Bradykinin is a physiologically and pharmacologically active nonapeptide produced in the body in response to many kinds of injuries. It is also involved in the normal physiological regulation of body homeostasis. The amino acid sequence of bradykinin is: arg - pro - pro - gly - phe - ser - pro - phe - arg. Its empirical formula is therefore C50H73N15O11. Bradykinin together with its homologs is collectively referred to as kinins (1).
Bradykinin was discovered by three Brazilian physiologists and pharmacologists (Maurício Rocha e Silva, Wilson Teixeira Beraldo and Gastão Rosenfeld) working at the Instituto de Biologia de São Paulo, in São Paulo city; the group was led by Dr. Maurício Rocha e Silva. In 1949, Rocha e Silva (2) reported the existence of a new relaxing substance liberated in plasma by the action of trypsin or the snake venom of Bothrops jararaca (Brazilian lancehead snake), which was brought by Rosenfeld from the Butantan Institute (2).
They called the substance ‘bradykinin’
The formation of bradykinin in human plasma is basically due to interaction of three proteins (Hageman factor, prekallikrein and high molecular weight kininogen) to anionic surfaces (Figures 1a and 1b). Kininogens are enzymes defined by their role as precursors for kinin, in humans, kininogens exist in both high molecular weight and low molecular weight forms. Bradykinin and kallidin (The Kinins) are formed from the high and low molecular weight kininogens, by the action of serine protease kallikreins, both in plasma and peripheral tissues. Once released, these peptides are rapidly degraded by a group of enzymes generically called `kininases' (1).
Plasma and tissue kallikrein are the two main kininogenases, with tissue (glandular) kallikrein being the predominant kallikrein in the airways. Tissue kallikrein cleaves both high and low molecular weight kininogen equally, yielding bradykinin and kallidin (lysyl-bradykinin), respectively. Kallidin is then rapidly converted to bradykinin by the enzyme aminopeptidase-N (3). Figures 1a and 1b show the tissue and plasma biosynthetic pathway of bradykinin.
Figure 1a: Formation of bradykinin (BK) and Lys-bradykinin (Lys-BK) by plasma and tissue kallikreins. Figure from Marcondes and Antunes (4)
Figure 1b: The kinin-forming systems and its interactions with both intrinsic and extrinsic coagulation cascades and fibrinolysis.
According to Moreau et al (5), there are two main pathways by which kinins are generated. The plasma kallikrein-kinin system, by far the more complex, initiates activation of the intrinsic coagulation pathway. The second and simpler pathway of kinin generation involves tissue kallikrein and its substrate, low-molecular-weight kininogen (Figure 1b) (5).
Kinins exert their biological effects through the activation of two receptors, denoted as bradykinin B1 and bradykinin B2 receptors on the basis of their distinct pharmacology (6, 7). The existence of two types of bradykinin receptor was proposed by Regoli and colleagues in the late 1970s. B1 receptors were defined as those where the rank order of potency of kinin analogues in isolated tissues was [desArgg]- BK>[Tyr(Me)S]-BK >BK and B2 receptors were defined as having the rank order of potency [Tyr(Me)8]-BK>BK>[desArg9]-BK. The B1/B2 receptor classification scheme is now universally accepted (6-10).
Kinins are the endogenous agonists of the prevailing B2 receptor, while des-Arg9-bradykinin and des-Arg10-kallidin are the preferential agonists for the B1 receptor. There are some evidence to suggest that kallikreins and some other proteases activate human B2 receptor directly, independent of bradykinin release (11). Both bradykinin receptor genes have been cloned in human and various species and the hydrophobicity prediction for the residues indicates that both bradykinin B1 and B2 receptors have seven helix transmembrane domains, a structure common to other members of the rhodopsin superfamily of G-protein-coupled receptors (Gq/11 and Gi). The amino acid sequence of the human B1 receptor (353 amino acid protein) is only 36% identical to the amino acid sequence (364 amino acid protein) of the human B2 receptor (12).
There are ample evidence from the international literature based on discriminating agonists and antagonists to suggest the existence of interspecies variations in B1 and B2 receptor subtypes (13-15). Highly potent and selective peptide and nonpeptide agonists and antagonists are available for the bradykinin B2 receptor, while at the present time only peptide agonists and antagonists are readily available for the bradykinin B1 receptor (16-19). Whereas the B2 receptor is constitutive, the B1 receptor is generally absent in normal tissues and healthy animals but expressed in animals diagnosed with established infection (20). The B1 receptor is induced and over-expressed during tissue injury, following treatment with bacterial endotoxins and cytokines such as interleukin-1b and tumor necrosis factor alpha (10).
B1 receptors have now been documented in isolated preparations taken from the cardiovascular, urinary and intestinal systems and in cultured cells of vascular, endothelial, mesangial, tracheal, bone and fibroblast origin. These receptors have been implicated in mediating the effects of kinins in certain forms of hyperalgesia, plasma extravasation, and in the control of blood pressure (7, 20). On the other hand, B2 receptors have been described in numerous in vitro preparations, including those from the intestinal, cardiovascular, genitourinary and respiratory tracts and in ocular and neuronal tissues (20). In keeping with this widespread distribution, the majority of in vivo effects of kinins such as in bronchoconstriction, hypotension, acute inflammatory reactions, pain and hyperalgesia have been attributed to an activation of B2 receptors (20, 21).
A significant number of the research that now explains the pathophysiology of the kallikrein-kinin system as well as the effects mediated by B1 and B2 receptors have involved the cloning and sequencing of the B1 and B2 receptors and the use of knock-out models to both receptors. The use of receptor knockout mice has established that kinins, acting at B1 or B2 receptors, play a key role in controlling inflammatory and nociceptive processing mechanisms. Accordingly, the polymorphonuclear leukocyte accumulation into the pleural cavity induced by carrageenan is almost abolished in mice lacking B1 receptors, while in non-inflamed conditions these animals show a hypoalgesic effect in response to noxious stimulus (22, 23). Similarly, ablation of the gene of B1 receptor in mice (but not of B2 receptor) reduced the hyperalgesia induced by intraplantar injection of Freund's adjuvant to an extent similar to treating wild-type mice with the B1 antagonist des-Arg9-[Leu8]-BK (24).
The thermal hyperalgesia induced by bradykinin is suppressed in B2 receptor knockout and unaffected in B1 receptor knockout models, whereas that induced by the B1 agonist desArg9-BK is suppressed in B1 receptor knockout animals but rather exacerbated in B2 knockout mice (25). Also, the importance of B2 receptors in baroreflex control (26) and preservation of cardiac function and structure (27) has been evidenced by the use of B2 receptor knockout mice. Also, an essential role of B1 receptors in modulating angiogenic response to ischemia and blood perfusion recovery has been demonstrated using B1 knockout mice (8, 28).
The best known and most extensively characterised actions of kinins concern their pro-inflammatory actions. Kinins are potent vasoactive agents in the microcirculation, where they have actions on the microvessel smooth muscle or endothelial cells promoting arteriolar vasodilatation and plasma extravasation following inflammatory insult or tissue damage (20, 29). These effects are generally mediated via stimulation of B2 receptors. In addition, via a direct stimulation of sensory nerve endings, kinins activate pain pathways and promote neurogenic inflammation through the peripheral release of proinflammatory tachykinins (substance P and neurokinin A) and calcitonin gene-related peptide (21, 30; Figure 2).
Figure 2: Pro-inflammatory effects of bradykinin receptors in the microvasculature. Figure from Hall (9).
Kinins are produced at sites of tissue damage, where they activate endothelial B2 receptors to release nitric oxide, resulting in arteriolar vasodilatation and increased blood flow, and increase vascular permeability to promote plasma extravasation from postcapillary venules.
There are experimental evidences that 4 metallopeptidases are mainly responsible for the metabolism of bradykinin. These are angiotensin-I-converting enzyme (ACE), aminopeptidase P (APP), neutral endopeptidase 24.11 (NEP, neprilysin), and carboxypeptidases M and N (CPM, CPN) (5). There are also data to suggest that circulating or tissue levels of bradykinin peptides is not subject to short loop feedback regulation mediated through B2 receptors since B2 receptor antagonist icatibant (D-Arg-[Hyp3, Thi5, D-Tic7, Oic8]-bradykinin) did not influence circulating or tissue levels of bradykinin peptides. Figure 3 shows some of the enzyme responsible for the breakdown of kinin (5).
Figure 3 - Metabolism of kinin peptides. Some of the enzymes that metabolize kinin peptides are shown with their sites of cleavage of the kinin molecule. ACE, Angiotensin converting enzyme.
Because of its higher affinity (Km, approximately 0.18 μM) for bradykinin, ACE could also be now considered as a kininase (kininase II) (31, 32). ACE is a well-characterized type I ectoenzyme membrane anchored Zn2+-dependent dipeptidyl carboxypeptidase that regulates bioactivities of vasoactive peptides such as angiotensin I (Ang I) and bradykinin. As a peptidyl dipeptidase, ACE inactives bradykinin by hydrolyzing two separate bonds on its C-terminal end. It removes sequentially the dipeptide Phe8-Arg9 and next cleaves the Phe5-Ser6 bond to generate the second dipeptide Ser6-Pro7, transforming BK into its inactive final product (33, 34). ACE also metabolizes des-Arg9-BK by removing the carboxyterminal tripeptide Ser6-Pro7-Phe8, yielding the same final pentapeptide.
Figure 4: Pharmacological targets to modulate the kallikrein-kinin activity. Figure 4 from Moreau et al (5)
Angioedema (HAE) attacks involve the activation of two pathways namely, the classical complement and the contact system pathways (5). Patients with genetic deficiency in C1INH (Figure 4) suffer from hereditary angioedema. The contact system pathways is responsible for the release of vasoactive bradykinin (35); this is probably the main but not the sole mediator responsible for the increased vascular permeability that results in angioedema (36-39).
Research aimed at identifying a viable target for the treatment of HAE have used a murine model of HAE provided to support the hypothesis that bradykinin mediates HAE. In this model, mice heterozygous and homozygous for a gene coding for C1INH (Figure 4) demonstrated increased permeability and depletion of HK. When treated with a specific plasma kallikrein inhibitor or a B2R antagonist (Icatibant® or JE049®), the increased vascular permeability was completely reversed (5, 40). Icatibant was tested in clinical trials for treatment of HAE and a phase II proof-of-concept study in HAE was concluded with positive clinical results (5).
In vivo presentation of sepsis shows that the factors of the contact system are consumed in plasma of patients suffering from sepsis. A significant increase in plasma bradykinin was also measured in plasma of patients suffering from S. aureus sepsis while simultaneously treated with ACE inhibitors (41). Pharmacological agents designed to lower the plasma levels of bradykinin in this condition may be suitable treatment agents. There is evidence from animal models that the injection of endotoxins (lipopolysaccharide (LPS) from E. Coli into the dorsal skin of rats caused a dose-dependent increase in vascular permeability and this increase caused by LPS was attenuated by pretreatment with the B2R antagonist HOE 140 (42). The role of bradykinin receptors in the pathophysiology of this condition is thus highlighted.
Body substrates for ACE are numerous and they are widely distribution throughout the human body; this perhaps is an indicator that this enzyme may be involved in additional physiologic processes such as atherosclerosis and inflammation, in addition to an important role in cardiovascular homeostasis (5, 43). It is a scientific fact that the formation of Ang II from Ang I through the action of ACE will initiates a cascade of events producing high levels free radicals and promotes vascular smooth muscle cell proliferation (44). However bradykinin is more readily hydrolyzed by ACE than Ang I, it is thus logical to suppose that the hydrolysis of bradykinin may also contribute to the pathophysiology of these disorders (45).
The inhibition of ACE activity is reported to improve endothelial function and to stimulate vascular remodeling, as well as attenuate the progression of arteriosclerosis and the occurrence of cardiovascular events in humans (5, 46, 47). The introduction of many second-generation ACE inhibitors, with improved pharmacokinetic properties relative to captopril (a first-generation ACE inhibitor) has led to numerous multi-center outcome trials that have established the clinical effectiveness of ACE inhibitors for the treatment cardiovascular diseases. An appreciation of the role of bradykinin and the kallikrein-kinin system is therefore fundamental to the development of better pharmacological lead molecules.
Neutral endopeptidase (NEP) is the main enzyme responsible for the metabolism of kinins in the kidney; it regulates the degradation of natriuretic peptides (48) and plays an important role in the metabolism of bradykinin at the endothelium. NEP also inactivates other peptides like enkephalins, neurokinins, and amyloid-β peptide, a marker for Alzheimer disease of the CNS (49). NEP is thus a potential target for the disorders marked by an aberration in the levels of these endogenous substances.
Bradykinin administration reproduces two of the cardinal signs of inflammation (rubor, calor) through the activation of B2R that causes vasodilatation due to endothelial Nitric oxide synthase and phospholipase A2 stimulation leading to Nitric oxide and prostaglandin I2 production by vascular endothelial cells (Figure 5). The ensuing exudation of protein-rich fluid from the circulation, facilitated by kinins, is largely determined by the rise of vascular permeability, particularly at the level of postcapillary venules via endothelial cells contraction. This is the essentially vasogenic mechanism of a third cardinal sign of inflammation, swelling (tumor) (5). In addition, Icatibant (HOE 140), a widely used peptide B2R antagonist, has been found to significantly improve the ventilatory function in humans with asthma when administered in an aerosol form (50). The mode of action of this drug was not related to an acute bronchodilator action, but rather to a long-term anti-inflammatory effect. Bradykinin blockade is thus again showed to be a rational approach to the control of the inflammatory response.
Figure 5: Kinin receptors and their signaling pathways- Figure 5 from Moreau et al (5)
Relevance of B1 receptors to the inflammatory process
There are several lines of evidence that support the hypothesis that B1 receptor activation might be functionally involved in mediating the inflammatory response. The responses to des-Arg9-bradykinin (DABK) are mostly observed following a pathological insult, and experimentally this has been very well demonstrated using models of sepsis and nociceptive inflammation (51, 52). In both cases, a rise in local or circulating cytokine levels, particularly interleukin 1 (IL-1), has been implicated in the process of induction.
There is support for the concept that not only is B1 receptors upregulated by specific inflammatory stimuli, but that there is also an increase in the levels of DABK produced (52). This elevation could be due to an increase in the activity of carboxypeptidase M (CPM), an enzyme involved in the synthesis of DABK. Thus, during inflammation it is apparent that both agonist and receptor are upregulated. These lines of evidence suggest that B1 receptor activation might be functionally involved in mediating the cardinal signs of inflammation (Figure 6).
Figure 6: Schematic diagram of the synthesis and possible effector sites of des-Arg9-bradykinin (DABK) in inflammation. Figure from Ahluwalia and Perretti (52).
There is now a substantial body of evidence supporting a role for bradykinin in the pathophysiology of several inflammatory diseases, including pancreatitis, arthritis, cardiovascular disease, urinary tract disorders, upper and lower respiratory tract disorders including rhinitis and asthma, and in the pain and hyperalgesia that accompany inflammatory insult (53). In addition, clinical indications for bradykinin receptor antagonists include the prevention and treatment of oedema following brain trauma injury, bums and shock (54).
This major advance in the area of bradykinin receptor pharmacology have resulted from the use of effective bradykinin receptor antagonists and, more recently, through techniques of molecular biology, such as cloning and the generation of mice with knock-out of B1 and/or B2 receptors (55).
Indeed bradykinin is an important mediator of inflammation. B1 and B2 bradykinin receptors are currently targeted for treatment of various disorders through the control of bradykinin tissue of plasma levels and their effects. This is in addition to the array of molecules involved in the modulation of tissue and plasma bradykinin levels and in the kallikrein-kininogen-kinin system, any of which is a potential target for the regulation of the inflammatory response. These targets are viable and a number have been clinically proven. As the knowledge of effects of bradykinin receptors and the kallikrein-kininogen-kinin system deepens, one can reasonably expect the application in the development of suitably formulated, therapeutically potent drugs, targeted at bradykinin receptors or their genes.
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