Kinins are biologically active oligo peptides belonging to the tissue hormones ; they are released by kallikrein from kininogens (inactive precursors of kinins). The kinin-kallikrein system or simply kinin system is a poorly demarcated system of blood - proteins that play a role in inflammation , blood pressure control , coagulation and pain plays. Its important mediators bradykinin and kallidin are vasodilators and act on many cell types.
- Kinins may be responsible for smooth muscle organ activity.
- They regulate the vessel size and permeability.
- They influence the excitation of sensitive structures (pain).
- They are involved in the development of shock and inflammation.
Role in the disease
Disorders of the kinin-kallikrein system in diseases have generally not yet been adequately clarified. The system has been the subject of extensive research due to its relationship to the inflammatory and blood pressure systems .
The system was discovered in 1909 (Abelous & Bardier) when researchers discovered that injection with urine (high in kinine) resulted in hypotension (low blood pressure). The researchers Emil Karl Frey, Heinrich Kraut and Eugen Werle discovered high molecular weight kininogen in urine around 1930 .
The following kinins are known
- HMW-Kininogen is produced by the liver together with prekallikrein (see below). It acts primarily as a cofactor on clotting and inflammation and has no intrinsic catalytic effect.
- LMW kininogen is produced locally by numerous tissues and secreted together with tissue kallikrein.
- Bradykinin (BK), which acts on the B2 receptor and also to a minor extent on the B1 receptor, is produced when kallikrein releases it from HMW kininogen. It is a nonapeptide with the amino acid sequence Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg.
- Kallidin (KD) is released from LMW kininogen by tissue kallikrein. It's a decapeptide .
- Kallikrein (tissue and plasma kallikrein ) are serine proteases that release kinins (BK and KD) from kininogens. Prekallikrein is the precursor to plasma kallikrein. It can only activate kinins after it has been activated by factor XII or other stimuli.
- Carboxypeptidases exist in two forms: N circulates and M is membrane-bound. They remove arginine residues at the carboxy-terminal end of BK and KD.
- Angiotensin Converting Enzyme (ACE), also known as 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.
The inhibition of ACE with ACE inhibitors leads to a decrease in angiotensin (a vasoconstrictor ) but also to an increase in bradykinin due to a reduced breakdown. This explains why some patients on ACE inhibitor therapy develop a dry cough and some react with angioedema , a dangerous swelling of the head and neck area.
There are hypotheses that many of the beneficial effects of ACE inhibitors are due to their manipulation of the kinin-kallikrein system. This includes their effects in arterial hypertension , in ventricular remodeling (after a myocardial infarction) and possibly in diabetic nephropathy .
Degradation and Synthesis of Kinins
The kinin release is inhibited by aprotinin .
- physical synthesis:
Kinin is proteolytically metabolized by the breakdown of bradykinin to other kinins (by kininase II).
- JE Abelous, E. Bardier: Les substances hypotensives de l'urine humaine normal. In: CR Soc Biol. 66, 1909, pp. 511-520.
- A. Dendorfer, S. Wolfrum, P. Dominiak: Pharmacology and cardiovascular implications of the kinin-kallikrein system. In: Jpn J Pharmacol . 79, 1999, pp. 403-426. PMID 10361880 .
- H. Kraut, EK Frey, E. Werle: The detection of a circulatory hormone in the pancreatic gland. In: Hoppe Seylers Z Physiol Chem . 189, 1930, pp. 97-106.
- RA Skidgel, F. Alhenc-Gelas, WB Campbell: Relation of cardiovascular signaling by kinins and products of similar converning enzyme systems; prologue: kinins and related systems. New life for old discoveries. In: Am J Physiol Heart Circ Physiol. 284, 2003, pp. H1886-H1891. PMID 12742820 .