Inflammation Bradykinin

Bradykinin is also released from mast cells within damaged tissues. It produces inflammation and activates nociceptors via bradykinin B1 and B2 receptors. 

Increased capillary permeability may allow plasma proteins to leak into the interstitial spaces of a tissue. The presence of excess protein in these spaces causes an increase in interstitial fluid colloid osmotic pressure and pulls more fluid out of the capillaries. Mediators of inflammation such as histamine and bradykinin, which are active following tissue injury and during allergic reactions, increase capillary permeability and cause swelling. 

It has been well documented that the anaemia of chronic disease, ACD, results in a lowering of various haematological parameters. Several mediators are involved, among them histamine, serotonin, bradykinin, prostaglandins and, as found more recently, cytokines and nitric oxide. ACD is a parameter of systemic autoimmune disorders. The severe inflammatory stimuli lead to several systemic changes, mediated by inflammation-associated cytokines, e.g. IL-6, IL-1 TNFa, TGF beta that regulate hepatic synthesis of the acute phase proteins. 

While the majority of attention has focused on peptides contained within the nervous system, two other important methods for delivering peptides to the vicinity of the mast cell have been established (1) peptides produced and secreted by other cells of inflammation that may affect mast-cell function and (2) the local generation of mast-cell-active peptides by secreted enzymes acting on circulating protein precursors. Examples of the former include several, as yet ill-defined, peptide factors and cationic proteins from other immunocompetent cells [66-69], defined lymphokines such as the interleukin-1 [70] and interleukin-3 [71], and tumour necrosis factor [70], Examples of the latter include bradykinin [72] and a recently identified peptide produced by the action of acid proteinases on albumin [73, 74]. 

Bradykinin b2 Human cDNA Asthma, arthritis, cancer, hypertension, inflammation, migraine, myocardial ischemia, pain, rhinitis, diabetes, cystic fibrosis, nociception Vasodilatation, stimulation of natriuresis-diuresis in kidney, smooth muscle contraction, induction of hyperalgesia, edema, neuroprotection... 

Apart from their anti-inflammatory activity the NSAIDs also show, dependent on the condition and the type of pain, considerable analgesic efficacy. In some forms of postoperative pain the NSAID s can be as efficacious as opioids, especially when prostaglandins, bradykinin and histamine, which are released by inflammation, have caused sensitization of pain receptors to normally painless stimuli. In Table 4 some advantages and disadvantages of NSAID s and opioids are compared. Although analgesic effects at peripheral or central neurons cannot be excluded completely, most studies indicate that... 

Other actions of kinins include activation of clotting factors simultaneously with the production of bradykinin. In the kidney, bradykinin production results in an increase in renal papillary blood flow, with a secondary inhibition of sodium reabsorption in the distal tubule. In the peripheral nervous system, bradykinin is important for the initiation of pain signals. It is also associated with the edema, erythema, and fever of inflammation. 

Bradykinin has long been known to produce the four classic symptoms of inflammation—redness, local heat, swelling, and pain. Kinins are rapidly generated after tissue injury and play a pivotal role in the development and maintenance of these inflammatory processes. 

In contrast to the analgesic role of leu- and met-enkephalin, an analgesic action of dynorphin A—through its binding to (kappa) opioid receptors—remains controversial. Dynorphin A is also found in the dorsal horn of the spinal cord, where it may play a critical role in the sensitization of nociceptive neurotransmission. Increased levels of dynorphin can be found in the dorsal horn after tissue injury and inflammation. This elevated dynorphin level is proposed to increase pain and induce a state of long-lasting hyperalgesia. The pronociceptive action of dynorphin in the spinal cord appears to be independent of the opioid receptor system but dependent on the activation of the bradykinin receptor. Moreover, dynorphin A can bind and activate the N -methyl-D-aspartate (NMDA) receptor complex, a site of action that is the focus of intense therapeutic development. 

Many small peptides exert their effects at very low concentrations. For example, a number of vertebrate hormones (Chapter 23) are small peptides. These include oxytocin (nine amino acid residues), which is secreted by the posterior pituitary and stimulates uterine contractions bradykinin (nine residues), which inhibits inflammation of tissues and thyrotropin-releasing factor (three residues), which is formed in the hypothalamus and stimulates the release of another hormone, thyrotropin, from the anterior pituitary gland. Some extremely toxic mushroom poisons, such as amanitin, are also small peptides, as are many antibiotics. 

The stimulation of C fibers by capsaicin causes a subset of sensory airway neurons to release several neuropeptides, which include tachykinin, substance P and neurokinin A. In addition to capsaicin, other endogenous mediators including histamine, prostaglandins and bradykinins can also result in their release. These neuropeptides are responsible for neurogenic inflammation, which is characterized by vasodilation, mucus secretion, plasma protein extravasation, increased expression of the adhesion molecules and bronchoconstriction. 

Pain. Prostaglandins appear to help mediate painful stimuli in a variety of conditions (including inflammation). The compounds do not usually produce pain directly but are believed to increase the sensitivity of pain receptors to mechanical pressure and the effects of other pain-producing substances such as bradykinin.73... 

Ueno A, Oh-ishi S. Critical roles for bradykinin and prostanoids in acute inflammatory reactions a search using experimental animal models. Curr Drug Targets Inflamm Allergy. 2002 1 363-376. 

Icatibant is a second generation B2 receptor antagonist. It is orally active, potent, and selective, has a long duration of action (> 60 minutes), and displays high B2 receptor affinity in humans and all other species in which it has been tested. Icatibant has been used extensively in animal studies to block exogenous and endogenous bradykinin and in human studies to evaluate the role of kinins in pain, hyperalgesia, and inflammation. 

Its mechanism of action, however, is not completely elucidated. Kamakura et aL [94] studied the effects of stem bromelain on tlw plasma kallikrein system, bradykinin levels and plasma exudation at the inflammatory site in rats with a kaolin-induced inflammation of an air couch. Bromelain caused a dose-... 

---