(Hypertension. 1995;25:524-530.)
© 1995 American Heart Association, Inc.
Articles |
Brain Kallikrein-Kinin System Abnormalities in Spontaneously Hypertensive Rats
From the Departments of Pharmacology (I.M.K., D.H.M., J.S., H.S.M., P.J.P.) and Medicine (H.S.M.), Medical University of South Carolina, Charleston.
Correspondence to Philip J. Privitera, PhD, Department of Pharmacology, Medical University of South Carolina, 171 Ashley Ave, Charleston, SC 29425.
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Abstract The objective of the present study was to determine whether the brain kallikrein-kinin system differs between spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) and if so, whether any detected differences occur before the development of hypertension in SHR. We measured cerebrospinal fluid levels of various components of the system in adult and young prehypertensive SHR and WKY. Cerebrospinal fluid kinin concentration and appearance rate were higher in SHR. Cerebrospinal fluid active kallikrein level and kininogenase activity were also higher in adult SHR. In addition, cerebrospinal fluid kinin concentration and appearance rate were higher in prehypertensive, 5- to 6-week-old SHR compared with age-matched WKY. However, no differences in cerebrospinal fluid kallikrein or kininogenase activity were observed between the two strains of young rats. Cerebrospinal fluid kinin concentration was higher in young versus adult rats of the same strain. In WKY, cerebrospinal fluid kallikrein also decreased with age although cerebrospinal fluid kallikrein concentration did not decrease in young and adult SHR. Together, these data suggest that there is a hyperactive kallikrein-kinin system in the brain of SHR that may contribute to the hypertensive state in this animal model.
Key Words: kallikrein-kinin system • central nervous system • cerebrospinal fluid • blood pressure • kallikrein • rats, inbred SHR
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All components of the kallikrein-kinin system, ie, kallikrein,1 2 3 kinin,4 5 6 kininases,7 8 kininogens,9 and kinin receptors,10 11 12 are present within the brain. Microinjection of bradykinin into specific brain areas, such as the lateral septal area,13 third ventricle,14 hypothalamic nuclei,15 fourth ventricle,16 area postrema,17 and rostral ventrolateral medulla,18 results in a hypertensive response. In addition, activation of the brain kallikrein-kinin system by afferent vagal stimulation or by intracerebroventricular administration of melittin, a peptide from bee venom that activates membrane-bound kallikrein, increases blood pressure in association with increased cerebrospinal fluid (CSF) kinin levels.19 20 The pressor effect of melittin can be blocked by aprotinin, an inhibitor of kallikrein-like serine proteinases, and by a bradykinin receptor antagonist.20 21 Intracerebroventricular administration of tissue kallikrein also produces a hypertensive response in rats that is accompanied by an increase in brain tissue kinin content.22 These studies support the concept that a brain kallikrein-kinin system may play a role in the central regulation of the cardiovascular system.
Although the mechanism for the kinin-mediated pressor response has not been elucidated, it is suggested that kinins produce a hypertensive response through an increase in central sympathetic outflow.23 In addition, adrenergic,24 cholinergic,25 histaminergic,24 and serotonergic26 agonists as well as prostaglandins23 and vasopressin27 are proposed to mediate the pressor response produced by central administration of kinins.
Evidence suggests that the brain kallikrein-kinin system may play a role in the central regulation of blood pressure in hypertensive rats. Injection of bradykinin into the brain ventricles or rostral ventrolateral medulla produces a significantly greater pressor response in spontaneously hypertensive rats (SHR) than in normotensive Wistar-Kyoto rats (WKY) or Sprague-Dawley rats.16 18 Intracerebroventricular administration of a kininase II inhibitor (captopril) produces a hypertensive response only in SHR and not in normotensive WKY or Sprague-Dawley rats.28 The pressor response to intracerebroventricular captopril is blocked by a kinin receptor antagonist, suggesting a causal relationship between the increased blood pressure and a possible increase in brain kinin concentration after inhibition of kininase II.28
Little information exists regarding the activity of the endogenous brain kallikrein-kinin system in normal and hypertensive rats. It has recently been reported that CSF of SHR contains increased concentrations of kininogen and bradykinin compared with that of WKY rats.29 In addition, we recently demonstrated30 that total tissue kallikrein is higher in the CSF of adult SHR than in age-matched normotensive WKY rats. Collectively, these findings suggested the need for a further, more-detailed evaluation of the brain kallikrein-kinin system.
In the present study, we measured and compared blood pressure, CSF kinin and tissue kallikrein concentrations, and kininogenase activity in adult (18 to 19 weeks old) and young (5 to 6 weeks old) SHR and WKY. Tissue kallikrein was also measured in selected brain regions of adult and young rats of both strains.
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Animals
Experiments were performed on age-matched 5- to 6-week-old and 18- to 19-week-old male SHR and WKY (Charles River Laboratories Inc, Wilmington, Mass). All rats were housed in facilities accredited by the American Association for Accreditation of Laboratory Animal Care, and all animal studies were approved by the Institutional Animal Care and Use Committee.
Blood Pressure Measurement and CSF Collection
Rats were anesthetized with sodium pentobarbital (Nembutal, 50
mg/kg IP; Abbott Laboratories) and mean arterial pressure (MAP) was
measured from a polyvinyl cannula inserted into a femoral artery and
connected to a pressure transducer (Statham Laboratories, Inc) coupled
to a polygraph (Grass Instrument Co). Rectal temperature was maintained
between 37° and 37.5°C. After a 30-minute stabilization period, MAP
was recorded continuously for 10 minutes, and the highest and lowest
pressure readings during this time were averaged. The animals were
allowed to recover for 2 to 3 days before CSF collection. Rats were
again anesthetized with sodium pentobarbital (50 mg/kg IP), and the
head was fixed in a stereotaxic frame (David Kopf Instruments). The
atlanto-occipital membrane was exposed, and a cannula with a 26-gauge
needle tip attached was inserted into the cisterna magna. Freely
flowing CSF was collected into ice-cold polypropylene tubes for
measurement of kinin, active tissue kallikrein, and kininogenase
activity. CSF volume was measured for determination of CSF flow rate
over each collection period. CSF samples found to be free of blood, as
determined by spectrophotometric analysis for
hemoglobin,31 were stored at -20°C until assayed.
Biochemical Measurements
Measurement of Kallikrein in CSF
Active tissue kallikrein in CSF was measured with the use of a
rat urinary kallikrein radioimmunoassay (RIA) previously
described,32 which uses a monoclonal antibody hybridoma
clone (V1C3) that recognizes only active tissue
kallikrein but not the zymogen prokallikrein.33 The
monoclonal antibody used does not cross-react with trypsin,
collagenase, human urinary kallikrein, rat urinary esterase
A32, or T-kininogenase (personal communication, J.
Chao, 1994) in the RIA procedure. Purified rat urinary kallikrein was
labeled with 125I by the chloramine T
method,34 purified on a Sephadex G-100 column, and eluted
with 0.05 mol/L phosphate buffer (pH 7.4) containing 0.5% bovine serum
albumin (BSA). Purified rat urinary kallikrein was used to construct
standard curves ranging from 0.16 to 20.00 ng per tube. Standards,
samples, and iodinated kallikrein were diluted in assay buffer (0.14
mol/L NaCl in 0.01 mol/L Na2HPO4, pH
7.0, 1% BSA). Total incubation volume was 0.8 mL containing 10 000
cpm 125I–rat urinary kallikrein, unlabeled standard or
sample, and a monoclonal antibody to rat urinary kallikrein
([V1C3] 1:5 000 000 final
dilution).33 After 48 hours of incubation, 15 µL of a
second antibody (sheep anti-mouse IgG) was added, and tubes were
incubated for an additional 24 hours. The tubes were centrifuged at
5000 rpm for 30 minutes, the supernatant was aspirated, and the
precipitate was counted in a gamma scintillation spectrometer. With the
use of this RIA, no cross-reactivity was observed with trypsin,
collagenase, rat urinary esterase A, or human urinary kallikrein.
Measurement of Kininogenase Activity in CSF
Kininogenase activity was measured according to the method of
Shimamoto et al35 with modifications. Aliquots (150 µL)
of CSF, 30 µL of assay buffer (0.1 mol/L Tris-HCl, pH 8.0), and 20
µL (2.5 mg/mL in assay buffer) of purified low molecular weight
bovine kininogen (Seikagaku Kogyoco) solution were added to
polypropylene tubes. Blanks contained only buffer and kininogen. The
mixture was incubated at 37°C for 24 hours. The tubes were then
boiled for 10 minutes followed by immersion in ice. The contents of the
tubes were diluted 1:100 in kinin RIA buffer, and duplicate aliquots
were assayed with the use of a kinin RIA.36
Measurement of Kinin in CSF
CSF was collected into polypropylene tubes containing the
following inhibitors: 80 µg/mL soybean trypsin inhibitor, 40 µg/mL
polybrene, 1000 kallikrein inhibitor units/mL trasylol, 2 mg/mL
EDTA, and 1 mg/mL 1,10-phenanthroline. Immediately after collection,
the samples were mixed and frozen at -20°C until assayed. The RIA
was a modification19 20 of that described by Shimamoto et
al.36 Synthetic Tyr8-bradykinin was labeled
with 125I by the chloramine T method.34
Iodinated bradykinin was applied to a 0.7x20.0-cm column of superfine
Sephadex G-25 and eluted with 0.01 mol/L acetic acid containing 0.5%
BSA. 125I-Tyr8-Bradykinin, antiserum, and
standards were diluted in assay buffer (phosphate-buffered saline, pH
7.0, 30 mmol/L EDTA, 3 mmol/L phenanthroline, 0.1% egg albumin). The
final assay incubation volume was 0.40 mL containing 0.10 mL of CSF
sample or standard (2.0 pg to 0.5 ng per tube), antiserum
(1:1 000 000 final dilution), and 125I-bradykinin
(10 000 cpm). After incubation for 14 to 16 hours at 4°C, free and
antibody-bound ligands were separated with the use of polyethylene
glycol and bovine gamma globulin (final concentrations, 12.5% and
0.25%, respectively). The recovery of bradykinin added to rat CSF
immediately after CSF collection and before the sample was frozen was
97±7% (n=6).
Measurement of Kallikrein in Brain Tissue
For collection of brain tissue, 0.1 mL heparin (1000 U/mL) was
injected into the right atrium of anesthetized rats. After 30 to 60
seconds, a cannula was placed into the left atrium, the vena cava was
cut, and 0.9% ice-cold saline was infused. Saline infusion was
continued until the effluent from the vena cava was free of blood. The
cranium was opened and the brain carefully removed and dissected to
obtain the hypothalamus, medulla oblongata, pons, and cerebellum.
Tissue samples were placed into polypropylene tubes and stored at
-20°C until assayed. Tissues were thawed, minced, and homogenized in
glass centrifuge tubes (10x75 mm) containing 1000 µL ice-cold
phosphate-buffered saline (pH 7.4). The tissues were sonicated for 4 to
5 seconds (model W185 F, Heat Systems-Ultrasonic Inc) with the glass
tubes in ice. Homogenized tissue samples were then centrifuged at
15 000 rpm. The supernatant was aspirated, and 800 µL supernatant
was lyophilized. The lyophilized samples were reconstituted in
600 µL rat urinary kallikrein RIA buffer (1% BSA in
phosphate-buffered saline, pH 7.4). Active tissue kallikrein in the
brain regions was measured with the use of the RIA described above.
Total protein concentration in the samples was measured by the method
of Lowry et al37 using BSA as the standard.
Statistical Analysis
Results were analyzed using Student's t test for
independent groups or by ANOVA followed by post hoc comparisons using
Scheffé's method. All values presented in the text and in
figures are group mean±SEM.
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Kinin Concentration in CSF
In adult WKY and SHR, MAP was 135±4 and 189±6 mm Hg, respectively (P<.025, Fig 1A). CSF kinin concentration in SHR (108±9 pg/mL) was also higher than in WKY (70±11 pg/mL, P<.025, Fig 1B). CSF production during the collection period was not different between WKY (18.7±1.1 µL/min) and SHR (20.0±1.9 µL/min, Fig 1C). Thus, the appearance of kinin in CSF was higher in adult SHR (2.20±0.23 versus 1.27±0.20 pg/min, P<.05, Fig 1D).
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P<.05 compared with
WKY.In young rats, MAP was also significantly higher in SHR (98±3 versus 78±2 mm Hg, P<.001, Fig 2A). CSF kinin concentration in these SHR (1800±243 pg/mL) was more than twice that of WKY (726±123 pg/mL, P<.001, Fig 2B). No difference in CSF production was noted over the collection period (WKY, 3.1±0.1 µL/min; SHR, 3.2±0.1 µL/min; Fig 2C). Thus, kinin appearance was also higher in young SHR (5.93±0.86 pg/min) than in WKY (2.17±0.42 pg/min, P<.01, Fig 2D).
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Comparisons of arterial pressure and CSF kinins in young and adult rats of each strain are shown in Table 1. MAP of the young animals of each strain was significantly lower than that of adults, but SHR blood pressures were higher than WKY pressures at each age. On the other hand, CSF kinin concentration was more than 10-fold higher in the young (726±123 pg/mL) versus adult (70±11 pg/mL, P<.001) WKY and 18-fold higher in the young (1800±243 pg/mL) versus adult (108±9 pg/mL, P<.001) SHR. In addition, the appearance rate of kinin in the CSF of young SHR (5.93±0.86 pg/min) was more than twice that of adult SHR (2.20±0.23 pg/min, P<.01), but there was no difference between young (2.17±0.42 pg/min) and adult (1.27±0.20 pg/min) WKY.
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CSF flow rate was lower in young (SHR, 3.3±0.1 µL/min; WKY, 3.1±0.1 µL/min) than in adult (SHR, 20.1±1.9 µL/min; WKY, 18.7±1.1 µL/min; P<.001) rats of each strain. There was a positive correlation between CSF flow rate and body weight of the animals (r=.966, P<.001, n=60). The body weights of both young WKY and SHR were 87±2 g, whereas those of the adult WKY and SHR were 323±13 and 332±14 g, respectively. Thus, when the CSF kinin appearance rates are expressed in terms of kilograms of body weight, the rates in young rats (SHR, 69.30±9.90 pg/kg per minute; WKY, 26.63±4.87 pg/kg per minute) were significantly higher (P<.01) than in adults of both strains (SHR, 6.74±0.82 pg/kg per minute; WKY, 4.06±0.66 pg/kg per minute, respectively). In other words, the brains of young rats of each strain release from 6- to 10-fold more kinin than those of adults of the same strain.
Kallikrein in CSF
Kallikrein concentration and appearance rate in CSF (Fig 3) were higher in 18- to 19-week-old SHR (4.83±0.61
ng/mL and 64.85±7.78 pg/kg per minute, respectively) than in WKY
(2.81±0.26 ng/mL, P<.01, and 36.84±3.71 pg/kg per minute,
P<.01, respectively). However, neither CSF kallikrein
concentration nor appearance rate was significantly different between
young SHR (4.29±0.40 ng/mL and 125.94±13.43 pg/kg per minute,
respectively) and WKY (5.08±0.42 ng/mL and 151.85±12.50 pg/kg per
minute, respectively, Fig 4).
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When CSF kallikrein concentration and appearance rate were compared in young versus adult rats (Table 2), values were generally higher in young than adult rats of the same strain with the exception of CSF kallikrein concentration in SHR, where there was no difference between the age groups.
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Kininogenase in CSF
CSF kininogenase activity was also measured for determination of
whether active kallikrein measured by RIA in rat CSF can generate
kinin. No difference in kininogenase activity was found between the
young SHR and WKY (16.51±4.73 versus 14.68±5.61 ng kinin/mL per 24
hours). The data show that a lack of difference in kallikrein measured
by RIA in the CSF of young SHR and WKY is accompanied by a comparable
lack of difference in kinin-generating activity. However, we previously
reported that kininogenase activity in the CSF of adult SHR was
significantly higher than in WKY (2.46±0.62 versus 0.33±0.06 ng
kinin/mL per 24 hours, P<.01).30
Ratios of CSF kininogenase to active kallikrein were approximately 3.8 and 2.9 in young SHR and WKY, respectively, whereas in adult rats (using previously published kininogenase activity data30 ) ratios were 0.51 in SHR and 0.12 in WKY. Measurement of the kininogenase activity of purified rat urinary kallikrein in a concentration similar to that found in CSF of adult rats yielded a ratio of kininogenase to active kallikrein of approximately 5.0.
When the CSF kininogenase activity determined in young rats in the present study was compared with previously published data30 in adult rats, CSF kininogenase activity was more than 44-fold higher in young than in adult WKY (14.68±5.61 versus 0.33±0.06 ng kinin/mL per 24 hours, respectively; P<.01). In SHR, CSF kininogenase activity was more than sixfold higher in young than in adult rats (16.51±4.73 versus 2.46±0.62 ng kinin/mL per 24 hours, respectively; P<.01).
Kallikrein in Specific Brain Regions
Kallikrein did not differ between adult SHR and WKY in the
medulla (1.04±0.04 versus 1.07±0.03 ng/mg protein, respectively),
hypothalamus (1.89±0.10 versus 1.88±0.13 ng/mg protein,
respectively), pons (0.65±0.03 versus 0.64±0.03 ng/mg protein,
respectively), and cerebellum (0.36±0.02 versus 0.36±0.02 ng/mg
protein, respectively). Similarly, no differences in kallikrein levels
were observed between young SHR and WKY in the medulla (0.81±0.03
versus 0.78±0.02 ng/mg protein, respectively), hypothalamus
(1.68±0.08 versus 1.57±0.07 ng/mg protein, respectively), pons
(0.79±0.03 versus 0.71±0.03 ng/mg protein, respectively), and
cerebellum (0.31±0.01 versus 0.29±0.01 ng/mg protein,
respectively).
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We designed the present study to determine whether the brain kallikrein-kinin system differs between SHR and normotensive WKY and if so, whether any detected differences occur before the development of hypertension in SHR. We measured CSF levels of various components of the system in adult and young prehypertensive SHR and WKY. CSF kinin levels were higher in adult SHR than in WKY. Active kallikrein levels and kininogenase activity were also higher in CSF of adult SHR. In addition, CSF kinin levels were higher in young prehypertensive SHR than in age-matched WKY. However, no differences in CSF active kallikrein concentration or kininogenase activity were found between the two rat groups at this age. The increased CSF kinin in young prehypertensive SHR suggests increased brain kallikrein-kinin system activity before the development of hypertension.
The finding that CSF active kallikrein is higher in adult SHR than in WKY extends our earlier observation that the total kallikrein level in adult SHR was higher than in adult WKY.30 Active kallikrein was measured by radioimmunoassay with the use of a monoclonal antibody to rat urinary kallikrein that does not recognize the inactive zymogen prokallikrein.33 The data suggest that local kinin-generating activity in the brain may be higher in adult SHR than in WKY. Our observation that CSF kininogenase activity was higher in adult SHR than in WKY30 is consistent with this view. In young rats, both active kallikrein levels and kininogenase activity in CSF were not different between the two strains. However, age-related reductions in both CSF active kallikrein levels and kininogenase activity were observed in WKY, whereas only kininogenase activity was observed to be lower in adult than in young SHR.
It appears that most of the kininogenase activity observed in rat CSF may represent tissue kallikrein activity because aprotinin completely inhibited the kininogenase activity in the CSF of adults rats, whereas soybean trypsin inhibitor inhibited only 28% of the activity.30 To our knowledge, CSF kininogenase activity has been measured in only one other study, in Sprague-Dawley rats.21 In that study, CSF kininogenase activity was higher (0.13±0.05 ng kinin/mL per minute) than that in the present study (0.068±0.001 ng kinin/mL per minute). However, semipurified dog kininogen was used as a substrate rather than the bovine low molecular weight kininogen used here.
In the present study, although the CSF active kallikrein measured by RIA in adult SHR was 1.6 times higher than in adult WKY, kinin-generating activity in SHR is reported to be 10 times higher.30 Moreover, a comparison of the calculated ratios of kininogenase to active kallikrein in young versus adult rats indicates that the ratios were higher in young WKY and SHR (2.9 and 3.8, respectively) than their adult counterparts (0.12 and 0.51, respectively). The ratio of kininogenase to active kallikrein for purified rat urinary kallikrein used as the standard in the RIA for active kallikrein was 5, suggesting that the enzymatic activity of the immunologically determined active kallikrein in adult rats is greatly reduced compared with that in young rats. The reason for this apparent discrepancy is not clear but may be related to the presence of higher concentrations of inhibitors of tissue kallikrein38 39 in the CSF of adult rats than in the young rats of the same strain. The finding of lower kinin-generating activity in adult rats, however, is consistent with the lower CSF kinin levels found in adult versus young rats of the same strain.
Although CSF levels of active kallikrein are higher in adult SHR than WKY, there were no differences between SHR and WKY in active kallikrein concentrations in the brain regions studied. It is possible that the method of kallikrein measurement in these large regions may not be sensitive enough to detect differences in localized areas within these regions. Alternatively, it is possible that the higher kallikrein level in CSF of SHR reflects an increased kallikrein turnover in the brain, with increased release into the CSF but no change in brain tissue content.
The finding that kinin levels in the CSF of adult SHR are higher than in WKY is in agreement with the higher kallikrein and kininogenase activity in SHR. An increased concentration of bradykinin in CSF of adult SHR was also observed by other researchers.29 CSF kinin concentration and appearance rate were also higher in young SHR than in age-matched WKY, but no differences in CSF kallikrein or kininogenase activity were noted between the strains. The reason for this disparity is not clear. Since kinin level is related to both kinin generation and kinin metabolism, differences noted between the strains may be related to either or both of these factors. Previous studies indicate that brain kininase II activity is higher in adult SHR than in WKY, whereas in young rats, kininase II activity is essentially the same.40 The observation that intracerebroventricular administration of the kininase II inhibitor captopril increases blood pressure in SHR but not in WKY28 supports the notion that kininase II activity may be higher in adult SHR. In contrast, Lindsey et al16 suggested that brain kininase activity is higher in adult WKY than in SHR. Their conclusion was based on the fact that a kininase-resistant analogue of bradykinin, Lys-Lys-bradykinin, was 10 times more potent than bradykinin in its pressor action in the fourth ventricle of WKY but only twice as potent in SHR. Thus, the role of augmented brain kininase activity in one or the other strain is uncertain.
Since T-kinin can cross-react with the antiserum to bradykinin in the RIA used in our studies,41 it is possible that the higher CSF kinin levels in SHR are due to T-kinin. T-kininogen (a kininogen unique to rats) levels in the circulation and liver of newborn rats are significantly higher than in adult rats.42 Thus, the high level of immunoreactive kinin measured in CSF of young rats may be due in part to the presence of T-kinin. Since T-kinin injected into brain ventricles of rats also produces a hypertensive response that is blocked by the kinin B2 receptor antagonist D-Arg0-Hyp3-Thi5,8-D-Phe7-bradykinin,43 44 a higher T-kinin concentration in young SHR versus WKY may still support the hypothesis for the present work.
Kallikrein-kinin system components in CSF may reflect release from periventricular brain regions. Moreover, the differences found in concentrations between WKY and SHR suggest that such enhanced activity within the brain of SHR might contribute to their hypertension. However, the origin of the system components measured in the CSF is unknown. Bradykinin-immunoreactive cell bodies are found in rat hypothalamus,4 and immunoreactive bradykinin is widely distributed in the brain, with highest levels in the pituitary, hypothalamus, and medulla.5 6 Kallikrein is located in specific hypothalamic nuclei and ependymal cells lining the third ventricle.3 Moreover, kallikrein is present in various regions, with the highest concentrations being in the pituitary, pineal, and hypothalamus and lower levels in the cortex, brain stem, and cerebellum.2 Kininase activity is widely distributed in rat brain, with activity being highest in the cerebellum, pituitary, and striatum followed by the midbrain, medulla oblongata, and hippocampus.45 46 The lowest kininase activity is in the hypothalamus and cortex.45 46
In summary, the present data show that CSF kinin and kallikrein levels are higher in adult SHR than in age-matched normotensive WKY. Moreover, an increased CSF kinin level is detected in young prehypertensive SHR before the development of hypertension, although there are no differences in CSF kallikrein or kininogenase activity between the two strains at this age. Together, these data suggest that a hyperactive brain kallikrein-kinin system in SHR may contribute to the hypertensive state in this rat model.
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Acknowledgments |
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This work was supported by National Heart, Lung, and Blood Institute grants HL-41921 and HL-17705 and a Medical University of South Carolina Biomedical Research Support grant.
Received November 23, 1993; first decision January 10, 1994; accepted December 16, 1994.
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