Bradykinin does not mediate cutaneous active vasodilation during heat stress in humans.

To test the hypothesis that bradykinin effects cutaneous active vasodilation during hyperthermia, we examined whether the increase in skin blood flow (SkBF) during heat stress was affected by blockade of bradykinin B(2) receptors with the receptor antagonist HOE-140. Two adjacent sites on the forearm were instrumented with intradermal microdialysis probes for local delivery of drugs in eight healthy subjects. HOE-140 was dissolved in Ringer solution (40 microM) and perfused at one site, whereas the second site was perfused with Ringer alone. SkBF was monitored by laser-Doppler flowmetry (LDF) at both sites. Mean arterial pressure (MAP) was monitored from a finger, and cutaneous vascular conductance (CVC) was calculated (CVC = LDF/MAP). Water-perfused suits were used to control body temperature and evoke hyperthermia. After hyperthermia, both microdialysis sites were perfused with 28 mM nitroprusside to effect maximal vasodilation. During hyperthermia, CVC increased at HOE-140 (69 +/- 2% maximal CVC, P < 0.01) and untreated sites (65 +/- 2% maximal CVC, P < 0.01). These responses did not differ between sites (P > 0.05). Because the bradykinin B(2)-receptor antagonist HOE-140 did not alter SkBF responses to heat stress, we conclude that bradykinin does not mediate cutaneous active vasodilation.     

Interplay between parasite cysteine proteases and the host kinin system modulates microvascular leakage and macrophage infection by promastigotes of the Leishmania donovani complex

Kinins, the vasoactive peptides proteolytically liberated from kininogens, were recently recognized as signals alerting the innate immune system. Here we demonstrate that Leishmania donovani and Leishmania chagasi, two etiological agents of visceral leishmaniasis (VL), activate the kinin system. Intravital microscopy in the hamster cheek pouch showed that topically applied promastigotes induced macromolecular leakage (FITC-dextran) through postcapillary venules. Peaking at 15 min, the parasite-induced leakage was drastically enhanced by captopril (Cap), an inhibitor of angiotensin-converting enzyme (ACE), a kinin-degrading metallopeptidase. The enhanced microvascular responses were cancelled by HOE-140, an antagonist of the B2 bradykinin receptor (B2R), or by pre-treatment of promastigotes with the irreversible cysteine proteinase inhibitor N-methylpiperazine-urea-Phe-homoPhe-vinylsulfone-benzene (N-Pip-hF-VSPh). In agreement with the above-mentioned data, the promastigotes vigorously induced edema in the paw of Cap-treated J129 mice, but not Cap-B2R-/- mice. Analysis of parasite-induced breakdown of high molecular weight kininogens (HK), combined with active site-affinity-labeling with biotin-N-Pip-hF-VSPh, identified 35-40 kDa proteins as kinin-releasing cysteine peptidases. We then checked if macrophage infectivity was influenced by interplay between these kinin-releasing parasite proteases, kininogens, and kinin-degrading peptidases (i.e. ACE). Our studies revealed that full-fledged B2R engagement resulted in vigorous increase of L. chagasi uptake by resident macrophages. Evidence that inflammatory macrophages treated with HOE-140 became highly susceptible to amastigote outgrowth, assessed 72 h after initial macrophage interaction, further suggests that the kinin/B2R activation pathway may critically modulate inflammation and innate immunity in visceral leishmaniasis.     

Diuretic response to acute hypertension is blunted during angiotensin II clamp

Acute hypertension inhibits proximal tubule (PT) fluid reabsorption. The resultant increase in end proximal flow rate provides the error signal to mediate tubuloglomerular feedback autoregulation of renal blood flow and glomerular filtration rate and suppresses renal renin secretion. To test whether the suppression of the renin-angiotensin system during acute hypertension affects the magnitude of the inhibition of PT fluid and sodium reabsorption, plasma ANG II levels were clamped by infusion of the angiotensin-converting enzyme (ACE) inhibitor captopril (12 microg/min) and ANG II after pretreatment with the bradykinin B(2) receptor blocker HOE-140 (100 microg/kg bolus). Because ACE also degrades bradykinin, HOE-140 was included to block effect of accumulating vasodilatory bradykinins during captopril infusion. HOE-140 increased the sensitivity of arterial blood pressure to ANG II: after captopril infusion without HOE-140, 20 ng x kg(-1) x min(-1) ANG II had no pressor effect, whereas with HOE-140, 20 ng x kg(-1) x min(-1) ANG II increased blood pressure from 104 +/- 4 to 140 +/- 6 mmHg. ANG II infused at 2 ng x kg(-1) x min(-1) had no pressor effect after captopril and HOE-140 infusion ("ANG II clamp"). When blood pressure was acutely increased 50-60 mmHg by arterial constriction without ANG II clamp, urine output and endogenous lithium clearance increased 4.0- and 6.7-fold, respectively. With ANG II clamp, the effects of acute hypertension were reduced 50%: urine output and endogenous lithium clearance increased two- and threefold, respectively. We conclude that HOE-140, an inhibitor of the B(2) receptor, potentiates the sensitivity of arterial pressure to ANG II and that clamping systemic ANG II levels during acute hypertension blunts the magnitude of the pressure diuretic response.     

Effect of bradykinin on membrane properties of guinea pig bronchial parasympathetic ganglion neurons

The effect of bradykinin on membrane properties of parasympathetic ganglion neurons in isolated guinea pig bronchial tissue was studied using intracellular recording techniques. Bradykinin (1-100 nM) caused a reversible membrane potential depolarization of ganglion neurons that was not associated with a change in input resistance. The selective bradykinin B(2) receptor antagonist HOE-140 inhibited bradykinin-induced membrane depolarizations. Furthermore, the cyclooxygenase inhibitor indomethacin attenuated bradykinin-induced membrane depolarizations to a similar magnitude ( approximately 70%) as HOE-140. However, neurokinin-1 and -3 receptor antagonists did not have similar inhibitory effects. The ability of bradykinin to directly alter active properties of parasympathetic ganglion neurons was also examined. Bradykinin (100 nM) significantly reduced the duration of the afterhyperpolarization (AHP) that followed four consecutive action potentials. The inhibitory effect of bradykinin on the AHP response was reversed by HOE-140 but not by indomethacin. These results indicate that bradykinin can stimulate airway parasympathetic ganglion neurons independent of sensory nerve activation and provide an alternative mechanism for regulating airway parasympathetic tone.     

Intrarenal infusion of bradykinin elicits a pressor response in conscious rats via a B2-receptor mechanism.

Bradykinin (BK) is a peptide known to activate afferent nerve fibers from the kidney and elicit reflex changes in the cardiovascular system. The present study was specifically designed to test the hypothesis that bradykinin B2 receptors mediated the pressor responses elicited during intrarenal bradykinin administration. Pulsed Doppler flow probes were positioned around the left renal artery to measure renal blood flow (RBF). A catheter, to permit selective intrarenal administration of BK, was advanced into the proximal left renal artery. The femoral artery was cannulated to measure mean arterial pressure (MAP). MAP, heart rate (HR), and RBF were recorded from conscious unrestrained rats while five-point cumulative dose-response curves during an intrarenal infusion of BK (5-80 microg x kg(-1) x min(-1)) were constructed. Intrarenal infusion of BK elicited dose-dependent increases in MAP (maximum pressor response, 26+/-3 mmHg), accompanied by a significant tachycardia (130+/-18 beats/min) and a 28% increase in RBF. Ganglionic blockade abolished the BK-induced increases in MAP (maximum response, -6+/-5 mmHg), HR (maximum response 31+/-14 beats/min), and RBF (maximum response, 7+/-2%). Selective intrarenal B2-receptor blockade with HOE-140 (50 microg/kg intrarenal bolus) abolished the increases in MAP and HR observed during intrarenal infusion of BK (maximum MAP response, -2+/-3 mmHg; maximum HR response, 15+/-11 beats/min). Similarly, the increases in RBF were prevented after HOE-140 treatment. In fact, after HOE-140, intrarenal BK produced a significant decrease in RBF (22%) at the highest dose of BK. Results from this study show that the cardiovascular responses elicited by intrarenal BK are mediated predominantly via a B2-receptor mechanism.     

Cardiac interstitial bradykinin and mast cells modulate pattern of LV remodeling in volume overload in rats

In the current study, interstitial fluid (ISF), bradykinin (BK), and angiotensin II (ANG II) levels were measured using cardiac microdialysis in conscious, nonsedated rats at baseline and at 48 h and 5 days after each of the following: sham surgery (sham, n = 6), sham + administration of ANG-converting enzyme inhibitor ramipril (R, n = 6), creation of aortocaval fistula (ACF, n = 6), ACF + R (n = 6), and ACF + R + BK2 receptor antagonist (HOE-140) administration (n = 6). At 5 days, both ISF ANG II and BK increased in ACF rats (P < 0.05); however, in ACF + R rats, ISF ANG II did not differ from basal levels and ISF BK increased greater than threefold above baseline at 2 and 5 days (P < 0.05). Five days after ACF, the left ventricular (LV) weight-to-body weight ratio increased 30% (P < 0.05) in ACF but did not differ from sham in ACF + R and ACF + R + HOE-140 rats despite similar systemic arterial pressures across all ACF groups. However, ACF + R + HOE-140 rats had greater postmortem wall thickness-to-diameter ratio and smaller cross-sectional diameter compared with ACF + R rats. There was a significant increase in mast cell density in ACF and ACF + R rats that decreased below sham in ACF + R + HOE-140 rats. These results suggest a potentially important interaction of mast cells and BK in the cardiac interstitium that modulates the pattern of LV remodeling in the acute phase of volume overload.     

The bradykinin B1 receptor antagonist R-954 inhibits Ehrlich tumor growth in rodents

The present study investigated the effects of a new bradykinin B₁ receptor antagonist, R-954, on the development of Ehrlich ascitic tumor (EAT) induced by the intraperitoneal inoculation of EAT cells in mice and the formation of a solid tumor by the subcutaneous injection of the cells in rat paw. The development of the tumor was associated with an increase in mouse total cell counts in bone marrow (10.8-fold), ascitic fluid (14.6-fold), and blood (12.6-fold). R-954 (2 mg/kg, s.c.) significantly reduced the ascitic fluid volume (63.7%) and the mouse weight gain (30.5%) after 10 consecutive days of treatment. The B₁ antagonist as well as the anti-neoplasic drug vincristine also significantly inhibited the increase in total cell count in bone marrow, ascitic fluid, and blood. R-954 reduced significantly the total protein extravasation (57.3%), the production of nitric oxide (56%), PGE₂ production (82%), and TNFα release (85.7%) in mice peritoneal cavity whereas vincristine reduced the release of these inflammatory mediators by 84-94%. The increase in paw edema after intraplantar injection of EAT cells was reduced by approximately 52% by either R-954 or vincristine treatment. In conclusion, this study presents for the first time the antitumoral activity of a new bradykinin B₁ receptor antagonist on ascitic and solid tumors induced by Ehrlich cell inoculation in mice and rats.     

研究报告：缓激肽上调豚鼠肠道黏膜下神经丛环氧合酶2的表达

目的缓激肽和缓激肽B2受体在肠神经系统中起重要作用。缓激肽通常参与肠道的炎症反应和神经保护,这种作用取决于缓激肽诱导前列腺素的形成。环氧合酶1 (COX1)和环氧合酶2 (COX2)催化花生四烯酸转化为前列腺素。本研究旨在探讨缓激肽刺激对豚鼠肠神经前列腺素E2 (p GE2)释放和COX2表达的影响及信号机制。方法本文通过免疫荧光检测肠神经细胞中COX2与神经细胞标志物Anti-Hu和ch AT的表达;采用PCR及蛋白质印迹(Western blot)检测不同条件下缓激肽刺激对COX2表达的影响;使用缓激肽B1受体的选择性拮抗剂Leu-8和B2受体的选择性拮抗剂HOE-140,研究缓激肽影响COX2表达的信号机制;利用COX2选择性拮抗剂NS398和COX1拮抗剂FR12207,观察COX2在缓激肽诱导p EG2释放的作用。结果 COX2与神经细胞标志物Anti-Hu和ch AT在肠神经细胞上共同表达,缓激肽可通过B2受体诱导肠神经细胞COX2的表达。缓激肽刺激引起的肠神经细胞p GE2的释放与COX2表达升高密切相关。结论缓激肽通过B2R影响肠道黏膜下神经丛COX2的表达,肠道缓激肽...     

Bradykinin receptor antagonists attenuate neointimal proliferation postangioplasty

Bradykinin has been linked to the development of restenosis in response to vascular injury. We therefore examined the effect of bradykinin on vascular smooth muscle cell growth and neointimal formation in organ culture. Bradykinin stimulated both RNA and DNA synthesis (by 175%) in smooth muscle cells from either porcine or human coronary arteries and increased cell number in a concentration-dependent manner. Both p42/44 mitogen-activated protein kinase (MAPK) and p38 kinase were also activated. Treatment with [Hyp(3),Tyr(Me)(8)]bradykinin, a B(2) receptor agonist, stimulated thymidine incorporation by 146%, whereas B(1)-selective Lys-des-Arg(9)-bradykinin had no effect. Addition of the B(2) antagonist HOE-140 reduced the stimulation by 56%, whereas B(1)-selective des-Arg-HOE-140 had no significant effect. Similarly, HOE-140 attenuated angioplasty-induced neointimal formation in organ culture with an efficacy approaching 100% inhibition. These experiments suggest that bradykinin promotes smooth muscle proliferation after vascular injury, presumably via B(2) receptor-dependent activation of MAPK family pathways, and may explain the negative outcome of angiotensin converting enzyme inhibitor therapy on restenosis in nonrodent models.     

Synergistic effect of angiotensin-(1-7) on bradykinin arteriolar dilation in vivo

The interaction between angiotensin [Ang-(1-7)] and bradykinin (BK) was determined in the mesentery of anesthetized Wistar rats using intravital microscopy. Topical application of BK and Ang-(1-7) induced vasodilation that was abolished by the BK B2 receptor antagonist HOE-140 and the Ang-(1-7) antagonist A-779, respectively. BK (1 pmol)-induced vasodilation, but not SNP and ACh responses, was potentiated by Ang-(1-7) 10 pmol and 100 pmols. The effect of 100 pmol of Ang-(1-7) on BK-induced vasodilation was abolished by A-779, indomethacin, and L-nitroarginine methyl esther, whereas losartan was without effect. Enalaprilat treatment enhanced the BK- and Ang-(1-7)-induced vasodilation and the potentiating effect of Ang-(1-7) on BK vasodilation. The potentiation of BK-induced vasodilation by Ang-(1-7) is a receptor-mediated phenomenon dependent on cyclooxygenase-related products and NO release.     

The Bradykinin B2 receptor is required for full expression of renal COX-2 and renin

Angiotensin converting enzyme (ACE) inhibition leads to increased levels of bradykinin, cyclooxygenase-2 (COX-2), and renin. Since bradykinin stimulates prostaglandin release, renin synthesis may be regulated through a kinin-COX-2 pathway. To test this hypothesis, we examined the impact of bradykinin B2 receptor (B2R) gene disruption in mice on kidney COX-2 and renin gene expression. Kidney COX-2 mRNA and protein levels were significantly lower in B2R-/- mice by 40-50%. On the other hand, renal COX-1 levels were similar in B2R-/- and +/+ mice. Renal renin protein was 61% lower in B2R-/- compared to B2R+/+ mice. This was accompanied by a significant reduction in renin mRNA levels in B2R-/- mice. Likewise, intrarenal angiotensin I levels were significantly lower in B2R-/- mice compared to B2R+/+ mice. In contrast, kidney angiotensin II levels were not different and averaged 261+/-16 and 266+/-15fmol/g in B2R+/+ and B2R-/- mice, respectively. Kidney angiotensinogen, AT1 receptor and ACE activity were not different between B2R+/+ and B2R-/- mice. The results of these studies demonstrate suppression of renal renin synthesis in mice lacking the bradykinin B2R and support the notion that B2R regulation of COX-2 participates in the steady-state control of renin gene expression.     

Neuronal differentiation of P19 embryonal carcinoma cells modulates kinin B2 receptor gene expression and function

Kinins are vasoactive oligopeptides generated upon proteolytic cleavage of low and high molecular weight kininogens by kallikreins. These peptides have a well established signaling role in inflammation and homeostasis. Nevertheless, emerging evidence suggests that bradykinin and other kinins are stored in the central nervous system and may act as neuromediators in the control of nociceptive response. Here we show that the kinin-B2 receptor (B2BKR) is differentially expressed during in vitro neuronal differentiation of P19 cells. Following induction by retinoic acid, cells form embryonic bodies and then undergo neuronal differentiation, which is complete after 8 and 9 days. Immunochemical staining revealed that B2BKR protein expression was below detection limits in nondifferentiated P19 cells but increased during the course of neuronal differentiation and peaked on days 8 and 9. Measurement of [Ca(2+)](i) in the absence and presence of bradykinin showed that most undifferentiated cells are unresponsive to bradykinin application, but following differentiation, P19 cells express high molecular weight neurofilaments, secrete bradykinin into the culture medium, and respond to bradykinin application with a transient increase in [Ca(2+)](i). However, inhibition of B2BKR activity with HOE-140 during early differentiation led to a decrease in the size of embryonic bodies formed. Pretreatment of differentiating P19 cells with HOE-140 on day 5 resulted in a reduction of the calcium response induced by the cholinergic agonist carbamoylcholine and decreased expression levels of M1-M3 muscarinic acetylcholine receptors, indicating crucial functions of the B2BKR during neuronal differentiation.     

Bradykinin receptor 2 extends inflammatory cell recruitment in a model of acute gouty arthritis

The aim of this study was determine the effect of bradykinin receptor antagonism on MSU crystal-induced chemokine production and leukocyte recruitment. Mice were injected intraperitoneally with monosodium urate (MSU) crystals ± bradykinin B1- or B2 receptor antagonists, Des-Arg-HOE-140 and HOE-140, respectively. MSU crystal-induced chemokine production and leukocyte recruitment in the peritoneum were measured over 24h and B1 and B2 receptor expression on leukocytes and peritoneal membrane was determined by flow cytometry and fluorescence microscopy. Data analysis showed that only B2 receptor antagonism decreased monocyte and neutrophil infiltration 24 h post MSU crystal administration. Decreased leukocyte infiltration was associated with reduced monocyte (CCL2) chemokine levels. MSU crystal-induced damage to the surrounding visceral membrane was also attenuated in the presence of B2 receptor antagonism. Together, these data show that bradykinin receptor 2 plays a role in maintaining MSU crystal-induced leukocyte infiltration and membrane permeability and identify the B2 receptor as a potential therapeutic target for managing inflammation in gout.     

Blockade of early and late retinal biochemical alterations associated with diabetes development by the selective bradykinin B1 receptor antagonist R-954

The chronic hyperglycemia measured alongside diabetes development is associated with significant long-term damage and failure of various organs. In the present study it was shown that hyperglycemia induced early and long term increases in nitric oxide (NO) levels, kallikrein activity and vascular capillary permeability measured as plasma extravasation, and decreases of Na/K ATPase activity in diabetic rat retina 4 and 12 weeks after streptozotocin (STZ) injection. Treatment of the animals for 5 consecutive days with a novel selective bradykinin B(1) receptor (BKB(1)-R) antagonist R-954 (2mg/kg s.c) at the end of the 4 and 12 week periods highly reduced NO, kallikrein and capillary permeability and increased Na/K ATPase activity in the retina. These results suggest that the BKB(1)-R receptor subtype is over-expressed during the streptozotocin-induced development of diabetes in rat retina as evidenced by the inhibitory effects of the BKB(1)-R antagonist R-954 on NO, kallikrein and vascular permeability increases as well as Na/K ATPase decreases. The beneficial role of the BKB(1)-R antagonist R-954 for the treatment of the diabetic retinopathy is also suggested.     

Role of bradykinin B2 and B1 receptors in the local, remote, and systemic inflammatory responses that follow intestinal ischemia and reperfusion injury

The administration of bradykinin may attenuate ischemia and reperfusion (I/R) injury by acting on B(2)Rs. Blockade of B(2)R has also been shown to ameliorate lesions associated with I/R injury. In an attempt to explain these contradictory results, the objective of the present work was to investigate the role of and interaction between B(1) and B(2) receptors in a model of intestinal I/R injury in mice. The bradykinin B(2)R antagonist (HOE 140) inhibited reperfusion-induced inflammatory tissue injury and delayed lethality. After I/R, there was an increase in the expression of B(1)R mRNA that was prevented by HOE 140. In mice that were deficient in B(1)Rs (B(1)R(-/-) mice), inflammatory tissue injury was abrogated, and lethality was delayed and partially prevented. Pretreatment with HOE 140 reversed the protective anti-inflammatory and antilethality effects provided by the B(1)R(-/-) phenotype. Thus, B(2)Rs are a major driving force for B(1)R activation and consequent induction of inflammatory injury and lethality. In contrast, activation of B(2)Rs may prevent exacerbated tissue injury and lethality, an effect unmasked in B(1)R(-/-) mice and likely dependent on the vasodilatory actions of B(2)Rs. Blockade of B(1)Rs could be a more effective strategy than B(2) or B(1)/B(2) receptor blockade for the treatment of the inflammatory injuries that follow I/R.     

B(1) and B(2) bradykinin receptors on adventitial fibroblasts of cerebral arteries are coupled to recombinant eNOS

Our previous ex vivo and in vivo studies reported that expression of the recombinant endothelial nitric oxide (NO) synthase (eNOS) gene in adventitial fibroblasts recovers NO production in arteries without endothelium in response to bradykinin. The present study was designed to characterize subtypes of bradykinin receptors on adventitial fibroblasts coupled to the activation of recombinant eNOS. Endothelium-denuded segments of canine basilar arteries were transduced with beta-galactosidase (beta-Gal) gene or eNOS gene ex vivo, using a replication-defective adenoviral vector (10(10) plaque-forming units/ml) for 30 min at 37 degrees C. Twenty-four hours later, isometric force recording or cGMP measurement was carried out. B(1) bradykinin receptor agonist (des-Arg(9)-bradykinin, 10(-10)-10(-8) mol/l) did not significantly affect vascular tone in control or beta-Gal gene-transduced canine basilar arteries without endothelium. In contrast, this agonist caused concentration-dependent relaxations in recombinant eNOS gene-transduced arteries without endothelium. Relaxations to B(1) receptor agonist in the eNOS arteries were abolished by B(1) receptor antagonist (des-Arg(9)-[Leu(8)]bradykinin, 6 x 10(-9) mol/l) but not by B(2) receptor antagonist (Hoe-140, 5 x 10(-8) mol/l). Bradykinin did not significantly alter vascular tone in control or beta-gal arteries without endothelium, whereas this peptide (10(-11)-10(-8) mol/l) induced concentration-dependent relaxations, as well as an increase in cGMP formation in endothelium-denuded eNOS-transduced arteries. Stimulatory effects of bradykinin were prevented in the presence of a B(2) receptor antagonist but not in the presence of a B(1) receptor antagonist. B(1) and B(2) receptor antagonists had no effect on relaxations to substance P, confirming the selectivity of the compounds. Our results suggest that B(1) and B(2) bradykinin receptors are coupled to activation of recombinant eNOS expressed in adventitial fibroblasts.     

In vitro sensitization of human bronchus by beta2-adrenergic agonists

Incubation of human distal bronchi from 48 patients for 15 h with 10(-7) M fenoterol induced sensitization characterized by an increase in maximal contraction to endothelin-1 (ET-1) and acetylcholine (ACh). Incubation of human bronchi with 10(-6), 3 x 10(-6), and 10(-5) M forskolin (an adenyl cyclase activator) reproduced sensitization to ET-1 and ACh. The sensitizing effect of fenoterol was inhibited by coincubation with gliotoxine (a nuclear factor-kappaB inhibitor), dexamethasone, indomethacin (a cyclooxygenase inhibitor), GR-32191 (a TP prostanoid receptor antagonist), MK-476 (a cysteinyl leukotriene type 1 receptor antagonist), SR-140333 + SR-48968 + SR-142801 (neurokinin types 1, 2, and 3 tachykinin receptor antagonists) with or without HOE-140 (a bradykinin B(2) receptor antagonist), SB-203580 (an inhibitor of the 38-kDa mitogen-activated protein kinase, p38(MAPK)), or calphostin C (a protein kinase C blocker). Our results suggest that chronic exposure to fenoterol induces proinflammatory effects mediated by nuclear factor-kappaB and pathways involving leukotrienes, prostanoids, bradykinin, tachykinins, protein kinase C, and p38(MAPK), leading to the regulation of smooth muscle contraction to ET-1 and ACh.     

Blockade of Bradykinin receptors worsens the dystrophic phenotype of <Emphasis Type="Italic">mdx</Emphasis> mice: differential effects for B1 and B2 receptors

The Kallikrein Kinin System (KKS) is a vasoactive peptide system with known functions in the maintenance of tissue homeostasis, renal function and blood pressure. The main effector peptide of KKS is Bradykinin (BK). This ligand has two receptors: a constitutive B2 receptor (B2R), which has been suggested to have anti-fibrotic effects in renal and cardiac models of fibrosis; and the inducible B1 receptor (B1R), whose expression is induced by damage and inflammation. Inflammation and fibrosis are hallmarks of Duchenne muscular dystrophy (DMD), therefore we hypothesized that the KKS may play a role in this disease. To evaluate this hypothesis we used the mdx mouse a model for DMD. We blocked the endogenous activity of the KKS by treating mdx mice with B2R antagonist (HOE-140) or B1R antagonist (DesArgLeu⁸BK (DALBK)) for four weeks. Both antagonists increased damage, fibrosis, TGF-β and Smad-dependent signaling, CTGF/CCN-2 levels as well as the number of CD68 positive inflammatory cells. B2R blockade also reduced isolated muscle contraction force. These results indicate that the endogenous KKS has a protective role in the dystrophic muscle. The KKS may be a new target for future therapies to reduce inflammation and fibrosis in dystrophic muscle.