Effects Of Kinins Research Articles

Novel Insights into the Kallikrein-Kinin System in Fulminant Myocarditis: Physiological Basis and Potential Therapeutic Advances.

Fulminant myocarditis (FM) is characterized by rapid cardiac deterioration often instigated by an inflammatory cytokine storm. The kallikrein-kinin system (KKS) is a metabolic cascade known for releasing vasoactive kinins, such as bradykinin-related peptides, possessing diverse pharmacological activities that include inflammation, regulation of vascular permeability, endothelial barrier dysfunction, and blood pressure modulation. The type 1 and type 2 bradykinin receptors (B1R and B2R), integral components of the KKS system, mediate the primary biological effects of kinin peptides.This review aims to offer a comprehensive overview of the primary mechanisms of the KKS in FM, including an examination of the structural components, regulatory activation, and downstream signaling pathways of the KKS. Furthermore, it explores the involvement of the tissue kallikrein/B1R/inducible nitric oxide synthase (TK/B1R/iNOS) pathway in myocyte dysfunction, modulation of the immune response, and preservation of endothelial barrier integrity. The potential therapeutic advances targeting the inhibition of the KKS in managing FM will be discussed, providing valuable insights for the development of clinical treatment strategies.

Effect of Kinins on the Hepatic Oxidative Stress in Mice Treated with a Methionine-Choline Deficient Diet.

Non-alcoholic fatty liver is the leading cause of hepatic disease worldwide and ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) due to cell injury, oxidative stress, and apoptosis. The kinins' role in the liver has been studied in experimental fibrosis, partial hepatectomy, and ischemia-reperfusion and is related to cell death and regeneration. We investigated its role in experimental NASH induced by a methionine-choline deficient diet for 4 weeks. After that, liver perfusion was performed, and bradykinin (BK) or des-Arg9-BK was infused. Cell death was evaluated by cathepsin-B and caspase-3 activity and oxidative stress by catalase (CAT), glutathione S-transferase, and superoxide dismutase (SOD) activities, as well as malondialdehyde and carbonylated proteins. In control livers, DABK increased CAT activity, which was reversed by antagonist DALBK. In the NASH group, kinins tend to decrease antioxidant activity, with SOD activity being significantly reduced by BK and DABK. Malondialdehyde levels increased in all NASH groups, but carbonylated protein did not. DABK significantly decreased cathepsin-B in the NASH group, while caspase-3 was increased by BK in control animals. Our results suggest that B1R and/or B2R activation did not induce oxidative stress but affected the antioxidant system, reducing SOD in the NASH group.

Mass spectrometric study of variation in kinin peptide profiles in nasal fluids and plasma of adult healthy individuals

BackgroundThe kallikrein-kinin system is assumed to have a multifunctional role in health and disease, but its in vivo role in humans currently remains unclear owing to the divergence of plasma kinin level data published ranging from the low picomolar to high nanomolar range, even in healthy volunteers. Moreover, existing data are often restricted on reporting levels of single kinins, thus neglecting the distinct effects of active kinins on bradykinin (BK) receptors considering diverse metabolic pathways. A well-characterized and comprehensively evaluated healthy cohort is imperative for a better understanding of the biological variability of kinin profiles to enable reliable differentiation concerning disease-specific kinin profiles.MethodsTo study biological levels and variability of kinin profiles comprehensively, 28 healthy adult volunteers were enrolled. Nasal lavage fluid and plasma were sampled in customized protease inhibitor prespiked tubes using standardized protocols, proven to limit inter-day and interindividual variability significantly. Nine kinins were quantitatively assessed using validated LC–MS/MS platforms: kallidin (KD), Hyp4-KD, KD1-9, BK, Hyp3-BK, BK1-8, BK1-7, BK1-5, and BK2-9. Kinin concentrations in nasal epithelial lining fluid were estimated by correlation using urea.ResultsCirculating plasma kinin levels were confirmed in the very low picomolar range with levels below 4.2 pM for BK and even lower levels for the other kinins. Endogenous kinin levels in nasal epithelial lining fluids were substantially higher, including median levels of 80.0 pM for KD and 139.1 pM for BK. Hydroxylated BK levels were higher than mean BK concentrations (Hyp3-BK/BK = 1.6), but hydroxylated KD levels were substantially lower than KD (Hyp4-KD/KD = 0.37). No gender-specific differences on endogenous kinin levels were found.ConclusionsThis well-characterized healthy cohort enables investigation of the potential of kinins as biomarkers and would provide a valid control group to study alterations of kinin profiles in diseases, such as angioedema, sepsis, stroke, Alzheimer’s disease, and COVID-19.

Kinins and Their Receptors as Potential Therapeutic Targets in Retinal Pathologies.

The kallikrein-kinin system (KKS) contributes to retinal inflammation and neovascularization, notably in diabetic retinopathy (DR) and neovascular age-related macular degeneration (AMD). Bradykinin type 1 (B1R) and type 2 (B2R) receptors are G-protein-coupled receptors that sense and mediate the effects of kinins. While B2R is constitutively expressed and regulates a plethora of physiological processes, B1R is almost undetectable under physiological conditions and contributes to pathological inflammation. Several KKS components (kininogens, tissue and plasma kallikreins, and kinin receptors) are overexpressed in human and animal models of retinal diseases, and their inhibition, particularly B1R, reduces inflammation and pathological neovascularization. In this review, we provide an overview of the KKS with emphasis on kinin receptors in the healthy retina and their detrimental roles in DR and AMD. We highlight the crosstalk between the KKS and the renin–angiotensin system (RAS), which is known to be detrimental in ocular pathologies. Targeting the KKS, particularly the B1R, is a promising therapy in retinal diseases, and B1R may represent an effector of the detrimental effects of RAS (Ang II-AT1R).

Role of Kinins in Hypertension and Heart Failure.

The kallikrein–kinin system (KKS) is proposed to act as a counter regulatory system against the vasopressor hormonal systems such as the renin-angiotensin system (RAS), aldosterone, and catecholamines. Evidence exists that supports the idea that the KKS is not only critical to blood pressure but may also oppose target organ damage. Kinins are generated from kininogens by tissue and plasma kallikreins. The putative role of kinins in the pathogenesis of hypertension is discussed based on human mutation cases on the KKS or rats with spontaneous mutation in the kininogen gene sequence and mouse models in which the gene expressing only one of the components of the KKS has been deleted or over-expressed. Some of the effects of kinins are mediated via activation of the B2 and/or B1 receptor and downstream signaling such as eicosanoids, nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF) and/or tissue plasminogen activator (T-PA). The role of kinins in blood pressure regulation at normal or under hypertension conditions remains debatable due to contradictory reports from various laboratories. Nevertheless, published reports are consistent on the protective and mediating roles of kinins against ischemia and cardiac preconditioning; reports also demonstrate the roles of kinins in the cardiovascular protective effects of the angiotensin-converting enzyme (ACE) and angiotensin type 1 receptor blockers (ARBs).

Physiological effects of biostable kinin and CAPA analogs in the Chagas disease vector, Rhodnius prolixus

In the Chagas disease vector Rhodnius prolixus, the kinin and CAPA family of neuropeptides are implicated in feeding and diuresis-related behaviours, with Rhopr-kinins stimulating contractions of the midgut, salivary glands, and hindgut, and RhoprCAPA-2 functioning as an anti-diuretic hormone. The current study examined the effects of kinin and CAPA neuropeptides and their analogs on feeding and diuresis, and on hindgut contractions and MT fluid secretion in R. prolixus. The biostable Aib-containing kinin analog 2139[Φ1]wp-2 was found to have antifeedant effects, and to be more potent than Rhopr-kinin 2 in stimulating hindgut contractions. The CAPA analog 2129-SP3[Φ3]wp-2 induced the intake of a larger blood meal, and increased the rate of post-prandial rapid diuresis. RhoprCAPA-2, but not its analog, potentiated hindgut contractions induced by Rhopr-kinin 2. Potentiation was observed with the CAPA analog on 5-HT-stimulated increases in frequency of hindgut contractions, whereas RhoprCAPA-2 inhibited this 5-HT-mediated stimulation. The CAPA analog induced hindgut contractions and prevented the inhibition induced by RhoprCAPA-2 on 5-HT-stimulated MT secretion. These results demonstrate novel interactions between Rhopr-kinin and RhoprCAPA-2 on the hindgut, possibly influencing post-feeding excretion. The kinin analog is a potent agonist of the kinin receptor, and the CAPA analog an antagonist of the CAPA receptor. The use of neuropeptide mimetics is a promising approach to vector control as they can disrupt behaviours, and the effects of these neuropeptide analogs highlight their value as lead compounds, given their ability to interfere with epidemiologically-relevant behaviours.

TGF-β1 induced up-regulation of B1 kinin receptor promotes antifibrotic activity in rat cardiac myofibroblasts.

Cardiac myofibroblast (CMF) are non-muscle cardiac cells that play a crucial role in wound healing and in pathological remodeling. These cells are mainly derived of cardiac fibroblast (CF) differentiation mediated by TGF-β1. Evidence suggests that bradykinin (BK) regulates cardiac fibroblast function in the heart. Both B1 and B2 kinin receptors (B1R and B2R, respectively) mediate the biological effects of kinins. We recently showed that both receptors are expressed in CMF and its stimulation decreases collagen secretion. Whether TGF-β1 regulates B1R and B2R expression, and how these receptors control antifibrotic activity in CMF remains poorly understood. In this work, we sought to study, the regulation of B1R expression in cultured CMF mediated by TGF-β1, and the molecular mechanisms involved in B1R activation on CMF intracellular collagen type-I levels. Cardiac fibroblast-primary culture was obtained from neonatal rats. Hearts were digested and CFs were attached to dishes and separated from cardiomyoctes. CMF were obtained from CF differentiation with TGF-β1 5ng/mL. CF and CMF were treated with B1R and B2R agonists and with TGF-β1 at different times and concentrations, in the presence or absence of chemical inhibitors, to evaluate signaling pathways involved in B1R expression, collagen type-I and prostacyclin levels. B1R and collagen type-I levels were evaluated by western blot. Prostacyclin levels were quantified by an ELISA kit. TGF-β1 increased B1R expression via TGFβ type I receptor kinase (ALK5) activation and its subsequent signaling pathways involving Smad2, p38, JNK and ERK1/2 activation. Moreover, in CMF, the activation of B1R and B2R by their respective agonists, reduced collagen synthesis. This effect was mediated by the canonical signaling pathway; phospholipase C (PLC), protein kinase C (PKC), phospholipase A2 (PLA2), COX-2 activation and PGI2 secretion and its autocrine effect. TGF-β1 through ALK5, Smad2, p38, JNK and ERK1/2 increases B1R expression; whereas in CMF, B1R and B2R activation share common signaling pathways for reducing collagen synthesis.

Desiccation, thermal stress and associated mortality in Drosophila fruit flies induced by neuropeptide analogue treatment

Drosophila suzukii is a serious pest of soft fruit worldwide. With the global over-dependence on broad-spectrum pesticides, a strong imperative exists for more environmentally friendly and targeted methods of control. One promising avenue involves employing synthetic neuropeptide analogues as insecticidal agents to reduce pest fitness. Neuropeptides, central to the regulation of physiological and behavioural processes, play a vital role in cold and desiccation survival. Building upon this, the current study investigated the effects of biostable kinin, the cardioacceleratory peptide CAP2b and pyrokinin (PK) analogues (the latter of which have previously displayed cross-talk with the capa receptor), on desiccation, starvation and cold stress tolerance of the pest, D. suzukii, and the closely related non-pest, D. melanogaster. Results demonstrated analogues of the superfamily (CAP2b and PK derived) significantly impacted survival of the target insect under conditions of desiccation stress. However, these peptides enhanced desiccation stress survival in relation to controls, suggesting that they may act as antagonists of the capa signalling pathway in the Malpighian tubules. Of particular note was the ability of analogues 1895 (2Abf-Suc-FGPRLa) and 1902 (2Abf-Suc-FKPRLa) to impact D. suzukii but not D. melanogaster. A focus on native Drosophila CAP2b/PK and kinin sequences in analogue development may yield pure agonists with diuretic action that may reduce desiccation stress survival in the pest flies. In highlighting the PRXamide neuropeptide superfamily more generally, and the structures of promising analogues more specifically, this research will feed the evolution of next-generation analogues and drive forward the development of neuropeptidomimetic-based agents.

Kinin receptors: Key regulators of autoimmunity.

The central function of the immune system is to protect the host from environmental agents such as microbes or chemicals, thereby preserving the integrity of the body, and preventing the onset of illness and infection. Moreover, the immune system is constantly challenged to discriminate self vs. non-self and mediate the correct response, a phenomenon called self-tolerance. The failure of mechanisms responsible for self-tolerance and induction of an immune response against components of the self, induces autoimmunity and culminates however, in several autoimmune diseases. The precise etiology of autoimmune diseases is not known, although the classic sign of an autoimmune disease is inflammation. In this context, kinins are a family of peptides involved in different physiological and pathological states, comprising inflammatory, vascular and pain processes, and are highly relevant as well as to a variety of diseases including hypertension, kidney diseases, Alzheimer's disease, cancer, obesity, epilepsy and traumatic injuries. These kinin effects are mediated by two related G-protein-coupled receptors named the bradykinin receptors (BKRs), B1 and B2. The kallikrein-kinin system (KKS) and their receptors appear to be involved in both the development and progression of autoimmune diseases, suggesting that modulators of BKRs, administered in monotherapy or in combination with existing therapies, may represent a potential new venue for an effective autoimmune disease treatment. This review article highlights historical and recent progress in understanding the role of BKRs as potential therapeutics for a number of autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, type I diabetes mellitus, inflammatory bowel diseases, and others.

HAE Pathophysiology and Underlying Mechanisms.

Remarkable progress in understanding the pathophysiology and underlying mechanisms of hereditary angioedema has led to the development of effective treatment for this disorder. Progress in three separate areas has catalyzed our understanding of hereditary angioedema. The first is the recognition that HAE type I and type II result from a deficiency in the plasma level of functional C1 inhibitor. This observation has led to a detailed understanding of the SERPING1 mutations responsible for this deficiency as well as the molecular regulation of C1 inhibitor expression and function. The second is that the fundamental cause of swelling is enhanced contact system activation leading to increased generation of bradykinin. Substantial progress has been made in defining the parameters regulating bradykinin generation and catabolism as well as the receptors that transduce the biologic effects of kinins. The third is the understanding that tissue swelling in hereditary angioedema primarily involves the function of endothelial cell adherens junctions. This knowledge is driving increased attention to the role of endothelial biology in determining disease activity in hereditary angioedema. While there has been considerable progress made, large gaps still remain in our knowledge. Important areas that remain poorly understood include the factors that lead to very low plasma functional C1 inhibitor levels, the triggers of contact system activation in hereditary angioedema, and the role of the bradykinin B1 receptor. The phenotypic variability of hereditary angioedema has been extensively documented but never understood. The mechanisms discussed in this chapter likely contribute to this variability. Future progress in understanding these mechanisms should provide new means to improve the diagnosis and treatment of hereditary angioedema.

Modulatory and plastic effects of kinins on spinal cord networks.

Inflammatory kinins are released following spinal cord injury or neurotrauma. The effects of these kinins on ongoing locomotor activity of central pattern generator networks are unknown. In the present study, kinins were shown to have short- and long-term effects on motor networks. The short-term effects included direct depolarization of interneurons and motoneurons in the ventral horn accompanied by modulation of transient receptor potential vanilloid 1-sensitive nociceptors in the dorsal horn. Over the long-term, we observed a bradykinin-mediated effect on promoting plasticity in the spinal cord. In a model of spinal cord injury, we observed an increase in microglia numbers in both the dorsal and ventral horn and, in a microglia cell culture model, we observed bradykinin-induced expression of glial-derived neurotrophic factor. The expression and function of inflammatory mediators in the developing spinal cord remain poorly characterized. We discovered novel, short and long-term roles for the inflammatory nonapeptide bradykinin (BK) and its receptor bradykinin receptor B2 (B2R) in the neuromodulation of developing sensorimotor networks following a spinal cord injury (SCI), suggesting that BK participates in an excitotoxic cascade. Functional expression of B2R was confirmed by a transient disruptive action of BK on fictive locomotion generated by a combination of NMDA, 5-HT and dopamine. The role of BK in the dorsal horn nociceptive afferents was tested using spinal cord attached to one-hind-limb (HL) preparations. In the HL preparations, BK at a subthreshold concentration induced transient disruption of fictive locomotion only in the presence of: (1) noxious heat applied to the hind paw and (2) the heat sensing ion channel transient receptor potential vanilloid 1 (TRPV1), known to be restricted to nociceptors in the superficial dorsal horn. BK directly depolarized motoneurons and ascending interneurons in the ventrolateral funiculus. We found a key mechanism for BK in promoting long-term plasticity within the spinal cord. Using a model of neonatal SCI and a microglial cell culture model, we examined the role of BK in inducing activation of microglia and expression of glial-derived neurotrophic factor (GDNF). In the neonatal SCI model, we observed an increase in microglia numbers and increased GDNF expression restricted to microglia. In the microglia cell culture model, we observed a BK-induced increased expression of GDNF via B2R, suggesting a novel mechanism for BK spinal-mediated plasticity.

Tissue kallikrein is required for the cardioprotective effect of Cyclosporin A in myocardial ischemia in the mouse

Clinical and experimental studies suggest that pharmacological postconditioning with Cyclosporin A (CsA) reduces infarct size in cardiac ischemia and reperfusion. CsA interacts with Cyclophilin D (CypD) preventing opening of the mitochondrial permeability transition pore (mPTP). Tissue kallikrein (TK) and its products kinins are involved in cardioprotection in ischemia. CypD knockout mice are resistant to the cardioprotective effects of both CsA and kinins suggesting common mechanisms of action. Using TK gene knockout mice, we investigated whether the kallikrein-kinin system is involved in the cardioprotective effect of CsA.Homozygote and heterozygote TK deficient mice (TK−/−, TK+/−) and wild type littermates (TK+/+) were subjected to cardiac ischemia–reperfusion with and without CsA postconditioning. CsA reduced infarct size in TK+/+ mice but had no effect in TK+/− and TK−/− mice. Cardiac mitochondria isolated from TK−/− mice had indistinguishable basal oxidative phosphorylation and calcium retention capacity compared to TK+/+ mice but were resistant to CsA inhibition of mPTP opening. TK activity was documented in mouse heart and rat cardiomyoblasts mitochondria. By proximity ligation assay TK was found in close proximity to the mitochondrial membrane proteins VDAC and Tom22, and CypD.Thus, partial or total deficiency in TK induces resistance to the infarct size reducing effect of CsA in cardiac ischemia in mice, suggesting that TK level is a critical factor for cardioprotection by CsA. TK is required for the mitochondrial action of CsA and may interact with CypD. Genetic variability in TK activity has been documented in man and may influence the cardioprotective effect of CsA.

Kinin Upregulates CXCL1 and CXCL8 Chemokine Expression in Human Nasal Mucosa–Derived Fibroblasts

Objectives: Chronic rhinosinusitis (CRS) is a chronic inflammatory disease involving the mucosa of the nasal cavity and sinuses. It can be classified into CRS with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP). It is often described as a chronic inflammatory condition of the sinonasal mucosa and followed by a continuous tissue remodeling process. The CXC chemokine such as CXCL1 and CXCL8 are primarily chemotactic for endothelial cells and neutrophils, whch are potent promoters of angiogensis and inflammation. Methods: In this study, we examined the effects of kinin on CXC chemokine expression in human nasal fibroblasts from mucosa specimens of patients with CRSsNP. Results: We found kinin increased CXCL1 and CXCL8 release in a concentration- and time-dependent manner, as determined by enzyme-linked immunosorbent assay. In parallel, reverse transcriptase polymerase chain reaction analysis showed the kinin increased CXCL1 and CXCL8 mRNA level, suggesting this process involved transcriptional regulation. The increased CXCL chemokines appeared to have chemoattractive ability toward monocyte. We found monocyte migration increased as monocytes and fibroblasts were cocultured and the fibroblasts were stimulated with kinin in an indirect transwell co-culture system. Conclusions: Our results suggest that kinin may play a role in causing chemokine release and recruit leukocytes infiltration in the nasal inflammation microenvironment during chronic rhinosinusitis.

Differential regulation of astrocyte prostaglandin response by kinins: Possible role for mitogen activated protein kinases

The role of kinins, well known as peripheral inflammatory mediators, in the modulation of brain inflammation is not completely understood. The present data show that bradykinin, a B2 receptor agonist, enhanced both basal and lipopolysaccharide (LPS)-induced cyclooxygenase-2 mRNA and protein levels and prostaglandin E2 synthesis in primary rat astrocytes. By contrast, Lys-des-Arg9-bradykinin, which is a bradykinin breakdown product and a selective kinin B1 receptor agonist, attenuated both basal and LPS-induced astrocyte cyclooxygenase-2 mRNA levels and prostaglandin E2 production. Pre-treating the cells with p42/p44 MAPK but not with JNK or p38 inhibitors completely abrogated PGE2 synthesis in cells stimulated with LPS in the presence of bradykinin or bradykinin B1 receptor agonist. Bradykinin, but not the bradykinin B1 receptor agonist, augmented p42/p44 MAPK phosphorylation. The phosphorylation of JNK and p38 was not altered upon exposure to Bradykinin or the bradykinin B1 receptor agonist. These results suggest that the dual delayed effect of kinins on PGE2 synthesis may be due to differential regulation of COX-2 and signaling molecules such as p42/p44 MAPKs. Thus, kinins may exert opposing actions on brain inflammation and neurodegenerative diseases.

What have we learned about the kallikrein-kinin and renin-angiotensin systems in neurological disorders?

The kallikrein-kinin system (KKS) is an intricate endogenous pathway involved in several physiological and pathological cascades in the brain. Due to the pathological effects of kinins in blood vessels and tissues, their formation and degradation are tightly controlled. Their components have been related to several central nervous system diseases such as stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy and others. Bradykinin and its receptors (B1R and B2R) may have a role in the pathophysiology of certain central nervous system diseases. It has been suggested that kinin B1R is up-regulated in pathological conditions and has a neurodegenerative pattern, while kinin B2R is constitutive and can act as a neuroprotective factor in many neurological conditions. The renin angiotensin system (RAS) is an important blood pressure regulator and controls both sodium and water intake. AngII is a potent vasoconstrictor molecule and angiotensin converting enzyme is the major enzyme responsible for its release. AngII acts mainly on the AT1 receptor, with involvement in several systemic and neurological disorders. Brain RAS has been associated with physiological pathways, but is also associated with brain disorders. This review describes topics relating to the involvement of both systems in several forms of brain dysfunction and indicates components of the KKS and RAS that have been used as targets in several pharmacological approaches.

The molecular characterization of the kinin transcript and the physiological effects of kinins in the blood-gorging insect, Rhodnius prolixus

The dramatic feeding-related activities of the Chagas’ disease vector, Rhodnius prolixus are under the neurohormonal regulation of serotonin and various neuropeptides. One such family of neuropeptides, the insect kinins, possess diuretic, digestive and myotropic activities in many insects. In this study, we have cloned and examined the spatial expression of the R. prolixus kinin (Rhopr-kinin) transcript. In addition, in situ hybridization has been used to map the distribution of neurons expressing the kinin transcript. Physiological bioassays demonstrate the myostimulatory effects of selected Rhopr-kinin peptides and also illustrate the augmented responses of hindgut contractions to co-application of Rhopr-kinin and a R. prolixus diuretic hormone. Two synthetic kinin analogs have also been examined on the hindgut. These reveal interesting properties including a relatively irreversible effect on hindgut contractions and activity at very low concentrations.

Effects of kinin B(1) and B(2) receptor antagonists on overactive urinary bladder syndrome induced by spinal cord injury in rats.

Kinin B(1) and B(2) receptors have been implicated in physiological and pathological conditions of the urinary bladder. However, their role in overactive urinary bladder (OAB) syndrome following spinal cord injury (SCI) remains elusive. We investigated the role of kinin B(1) and B(2) receptors in OAB after SCI in rats. SCI was associated with a marked inflammatory response and functional changes in the urinary bladder. SCI resulted in an up-regulation of B(1) receptor mRNA in the urinary bladder, dorsal root ganglion and spinal cord, as well as in B(1) protein in the urinary bladder and B(1) and B(2) receptor protein in spinal cord. Interestingly, both B(1) and B(2) protein expression were similarly distributed in detrusor muscle and urothelium of animals with SCI. In vitro stimulation of urinary bladder with the selective B(1) or B(2) agonist elicited a higher concentration-response curve in the SCI urinary bladder than in naive or sham urinary bladders. Cystometry revealed that treatment of SCI animals with the B(2) selective antagonist icatibant reduced the amplitude and number of non-voiding contractions (NVCs). The B(1) antagonist des-Arg(9) -[Leu(8) ]-bradykinin reduced the number of NVCs while the non-peptide B(1) antagonist SSR240612 reduced the number of NVCs, the urinary bladder capacity and increased the voiding efficiency and voided volume. Taken together, these data show the important roles of B(1) and B(2) receptors in OAB following SCI in rats and suggest that blockade of these receptors could be a potential therapeutic target for controlling OAB.

Kinin-mediated inflammation in neurodegenerative disorders

The mediatory role of kinins in both acute and chronic inflammation within nervous tissues has been widely described. Bradykinin, the major representative of these bioactive peptides, is one of a few mediators of inflammation that directly stimulates afferent nerves due to the broad expression of specific kinin receptors in cell types in these tissues. Moreover, kinins may be delivered to a site of injury not only after their production at the endothelium surface but also following their local production through the enzymatic degradation of kininogens at the surface of nerve cells. A strong correlation between inflammatory processes and neurodegeneration has been established. The activation of nerve cells, particularly microglia, in response to injury, trauma or infection initiates a number of reactions in the neuronal neighborhood that can lead to cell death after the prolonged action of inflammatory substances. In recent years, there has been a growing interest in the effects of kinins on neuronal destruction. In these studies, the overexpression of proteins involved in kinin generation or of kinin receptors has been observed in several neurologic disorders including neurodegenerative diseases such Alzheimer’s disease and multiple sclerosis as well as disorders associated with a deficiency in cell communication such as epilepsy. This review is focused on recent findings that provide reliable evidence of the mediatory role of kinins in the inflammatory responses associated with different neurological disorders. A deeper understanding of the role of kinins in neurodegenerative diseases is likely to promote the future development of new therapeutic strategies for the control of these disorders. An example of this could be the prospective use of kinin receptor antagonists.

Inhibitory role of kinins on microglial nitric oxide and tumor necrosis factor-α production

Brain inflammation is sustained by chronic activation of microglia and the over-production of pro-inflammatory cytokines and nitric oxide (NO), which in turn can be highly neurotoxic. Microglial activation can be regulated by neuropeptides such as bradykinin (BK) and other members of the kinin family. Kinins are well known inflammatory regulators outside the CNS. Although the kinin system is well distributed throughout the brain, the precise role of BK in the CNS is not yet clear. The aim of this study was to examine and characterize the effects of BK and related kinins on the production of NO and TNF-α in microglia. We found that BK and selective agonists for both B1 and B2 receptors, attenuated both NO and TNF-α levels in the media of BV2 microglial cells that had been stimulated with LPS. The effects of BK that were observed in BV2 cells were confirmed in primary neonatal rat microglial cells as well. In addition, all kinin agonists reduced the expression of iNOS and TNF-α protein and mRNA levels in LPS-stimulated BV2 cells. Also, while LPS activated the nuclear factor-κB (NF-κB) pathway, BK inhibited NF-κB activation by preventing degradation of the κB protein (IκB) inhibitor, abolishing translocation of p65 and p50 subunits to the nucleus and inhibiting NF-κB transcription activity. These results suggest a role for bradykinin in modulation of glial inflammation, as evidenced by attenuation of NO and TNF-α synthesis pathways in activated microglial cells.

Anti‐nociceptive effect of kinin B1 and B2 receptor antagonists on peripheral neuropathy induced by paclitaxel in mice

In the current study, we investigated the role of both kinin B₁ and B₂ receptors in peripheral neuropathy induced by the chronic treatment of mice with paclitaxel a widely used chemotherapeutic agent. Chemotherapy-evoked hyperalgesia was induced by i.p. injections of paclitaxel (2 mg·kg⁻¹) over 5 consecutive days. Mechanical and thermal hyperalgesia were evaluated between 7 and 21 days after the first paclitaxel treatment. Treatment with paclitaxel increased both mechanical and thermal hyperalgesia in mice (C57BL/6 and CD1 strains). Kinin receptor deficient mice (B₁, or B₂ receptor knock-out and B₁B₂ receptor, double knock-out) presented a significant reduction in paclitaxel-induced hypernociceptive responses in comparison to wild-type animals. Treatment of CD1 mice with kinin receptor antagonists (DALBK for B₁ or Hoe 140 for B₂ receptors) significantly inhibited both mechanical and thermal hyperalgesia when tested at 7 and 14 days after the first paclitaxel injection. DALBK and Hoe 140 were also effective against paclitaxel-induced peripheral neuropathy when given intrathecally or i.c.v. A marked increase in B₁ receptor mRNA was observed in the mouse thalamus, parietal and pre-frontal cortex from 7 days after the first paclitaxel treatment. Kinins acting on both B₁ and B₂ receptors, expressed in spinal and supra-spinal sites, played a crucial role in controlling the hypernociceptive state caused by chronic treatment with paclitaxel.