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1 Baker Heart Research Institute, Melbourne, Victoria 8008; and 2 Centre for Inflammatory Diseases, Monash University, Clayton, Victoria 3168, Australia
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Bradykinin is a vasoactive peptide that has been shown to increase the permeability of the cerebral microvasculature to blood-borne macromolecules. The two zinc metalloendopeptidases EC 3.4.24.15 (EP 24.15) and EC 3.4.24.16 (EP 24.16) degrade bradykinin in vitro and are highly expressed in the brain. However, the role that these enzymes play in bradykinin metabolism in vivo remains unclear. In the present study, we investigated the role of EP 24.15 and EP 24.16 in the regulation of bradykinin-induced alterations in microvascular permeability. Permeability of the cerebral microvasculature was assessed in anesthetized Sprague-Dawley rats by measuring the clearance of 70-kDa FITC dextran from the brain. Inhibition of EP 24.15 and EP 24.16 by the specific inhibitor N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Aib-Tyr-p-aminobenzoate (JA-2) resulted in the potentiation of bradykinin-induced increases in cerebral microvessel permeability. The level of potentiation was comparable to that achieved by the inhibition of angiotensin-converting enzyme. These findings provide the first evidence of an in vivo role for EP 24.15/EP 24.16 in brain function, specifically in regulating alterations in microvessel permeability induced by exogenous bradykinin.
HOE 140; EP 24.15; EP 24.16; microvascular permeability
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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BRADYKININ is a vasoactive peptide with potent effects on the microvasculature, including arteriolar vasodilation and increased vascular permeability (18). This peptide has a very short half-life in the circulation, reflecting its rapid inactivation by several peptidases. The predominant peptidases (kininases) that degrade bradykinin in the circulation are thought to include angiotensin-converting enzyme (ACE, EC 3.4.15.1), neutral endopeptidase (NEP, EC 3.4.24.11), aminopeptidase P (APP, EC 3.4.11.9), and carboxypeptidase N (CPN, EC 3.4.17.3) (22). In addition to these enzymes, we have recently shown that the ubiquitously distributed zinc metalloendopeptidases EC 3.4.24.15 (EP 24.15) and EC 3.4.24.16 (EP 24.16) can degrade bradykinin in the circulation. We used a novel, specific inhibitor of these enzymes, N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Aib-Tyr-p-aminobenzoate (JA-2) (20), to demonstrate that inhibition of EP 24.15/EP 24.16 potentiates the pressor response to intravenous bradykinin in conscious rabbits (23). This was the first indication that EP 24.15 and EP 24.16 might play a role in bradykinin metabolism in the systemic circulation. However, it remains unknown whether these effects extend to the predominant site of bradykinin activity, the microcirculation.
EP 24.15 and EP 24.16 are very two very closely related enzymes that have considerable sequence identity and similar endogenous substrate specificities (21). Given the similarity between these peptidases, particularly within the active site motif, it has been difficult to develop specific, potent inhibitors that can distinguish between EP 24.15 and EP 24.16 activity in vivo. Indeed, although the stable inhibitor JA-2 does not inhibit any other zinc metalloendopeptidases to a significant degree, this inhibitor does not select between EP 24.15 [inhibitory constant (Ki) = 23 nM] and EP 24.16 (Ki = 610 nM) at the doses required to inhibit them in vivo (20). The substrate similarity and the difficulty in developing selective in vivo inhibitors for EP 24.15 and EP 24.16 has made it difficult to discern the individual tissue and cell distribution of these enzymes, but also more importantly, the functions of EP 24.15 and EP 24.16 in physiological processes.
The role that a particular kininase plays in the metabolism of bradykinin is dependent on its localization and the presence of other peptidases in the tissue (22). For example, bradykinin administered intravenously is rapidly cleared from the circulation mainly by ACE expressed in the lungs and NEP expressed in the kidney, respective tissues in which each of these enzymes is highly expressed (16, 22). Both EP 24.15 and EP 24.16 have high levels of activity in the brain (7, 8); however, the exact physiological function of these enzymes in the brain has not been elucidated. The high expression of these enzymes in the brain raises the possibility that they may regulate bradykinin activity in this tissue. Indeed, bradykinin is one of the few mediators that can modulate the permeability of the vasculature that supplies the brain (2). Under normal circumstances, molecular leakage across the cerebral endothelium is severely restricted (1, 2). However, exposure of the pial microvasculature to bradykinin has been shown to increase its permeability to intravascular tracers of a range of molecular sizes (19, 26, 31). Whether the high expression of EP 24.15 and EP 24.16 in the brain is associated with a role for these enzymes in the regulation of bradykinin activity in the cerebral microcirculation remains unknown.
The only zinc metalloendopeptidases that have been shown thus far to modulate bradykinin-induced alterations of cerebral microvascular permeability are ACE and NEP. The inhibition of ACE or NEP augments the increased cerebrovascular permeability elicited by bradykinin (19), indicating that these enzymes influence bradykinin metabolism in the cerebral microvasculature. However, the role that other peptidases such as EP 24.15 and EP 24.16 play in bradykinin degradation in the cerebral microvasculature has not been examined. Therefore, the aim of the present study was to assess the role of EP 24.15 and EP 24.16 in the regulation of the effects of bradykinin in the cerebral microvasculature by using JA-2, the inhibitor of both these enzymes.
To achieve this aim an open cranial window technique was used to examine the pial microvasculature (the surface vessels of the brain), and bradykinin was administered to these exposed microvessels. Recent studies have revealed the presence of bradykinin B2 receptors on the abluminal side of endothelial cells (10). Furthermore, bradykinin administered directly to the surface of the brain has repeatedly been observed to alter the function of the pial vasculature and indeed mediates a different response from luminally administered bradykinin (27, 28). A further rationale for the use of extravascular bradykinin administration is that it may mimic the generation of bradykinin that occurs within the brain parenchyma under pathological conditions (12, 24). With the use of this approach, these experiments have demonstrated that inhibition of EP 24.15 and EP 24.16 potentiates the bradykinin-induced increase in the permeability of the cerebral microvasculature, suggesting that these enzymes may regulate the function of bradykinin in this unique vasculature.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Male Sprague-Dawley rats weighing 200-250 g were used. Experiments were conducted in accordance with the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes (2000) and were approved in advance by the Baker Heart Research Institute Animal Ethics Committee.
The bradykinin B2-receptor antagonist D-Arg-[Hyp3,Thi5, D-Tic7,Oic8]bradykinin (HOE 140) (30) was a gift from Hoechst (Frankfurt, Germany). The EP 24.15/EP 24.16 specific inhibitor JA-2 was synthesized by Dr. G. Abbenante (Centre for Drug Design and Development, University of Queensland, Australia) as previously described (20). The intravascular tracer 70-kDa FITC dextran and the ACE inhibitor captopril were purchased from Sigma (Sigma Australia). Bradykinin was purchased from Auspep (Parkville, Victoria, Australia).
Surgical Procedures
Male Sprague-Dawley rats were anesthetized by intraperitoneal injection of a solution containing 8 mg/kg xylazine (Rompun 100, Bayer Australia) and 60 mg/kg ketamine hydrochloride (Parke Davis; Caringbah, New South Wales, Australia) diluted to volume with saline [0.9% (wt/vol) NaCl; Baxter; Old Toongabbie, New South Wales, Australia]. Additional anesthetic was administered intravenously as required. Animals were maintained at 37°C via a thermostat-controlled heating blanket, linked to a rectal temperature probe. The left femoral artery and vein were catheterized for arterial blood sampling and delivery of additional anesthetic or the intravascular tracer 70-kDa FITC dextran, respectively. The common carotid artery was catheterized to allow the measurement of mean arterial pressure (MAP).Cranial Window Preparation
To access the pial microvasculature, a cranial window was established in the right parietal cortex using methods described previously (14). Briefly, a midline incision was made in the skin and the skin retracted to the sides to expose the skull and muscle layers. Under a dissecting microscope, a rectangular section of bone in the right parietal cortex was thinned with a dental drill (014 size drill bit; Fine Science Tools, Vancouver, Canada) until the vessels underneath were visible. A stainless steel superfusion chamber, with inlet and outlet ports, was attached to the skin surrounding the cranial window using adhesive (Loctite 406 Instant Adhesive; Loctite Australia, Caringbah, New South Wales, Australia). The chamber was subsequently continuously superfused with artificial cerebrospinal fluid (CSF, in mM: 132 NaCl, 24.6 NaHCO3, 2.95 KCl, 1.4 MgSO4 · 7H2O, 3.71 sucrose, and 1.71 CaCl2), warmed to 37°C, and gassed with 12% O2-5% CO2-83% N2, at a flow rate of 0.8 ml/min. The thinned bone and the underlying dura were removed, exposing the underlying pial vasculature. The pial microvasculature was allowed to equilibrate for ~30-45 min after which the intravascular tracer was administered and the 60-min experimental period was commenced.Permeability of Pial Microvasculature
Permeability of the pial microvasculature was assessed by measuring the clearance (nl/s) of 70-kDa FITC dextran from the pial vessels into the suffused fluid as previously described (14). A bolus dose (125 mg/kg) of 70-kDa FITC-dextran (50 mg/ml; Sigma) was given at the start of the experimental period. The suffusate fluid (flow rate = 0.8 ml/min) was collected for the last minute of every 5-min period throughout the 60-min experimental period. Arterial blood samples (100 µl) were taken at 15-min intervals, and plasma was isolated by centrifugation. The concentration of fluorescence in the suffusate and plasma samples was measured on an fmax fluorescence microplate reader (
ex485 and em538) (Molecular Devices;
Sunnyvale, CA). Clearance (nl/s) was calculated as the ratio of
fluorescence (CSF) to fluorescence (plasma) × flow rate of the
CSF across the brain (14).
Experimental Protocol
Baseline and dose response to bradykinin superfusion. The baseline permeability of the pial microvasculature to 70-kDa FITC dextran was determined by measuring the clearance of the 70-kDa FITC dextran during superfusion of artificial CSF over the 60-min experimental period. To test the response of the pial microvasculature to bradykinin, pilot experiments were performed after the 60-min baseline experimental period. Bradykinin (10 and 100 µM) in artificial CSF was superfused across the brain for 5 min, and the clearance of 70-kDa FITC dextran was monitored for an additional 30 min.
Effect of bradykinin, the bradykinin B2 receptor antagonist (HOE 140), and EP 24.15/EP 24.16 inhibition (JA-2) on microvascular permeability. In experiments involving exposure to bradykinin, a 5-min superfusion of bradykinin (10 µM in artificial CSF solution) was administered, commencing 8 min into the experimental period, after which the superfusion was returned to normal CSF for the remainder of the experiment. Superfusion of JA-2 (10 µM in 0.04% DMSO in CSF) commenced at the start of the experimental period and continued until the superfusion of the bradykinin was finished, coinciding with the presence of bradykinin. In additional experiments, JA-2 was superfused for the entire 60-min experimental period. HOE 140 was given simultaneously as an intravenous bolus (10 µg/kg) and superfused across the brain in the artificial CSF buffer (10 nM). Superfusion of HOE 140 commenced at 0 min and continued until the termination of the bradykinin superfusion.
Effect of ACE inhibition (captopril) and EP 24.15/EP 24.16 inhibition (JA-2) on microvascular permeability. The effect of the ACE inhibitor captopril on the bradykinin-induced increase in permeability of the pial microvasculature was assessed in the absence and presence of JA-2. Captopril (10 µM in CSF) and JA-2 (10 µM in 0.04% DMSO in CSF) were superfused across the brain throughout the experimental period, whereas bradykinin was only superfused across the brain for 5 min.
Statistics
Data are expressed as means ± SE. P
0.05 was
considered to be significant. All the data were analyzed using the
statistical computer software package SIGMASTAT. Repeated-measures
ANOVA was used to compare between treatment groups across the entire
experimental period.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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MAP After 70-kDa FITC Dextran Administration
As FITC dextran has been reported to exert detrimental cardiovascular effects in rats, we first examined the effect of FITC dextran administration on systemic blood pressure. Thirty minutes after 70-kDa FITC dextran administration, MAP had not altered from basal levels (98 ± 9 mmHg). Subsequently, by 45 and 60 min, blood pressure had declined by 19 ± 4% and 26 ± 2% (means ± SE, n = 3), respectively. In subsequent experiments involving the use of bradykinin, the peak of the bradykinin-induced permeability response occurred 20-25 min after FITC dextran administration and was declining by 30 min. Therefore, the alterations in MAP at the later time points were unlikely to affect the rapid permeability responses examined in this study.EP 24.15/EP 24.16 Inhibition Potentiates Bradykinin-Induced Increase in Permeability
In initial experiments, we analyzed the clearance of 70-kDa FITC dextran in untreated animals. Baseline clearance of 70-kDa FITC-dextran over the 60-min experimental period was ~1 nl/s and increased slightly over time (Fig. 1). Pilot experiments revealed that 10 µM bradykinin induced a consistent submaximal increase in vascular permeability (data not shown). This dose was previously shown to significantly increase cerebral microvascular permeability in Wistar rats (19) and was used for all subsequent experiments.
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Administration of 10 µM bradykinin for 5 min resulted in a rapid but transient increase in permeability of the pial microvasculature to 70-kDa FITC dextran (PBK/Baseline < 0.001) (Fig. 1). The response peaked ~15 min after the initial exposure to bradykinin and returned to baseline levels 15-20 min later. At the peak of the response, there was a threefold increase in permeability above baseline levels. Administration of the bradykinin B2-receptor antagonist HOE 140 prevented the increase in permeability seen with bradykinin (Fig. 1).
To determine the role of EP 24.15/EP 24.16 in the regulation of
bradykinin in this setting, we next examined the effect of EP 24.15/EP
24.16 inhibition with the specific inhibitor JA-2. EP 24.15/EP 24.16 inhibition significantly potentiated the bradykinin-induced increase in
permeability of the pial microvasculature to 70-kDa FITC dextran
(PBK/BK+JA-2 = 0.005) (Fig.
2). The peak response observed in the
presence of JA-2 was twofold greater than the response induced by
bradykinin alone.
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We performed additional experiments to determine whether continuous
JA-2 administration further enhanced the increase in vascular permeability compared with short-term JA-2 administration. JA-2 superfusion for the entire experiment did not induce any additional increase in bradykinin-induced permeability above that induced by
short-term JA-2 superfusion (Fig. 3).
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ACE Inhibition Also Potentiates Effects of Bradykinin on Cerebral Vascular Permeability
Given that bradykinin is also targeted by other peptidases such as ACE, in further experiments we examined the effect of ACE inhibition on the bradykinin-induced increase in vascular permeability of the pial microvasculature. In previous studies, treatment with the ACE inhibitor captopril significantly enhanced the response of the pial microvasculature to bradykinin (19). Similarly, in the present experiments, captopril superfusion for the entire experimental period markedly potentiated the bradykinin-induced increase in permeability of the pial microvasculature to 70-kDa FITC dextran (PBK/captopril+BK = 0.008) (Fig. 4). However, the increase in permeability observed in response to continuous ACE inhibition was not significantly different from clearance levels observed after continuous treatment with JA-2 (PBK+captopril/BK+JA-2 = 0.068). We next examined the effect of combined inhibition of EP 24.15/EP 24.16 and ACE. Combined treatment with JA-2 and captopril did not increase the levels of bradykinin-induced permeability above treatment with captopril alone (PBK+captopril/BK+captopril+JA-2 = 0.97) (Fig. 5).
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In a final series of experiments, we examined the effect of EP 24.15/EP
24.16 inhibition and combined ACE and EP 24.15/EP 24.16 inhibition on
cerebral vascular permeability in the absence of exogenous bradykinin.
Treatment with JA-2, either for 13 min (Fig.
6) or continuously (data not shown), did
not alter clearance levels from baseline. Furthermore, combined
treatment with captopril and JA-2 was also without effect (Fig. 6).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Previous observations have revealed that both EP 24.15 and EP 24.16 are highly expressed in the brain (6, 7). Furthermore, these enzymes have been shown to have regulatory effects on the vasculature at a systemic level (20). Despite this, the role of EP 24.15 and EP 24.16 in the cerebral microvasculature remains unknown. This is particularly relevant given that these enzymes have been shown to be capable of metabolizing bradykinin, a mediator capable of increasing the permeability of the cerebral vasculature. EP 24.15 and EP 24.16 rapidly cleave bradykinin in vitro at its Phe5-Ser6 peptide bond (13, 15). The present results reveal the first evidence that EP 24.15/EP 24.16 regulate the activity of bradykinin in the cerebral microvasculature in vivo. Inhibition of EP 24.15/EP 24.16 with the specific inhibitor JA-2 potentiated the increase in permeability of the pial microcirculation induced by bradykinin. These findings indicate that EP 24.15/EP 24.16 have a previously unrecognized function in regulation of the effects of bradykinin on the cerebral vasculature.
The permeability of the cerebral vasculature is tightly controlled by structural and functional modifications of the cerebral endothelium and associated cells. Cerebral endothelial cells are joined by tight junctions and possess a paucity of pinocytotic vesicles relative to the endothelium of other vascular beds. The barrier is further regulated by the presence of astrocyte processes outside the basement membrane (1, 9) and by specific expression of transport proteins, which control molecular traffic across this barrier (4). In this study, we used the pial vasculature on the surface of the brain as a model for the analysis of blood-brain barrier function. In general, pial microvessels share many properties with cerebral vessels, including morphological features and high transendothelial electrical resistance; however, they lack the astrocytic ensheathment of cerebral microvessels and have subpopulations of tight junctions with small gaps between the membranes of adjacent cells (3). Therefore, it is possible that the pial microvasculature is more sensitive to changes in permeability than the cerebral microvasculature. Nevertheless, the pial microvasculature is one of the few vascular beds of the brain that can be accessed without trauma to the surrounding areas, and studies have shown that the barrier properties of the pial vasculature are similar to that of vessels present in the brain (3).
Bradykinin is capable of increasing blood flow and macromolecular leakage in the cerebral microvasculature during inflammatory responses (29). Given these abilities, regulation of bradykinin activity is critical, especially in the cerebral circulation, where increases in vascular permeability can have catastrophic consequences. It is conceivable that this vasculature may derive additional protection via site-specific expression of enzymes capable of degrading vasoactive mediators. The current findings provide support for this contention by demonstrating that EP 24.15/EP 24.16 are active in the regulation of bradykinin activity in the brain. Thus the high levels of expression of EP 24.15 and EP 24.16 may act as an additional form of protection for the cerebral vasculature by regulating the barrier-disrupting effects of bradykinin.
Of the group of zinc metalloendopeptidases capable of degrading bradykinin, only ACE and NEP have been shown previously to have bradykinin-degrading activity in vivo in the cerebral microvasculature (19). In the present study, the effect of inhibition of EP 24.15/EP 24.16 was compared with the effect of ACE inhibition, one of the best-characterized bradykinin-degrading enzymes. ACE inhibition strongly potentiated the bradykinin-induced increase in permeability of the pial microvasculature. Interestingly, superfusion of JA-2 throughout the entire experimental period potentiated the bradykinin-induced increase in microvascular permeability to a similar degree as that seen with ACE inhibition. It is noteworthy that, although inhibitors with similar structures to JA-2 have been shown in some cases to be metabolized in vivo to form potent ACE inhibitors (6), JA-2 is resistant to this process and does not inhibit ACE (20). Together these findings indicate that EP 24.15/EP 24.16 and ACE are of equivalent importance in the metabolism of bradykinin in this microvasculature.
Interestingly, the combined inhibition of EP 24.15/EP 24.16 and ACE did not increase permeability above that seen with either treatment alone, suggesting that the effects of these two treatments were not additive. There are a number of potential explanations for the absence of an additive effect in this system. This may reflect the limitations of the current assay. It is possible that the inhibition of either enzyme may have resulted in maximal blood-brain barrier opening, rendering any further increases in permeability induced by the dual inhibition of EP 24.15/EP 24.16 and ACE impossible to detect. This contention is supported by the finding that a 10-fold higher concentration of bradykinin did not increase permeability above that achieved by bradykinin and captopril (data not shown). Alternatively, as bradykinin is the target of several other peptidases such as NEP and CPN, it is conceivable that bradykinin continues to be degraded by one or more of these enzymes when both EP 24.15/EP 24.16 and ACE are inhibited. Finally, in additional experiments we also observed that baseline cerebral vascular permeability was not altered by inhibition of either EP 24.15/EP 24.16 or the combined inhibition of EP 24.15/EP 24.16 and ACE. This is not unexpected because the levels of circulating and tissue bradykinin are very low under normal conditions (5). Indeed these observations suggest that the level of bradykinin present under basal conditions is below that required to alter cerebral vascular permeability.
In previous studies we have shown that EP 24.15/EP 24.16 inhibition potentiates the pressor effect of intravenous bradykinin (23), indicating that these enzymes regulate bradykinin at a systemic level. The present experiments extend these observations by showing that bradykinin applied locally to a vascular bed can also be regulated by EP 24.15/EP 24.16. These enzymes are expressed in both soluble and membrane-bound forms, although it is unclear which form is responsible for the effects observed in these studies. Furthermore, the cellular source of these enzymes is unknown. However, the fact that in the present study, bradykinin administered locally is regulated by EP 24.15/EP 24.16 suggests that cells associated with the cerebral vasculature express the enzymes responsible for this activity. It is well recognized that neurons express both enzymes at high levels (11, 25). However, if endothelial cells expressed EP 24.15/EP 24.16, then this would localize these enzymes appropriately for them to regulate microvascular physiology. Indeed, EP 24.15/EP 24.16 activity has been detected in endothelial cells isolated from the sheep median eminence (13), raising the possibility that these enzymes are expressed in microvascular endothelial cells in vivo. Similarly, the subcellular localization of these enzymes in endothelial cells is not well understood and remains the focus of ongoing study in the laboratory (21). Thus the cellular source and subcellular location of EP 24.15/EP 24.16 responsible for the effects observed in the present experiments remain to be determined.
In conclusion, the findings of the present study provide clear evidence indicating that EP 24.15/EP 24.16 regulate the effect of exogenous bradykinin on cerebral vascular permeability. It remains to be determined whether these peptidases also mediate this effect on endogenous bradykinin released as part of an inflammatory response. Indeed, there is evidence that bradykinin is released into the local microvasculature in models of cerebral inflammation such as ischemia-reperfusion injury and exposure to bacterial endotoxin (12, 24). Future experiments will examine the role of EP 24.15/EP 24.16 in regulation of cerebral vascular permeability in these inflammatory responses.
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ACKNOWLEDGEMENTS |
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The authors acknowledge the assistance of Dr. G. Abbenante in the synthesis of JA-2.
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FOOTNOTES |
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This study was supported by funding from the National Health and Medical Research Council (NHMRC) of Australia. M. J. Hickey is a NHMRC R.D Wright Fellow.
Address for reprint requests and other correspondence: M. Hickey, Centre for Inflammatory Diseases, Dept. of Medicine, Monash Univ., 246 Clayton Rd., Clayton, Victoria 3168, Australia (E-mail: michael.hickey{at}med.monash.edu.au).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published February 13, 2003;10.1152/ajpheart.00948.2002
Received 6 November 2002; accepted in final form 6 February 2003.
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TOP
ABSTRACT
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MATERIALS AND METHODS
RESULTS
DISCUSSION
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