Kallikrein-kinin System

Diagram of the human kinin-kallikrein system including the native ligands for 1 and B2... 

The kinin-kallikrein system (kinin system) is a poorly delineated system of blood proteins that plays a role in inflammation, blood-pressure control, coagulation and pain. Kinins are small peptides produced from kininogen by kallikrein, which are subsequently degraded by kininases. They act on phospholipase and increase arachidonic acid release and thus prostaglandin (PGE2) production. 

Thi ,DPhe BK [Thi ,DPhe ]-bradykinin. bradykinin-potentiating peptide teprotide. bradykinin potentiator B teprotide. BRADYKININ RECEPTOR AGONISTS act at sites recognizing members and derivatives of the bradykinin family of hormone peptides - kinins - of which bradykinin (BK) and kallidin (lysyl-bradykinin Lys-BK KD) are the main mammalian members. The bradykinin family is distinct from the tachykinin family of peptides, though both have profound hypotensive actions and contract many intestinal and other smooth muscles. Historically, it was noted that the former action was relatively slow-developing, hence the name bradykinin. Notable actions of bradykinin and kallidin are to dilate blood vessels and increase their permeability to plasma proteins, and to stimulate sensory nerve C-fibres. These actions are pro-inflammatory, and reflect the fact that the kinin-formation system is activated in inflammation, and enzymes (kallikreins) form the kinins from blood-borne or tissue precursors (kininogens) on injurious insult. 

The renal kallikrein-kinin [40] system has been suggested as influencing renal hemodynamic as well as excretory function. This activity may also be linked to arachidonate metabolites, like PGEj, since increased excretion of cyclooxygenase products are associated with increased kallikrein-kinin excretion. However, the physiological significance of this relationship is uncertain. 

The release of kinins into an area of injury can take place in several ways. There can be the formation of kinins by means of the kallikrein system or possibly by means of the cathepsins as demonstrated some time ago in our laboratory (1). One other source of kinins are those formed from enzymes liberated from cellular elements that are drawn from the blood to the inflammatory site. 

In rare cases of a systemic release, kinins have the potential to cause severe hypotension. Uncontrolled activation of the contact system (Fig. 3) is thought to trigger a massive formation of kinins under certain pathological conditions [3]. For instance, this situation is seen in patients with underlying diseases such as systemic inflammatory response syndrome (SIRS) due to sepsis or trauma. SIRS progression is accompanied by depletion of contact system factors and low levels of H-kininogen and plasma kallikrein are indicative of a... 

Blais Jr, Marceau F, Rouleau JL et al (2000) The kallikrein-kininogen-kinin system lessons from the quantification of endogenous kinins. Peptides 21 1903—1940... 

Pixley RA, Colman RW (1997) The kallikrein-kinin system in sepsis syndrome. In Farmer SG (ed) Handbook of immunopharmacology - the kinin system. Academic Press, New York, pp 173-186... 

Bradykinin is part of the kallikrein-kinin system, which shares a link to the RAAS through angiotensin-converting enzyme. Bradykinin is a vasodilatory peptide that is released in response to a variety of stimuli, including neurohormonal and inflammatory mediators known to be activated in HF.9 As a... 

It was hoped that the more complete blockade of angiotensin II s AT effects would confer greater long-term efficacy with ARBs compared to ACE inhibitors. However, prospective, randomized trials suggest that the clinical efficacy of ARBs is similar to that of ACE inhibitors for reduction of hospitalizations for HF, sudden cardiac death, and all cause mortality.23-25 Despite poorer suppression of AT2, comparable efficacy of ACE inhibitors may be due to the additional effects on the kallikrein-kinin system. Although ARBs produce hemodynamic and neurohormonal effects similar to those of ACE inhibitors, they are considered second-line therapy due to the overwhelming clinical trial experience with ACE inhibitors. 

D9. DeLa Cadena, R. A., Suffredini, A. F Kaufman, N., Parrillo, J. E., and Colman, R. W., Activation of the kallikrein-kinin system after endotoxin administration to normal human volunteers. Blood 81,3313-3317(1993). 

Limited data on occupationally exposed men indicate that the effect of lead on blood pressure may be mediated in part through the renin-angiotensin system, as evidenced by lead-related increases in plasma renin and angiotensin I levels (Campbell et al. 1985) and the kallikrein-kinin system, as indicated by a correlation between renin and kallikrein (Boscolo et al. 1981). Evidence from patients with essential hypertension and renal impairment suggests that excessive lead absorption may be involved in the development of both conditions (Batuman et al. 1983). 

The kallikrein-kinin system is an enzymatic pathway giving rise to two predominant vasoactive peptides, kallidin and bradykinin. Kallikrein, the enzyme responsible for the formation of these peptides, exists in plasma and tissues. However, circulating levels of the end products, kalhdin and bradykinin, are quite low because the kalhkrein enzymes are present largely in inactive forms. In addition, the short half-life of these peptides (15 seconds) also contributes to low plasma levels. In general, the kinins produce relaxation of vascular smooth muscle and vasodilation. Bradykinin causes... 

Kinins are potent vasodilator peptides formed enzymatically by the action of enzymes known as kallikreins or kininogenases acting on protein substrates called kininogens. The kallikrein-kinin system has several features in common with the renin-angiotensin system. 

The kallikrein-kinin system. Kininase II is identical to converting enzyme peptidyl dipeptidase (ACE). 

Drugs that modify the activity of the kallikrein-kinin system are available, though none are in wide clinical use. Considerable effort has been directed toward developing kinin receptor antagonists, since such drugs have considerable therapeutic potential as anti-inflammatory and antinociceptive agents. Competitive antagonists of both and B2 receptors are available for research use. Examples of B receptor... 

Costa-Neto CM et al Participation of kallikrein-kinin system in different pathologies. Int Immunopharmacol 2008 8 135. [PMID 18182216]... 

Clements J. The molecular biology of the kallikreins and their roles in inflammation. In Farmer S, editor. The Kinin System. New York Academic Press, 1997 71-97. 

Sharma JN, Uma K, Noor AR, Rahman AR. Blood pressure regulation by the kallikrein-kinin system. Gen Pharmacol 1996 27 55-63. 

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