Kinin-kallikrein system

The kinin-kallikrein system or simply kinin system is a poorly delineated system of blood proteins that plays a role in inflammation, blood pressure control, coagulation and pain. Its important mediators bradykinin and kallidin are vasodilators and act on many cell types.

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History

The system was discovered in 1909 (Abelous & Bardier) when researchers discovered that injection with urine (high in kinins) led to hypotension (low blood pressure).^[1] The researchers Emil Karl Frey, Heinrich Kraut and Eugen Werle discovered high-molecular weight kininogen in urine around 1930.^[2]

Members

The system consists of a number of large proteins, some small polypeptides and a group of enzymes that activate and deactivate the compounds.

Proteins

High-molecular weight kininogen (HMWK) and low-molecular weight kininogen (LMWK) are precursors of the polypeptides. They have activity of themselves.

• HMWK is produced by the liver together with prekallikrein (see below). It acts mainly as a cofactor on coagulation and inflammation, and has no intrinsic catalytic activity.
• LMWK is produced locally by numerous tissues, and secreted together with tissue kallikrein.

Polypeptides

• Bradykinin (BK), which acts on the B2 receptor and slightly on B1, is produced when kallikrein releases it from HMWK. It is a nonapeptide with the amino acid sequence Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg.
• Kallidin (KD) is released from LMWK by tissue kallikrein. It is a decapeptide. KD has the same amino acid sequence as Bradykinin with the addition of a Lysine at the N-Terminus, thus is sometimes referred to as Lys-Bradykinin.

HMWK and LMWK are formed by alternative splicing of the same gene.^[3]

Enzymes

• Kallikreins (tissue and plasma kallikrein) are serine proteases that liberate kinins (BK and KD) from the kininogens. Prekallikrein is the precursor of plasma kallikrein. It can only activate kinins after being activated itself by factor XII or other stimuli.
• Carboxypeptidases are present two forms: N circulates and M is membrane-bound. They remove arginine residues at the carboxy-terminus of BK and KD.
• Angiotensin converting enzyme (ACE), also termed kininase II, inactivates a number of peptide mediators, including bradykinin. It is better known for activating angiotensin.
• Neutral endopeptidase also deactivates kinins and other mediators.

Pharmacology

Inhibition of ACE with ACE inhibitors leads to a decrease in angiotensin (a vasoconstrictor) but also to an increase in bradykinin due to decreased degradation. This explains why some patients of ACEi's develop a dry cough, and some react with angioedema, a dangerous swelling of the head and neck region.

There are hypotheses that many of the ACE-inhibitors' beneficial effects are due to their influence on the kinin-kallikrein system. This includes their effects in arterial hypertension, in ventricular remodeling (after myocardial infarction) and possibly diabetic nephropathy.

Role in disease

Defects of the kinin-kallikrein system in diseases are not generally recognized. The system is the subject of much research due to its relationship to the inflammation and blood pressure systems. It is known that kinins are inflammatory mediators that cause dilation of blood vessels and increased vascular permeability. Kinins are small peptides produced from kininogen by kallikrein and are broken down by kininases. They act on phospholipase and increase arachidonic acid release and thus prostaglandin (PGE2) production.

References

1. ^ Abelous JE, Bardier E. Les substances hypotensives de l'urine humaine normale. CR Soc Biol 1909;66:511-20.
2. ^ Kraut H, Frey EK, Werle E. Der Nachweis eines Kreislaufhormon in der Pankreasdruse. Hoppe-Seylers Z Physiol Chem 1930;189:97-106.
3. ^ Goodman & Gilman's Pharmacology; Chapter 24. Histamine, Bradykinin, and Their Antagonists

• Dendorfer A, Wolfrum S, Dominiak P. Pharmacology and cardiovascular implications of the kinin-kallikrein system. Jpn J Pharmacol 1999;79:403-26. PMID 10361880.
• Skidgel RA, Alhenc-Gelas F, Campbell WB. Relation of cardiovascular signaling by kinins and products of similar converning enzyme systems; prologue: kinins and related systems. New life for old discoveries. Am J Physiol Heart Circ Physiol 2003;284:H1886-91. PMID 12742820.