obtained between 9 and 10 AM from Wistar rats at different ages (from 13 to 60 days, n=at least 4 rats per group), using an amidolytic assay.18 Kallikrein activity was expressed in picokatals per micromole of creatinine (1 pkat represents the enzymatic activity able to cleave 1 pmol p-nitroaniline per second from substrate).
Northern Blot Analysis of Renal and Cardiac Kallikrein in
Adult Rats
Anesthetized Wistar rats were perfused with normal
saline via cardiac puncture. The heart and kidneys were removed
immediately, and RNAs were extracted by the guanidine
thiocyanate/cesium chloride gradient
ultracentrifugation method.19
Tissue kallikrein and ß-actin mRNAs were identified in the kidney and heart (ventricle) of Wistar rats by Northern blot analysis according to the procedures previously described.20 Twenty-five micrograms of total RNA were separated on a 1.5% agarose gel containing 0.66 mol/L formamide. RNA samples were transferred in 20x SSC for 12 to 16 hours by capillary action and immobilized onto an Immobilion-N membrane. The membrane was prehybridized in hybridization buffer (50% formamide, 0.25 mol/L sodium phosphate, pH 7.2, 0.25 mol/L NaCl, 1 mmol/L EDTA, 7% SDS) at 60°C for 4 hours. The kallikrein cDNA probe was prepared by restriction enzyme digestion and purified by agarose gel electrophoresis and electroelution. Kallikrein cDNA probe was labeled with 32P (New England Nuclear Research Products) using a nick-translation kit (Bethesda Research Laboratories) according to the protocols recommended by the manufacturer. Unincorporated label was removed by spin-column (G-50), and the specific activity of each probe was approximately 1 to 2x108 cpm/µg DNA. The membrane was hybridized with the kallikrein cDNA probe for 16 to 18 hours at 60°C and washed with 6x SSC at room temperature and exposed to x-ray film at -70°C. The membrane was stripped and reprobed with the 32P-labeled–human ß-actin cDNA insert (2000 bp, Clontech Lab Inc) as described above.
RT-PCR Southern Blot Analysis
RT-PCR Southern blot analysis
was performed using three
oligonucleotides specific for rat tissue kallikrein
essentially as previously described.21 Briefly, the tissue
kallikrein cDNA fragment was synthesized from the total kidney RNA of
male and female Wistar rats using a specific 3'-primer. After reverse
transcription (RT), the RT product was amplified for 30 cycles with
an annealing temperature of 55°C. The RT-PCR products (20, 10, 5,
and 2.5 µL) were dotted onto a nitrocellulose membrane and hybridized
at 50°C with a tissue kallikrein-specific
oligonucleotide probe.
Statistical Analysis
All data are expressed as
mean±SEM.
Multivariate repeated-measures ANOVA was performed
to test for interaction between time and grouping factor. Then
univariate ANOVA 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.
Least-squares analysis was used to calculate the correlation
between variables. 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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TopAbstractIntroductionMethods Results Discussion References |
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Cardiovascular Effects of Early Postnatal Hoe 140 Administration
As shown in Fig 1
(left), female
rats given Hoe 140
since the early phases of postnatal life showed higher SBP levels than
control animals at 7 and 9 weeks of age (125±2 versus 111±2
mm Hg
and 132±3 versus 116±2 mm Hg, respectively, P<.05).
In
male rats (Fig 1, right) a difference was found at 7 weeks
(122±4
versus 108±4 mm Hg, P<.05) but not at 9 weeks (123±4
versus 119±4 mm Hg, P=NS). At this stage, direct
measurement of MBP revealed higher levels in Hoe 140–treated rats
(female rats, 117±2 versus 107±3 mm Hg in control animals; male
rats, 119±3 versus 106±2 mm Hg in control animals;
P<.05
for both comparisons), whereas no difference was detected in HR. The
between-group differences in SBP and MBP were confirmed at 12
weeks, and they were more pronounced in females (SBP, 137±2 versus
110±2 mm Hg in control animals; MBP, 121±2 versus 100±3
mm Hg in
control animals; P<.01 for both comparisons) compared with
male rats (SBP, 130±3 versus 113±3 mm Hg in control animals;
MBP,
116±3 versus 104±2 mm Hg in control animals; P<.05
for
both comparisons).
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) or Hoe 140 (
) from early
phases of life. Values are mean±SEM. 
P<.05 vs
vehicle-treated group.
As shown in Table 1, the body weight
of Hoe 140–treated
female rats was greater than that of control animals at 10 days and
this difference persisted until 12 weeks of age. In males, a
between-group difference in body weight gain was detected after
weaning.
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As shown in Table 2, at 9 weeks of age urinary
volume
and urinary albumin excretion were similar between groups.
However, in 3 rats (2 females) urinary albumin exceeded the
upper limits of normal distribution (45, 35, and 80 mg/d per 100 g body
wt). Urinary creatinine excretion was significantly reduced
in Hoe 140–treated rats compared with control animals, whereas urinary
sodium excretion was higher.
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In Hoe 140–treated female rats, the ratio of heart weight to body weight was already increased at 9 weeks of age (330±6 versus 305±5 mg/100 g body wt in control animals, P<.05), and this difference persisted at 12 weeks of age (340±7 versus 308±4 mg/100 g body wt in control animals, P<.05); however, it was necessary to prolong Hoe 140 administration in male rats to develop heart hypertrophy (291±5 versus 287±8 in control animals at 9 weeks, P=NS; 300±4 versus 275±4 mg/100 g body wt in control animals at 12 weeks, P<.05). The ratio of heart weight to body weight was significantly correlated with MBP in female (r=.61 and r=.60 at 9 and 12 weeks, respectively, P<.01) but not in male rats (r=.18 and r=.15 at 9 and 12 weeks, respectively, P=NS).
At 12 weeks of age, the ratio of kidney weight to body weight was lower in Hoe 140–treated rats (females, 318±2 versus 358±5 mg/100 g body wt in control animals; males, 323±4 versus 366±6 mg/100 g body wt in control animals, P<.05 for both comparisons).
Renal and Urinary Kallikrein Levels in Male and Female
Rats
As shown in Table 3, urinary kallikrein excretion
was significantly greater in female compared with male rats at 8 weeks
and 7 months of age, and intrarenal immunoreactive kallikrein levels
were elevated in female compared with male rats at 7 months only. As
shown in Fig 2, urinary kallikrein
activity–creatinine ratio declined slowly in male rats
from approximately 13 (range, 13 to 16) to 57 (range, 57 to 60) days of
age. A biphasic pattern was observed in female rats, so that a sex
difference in urinary kallikrein activity became evident after
puberty.
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Northern Blot Analysis of Renal and Cardiac Kallikrein
in Rats
We analyzed the expression of tissue kallikrein in the
kidney and heart (ventricle) of male and female rats. Renal kallikrein
mRNA levels were higher in females than in male rats (Fig 3,
left). There was no difference in the mRNA levels of
tissue kallikrein in heart (ventricle) of female rats compared with
male rats. Densitometric tracings showed that the renal kallikrein mRNA
levels in female rats were 1.8-fold higher compared with male rats. The
same blot, which was stripped and reprobed with ß-actin cDNA,
showed no significant difference in the ß-actin mRNA levels in
both the kidney and heart of both male and female rats (Fig 3,
right).
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Densitometry measurements of RT-PCR dot blot analysis showed that tissue kallikrein mRNA levels in the kidney of 8-week-old female Wistar rats were 1.7-fold higher than those found in male Wistar rats.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The differential effects of testosterone and estrogen on rat tissue kallikrein gene expression creates a sexual dimorphism, the functional significance of which is as yet unclear.22 23 24 Our interest in evaluating a possible sexual dimorphism of kallikrein gene expression in cardiovascular tissue was stimulated by the demonstration of a local KKS in rat hearts,25 26 arteries, and veins,27 28 suggesting contribution of locally generated kinins to the regulation of cardiovascular function.29 We extended these observations by showing that kallikrein mRNA content in the heart is similar in adult female and male rats, whereas kallikrein gene expression is higher in the kidney of females. Specificity of this observation is confirmed by the finding that no sex difference was detected in renal ß-actin mRNA levels. In addition, RT-PCR dot blot analysis showed that renal kallikrein mRNA levels are 1.7-fold higher in 8-week-old female rats compared with male rats, and the urinary excretion of immunoreactive tissue kallikrein was found to be elevated at 8 weeks and at 7 months of age. On the other hand, intrarenal kallikrein content was not increased in female rats at 8 weeks of age. The latter finding implies that in young female rats the rates of synthesis and release of tissue kallikrein are equally accelerated compared with male rats, thus maintaining renal concentrations of the enzyme unaltered. The higher intrarenal concentrations of immunoreactive kallikrein found in 7-month-old female rats might be the consequence of an additional increase in the rate of synthesis.
Consistent with the possibility of a regulatory effect of
female sex hormones are our previous findings that ovariectomy
decreases renal and urinary kallikrein and renal kallikrein mRNA and
that estrogen restores renal kallikrein expression to preovariectomy
levels.6 Recently, we found that kininogen mRNA levels are
2.0-fold higher in the liver of female Sprague-Dawley rats
compared with male rats, whereas no sex difference was detected in
1-antitrypsin mRNA levels (J.C., unpublished
observations, 1995). Sex hormones are known to affect BP as they do
with other quantitative traits such as height and weight and this may
explain why (1) females tend to have lower BP levels than males, (2) BP
tends to rise after menopause, (3) hypertension develops less rapidly
in female than in male animals, and (4) the latter difference is
abolished by gonadectomy.8 9 10 Although
the
precise mechanisms underlying the cardiovascular
effects of female sex hormones remain unclear, their ability to
stimulate endothelium-dependent vasorelaxation
could be relevant in this context.7 The KKS, which acts by
stimulating the release of endothelium-derived
relaxing factors and prostaglandins and by directly
influencing renal excretory function, may also be implicated. Intrinsic
renal factors have been proposed to be responsible for determining
sexual BP dimorphism, and their dependency on the influence of sex
hormones is suggested by experiments in which renal transplantation, by
swapping kidneys from females into males and vice versa, failed to
alter the male-female BP difference of spontaneously hypertensive
rats.30
A recent study from our group demonstrated that early, long-term blockade of bradykinin receptors induces a modest but significant increase in BP in Wistar rats.15 Since this effect was associated with sodium retention and body fluid volume expansion, we concluded that endogenous kinins play an important role in the regulation of cardiovascular function. Besides confirming the results described above, the present study shows that the effects of Hoe 140 on BP are greater in females rats. The demonstration of a sexual dimorphism in the cardiovascular responses to early blockade of bradykinin receptors together with the observation of an enhanced expression of kallikrein gene in the female kidney suggest that kinins are functionally more important in the female rat. It is unlikely that cardiovascular effects induced by Hoe 140 are related to actions other than bradykinin antagonism since this compound proved to be very specific and devoid of toxicity.14 15 16 An adverse effect on growth was observed only when the antagonist was given during fetal development, in combination with very high salt intake.31 Obviously, the best approach would be to determine whether bradykinin replacement can normalize the effects of Hoe 140, but this is precluded by the fact that the latter compound blocks the action of endogenously and exogenously administered bradykinins at the receptor level.
Sodium retention, which has been shown to be responsible for the BP increase after long-term treatment with Hoe 140 in male rats,15 might have occurred at earlier stages of life in female rats, thus explaining the greater and earlier BP effects in the female sex. A finding that indirectly supports this possibility is that body weight gain was enhanced after the first weeks of life in female rats given the antagonist, whereas in male rats this pattern became evident only after weaning. On the other hand, water and sodium balance studies were not performed across these phases of life; thus we cannot say at which stage body fluid volume expansion occurred in female rats. We found that urinary sodium excretion was increased in Hoe 140–treated rats compared with control rats at 9 weeks of age. This finding is only apparently in contradiction with what is stated above. Indeed, urinary collections were obtained from rats deprived of food, the only possible source of sodium. It is likely that anti-natriuresis, consequent to acute sodium deprivation, was less pronounced in Hoe 140–treated rats because of a preexistent positive sodium balance in these animals.15 Consistent with this interpretation is the finding that prolongation of sodium deprivation for 5 days corrects the fluid volume expansion and normalizes the elevated BP levels of rats given lifelong treatment with Hoe 140.15
Nephrogenesis is still incomplete in the newborn rat, and postnatal renal maturation is associated with enhanced synthesis of active kallikrein, B2-receptor, and angiotensin-converting enzyme, with their mRNA expression increasing severalfold from the prenatal levels to the weaning.32 33 Sex-related differences in perinatal hormonal surge and in the responses of pups to maternal hormonal and behavioral changes during suckling might exert differential effects on the developmental maturation of the renal KKS in male and female rats. Whether this contributes to the blood pressure dimorphism observed in response to chronic bradykinin-receptor blockade remains to be elucidated. Consistent with a trophic role of bradykinin in postnatal renal development is the observation that early, lifelong blockade by Hoe 140 suppresses renal growth and reduces urinary creatinine excretion, whereas similar treatment of adult rats does not.15 In the present study, we were able to confirm these results in male rats and also to show similar effects of the antagonist in female rats. We extended the observation of a higher ratio of heart weight to body weight in rats given an early administration of Hoe 14015 by showing that this effect occurs earlier in female rats. These differences may be explained by the greater hemodynamic load observed in females, as also suggested by the observation of a significant correlation between heart weight and BP levels in female but not male rats.
How could the present results be extrapolated to humans? Besides being higher than in men, urinary kallikrein excretion is inversely related to BP levels in women as indicated by the following findings: (1) urinary kallikrein decreases after menopause (whereas BP tends to rise),6 (2) urinary kallikrein increases during pregnancy (a condition associated with systemic and renal vasodilation),34 35 and (3) renal kallikrein synthesis and excretion are reduced, whereas excretion of kallistatin (a potent kallikrein inhibitor) is increased in pregnancy-induced hypertension.36 Therefore, the KKS might play a protective role in the development of an excessive rise in BP during a woman's life and in particular at the occasion of pregnancy. The latter possibility is supported by the observation that Hoe 140 prevents the late gestational decrease in BP and the increase in renal blood flow that occur in salt-loaded pregnant rats.31
In conclusion, the present study confirms that the KKS plays an important role in the development of the adult cardiovascular phenotype, particularly in the female rat.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported in part by grants from the Minister of Universities and Scientific Research, the National Research Council (CNR) targeted project "Prevention and Controls of Disease Factors" (No. 91.001173.41), and the National Institutes of Health (HL-29397).
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