Kinins actions

KInIns, human peptide hormones implicated in many physiological and pathological processes, including reduction of blood pressure and regulation of sodium homeostasis, inflammation and the cardioprotective effects of preconditioning. The kallikrein-kinin system (KKS) of the plasma generates bradykinin (BK), whereas the tissue KKS is responsible for the formation of kallidin. The kinin action is mediated via two types of kinin receptor, the type 1 (Bi) and type 2 (B2). Bi... 

The reversal of kinin action suggests a novel role for kinin that may prove of benefit in some pathologic states where simultaneous or sequential release of kinin and other biochemical mediators may occur. Further study of the biochemical interactions between kinin and these mediators is essential before the overall physiologic and pathologic role of kinin is understood. 

As might be expected, the inhibition of kininase activity results in the enhancement and prolongation of kinin effects. This can be achieved with various agents. e.g. cystein. dimercaptopropanol (BAL). Ca-EDTA. e-aminocaproic acid. etc. Most of them are effective chelating agents and also block metalloenzymes such as alcohol dehydrogenase. However, the inhibition of kininase does not satisfactorily explain all the reported potentiations of kinin action... 

Relatively few sites of growth-modifying or growth-inhibitory action have been identified at the cellular and molecular level. Consequently, the exact action of, and relationships between, auxins, gib-berellins, kinins, and growth inhibitors remain to be elucidated. 

Kinins. Figure 1 Scheme of kin in liberation, turnover and action. 

ACE not only activates angiotensin but is also involved in the metabolism of other peptides, e.g., it is a major kinin-degrading enzyme. Therefore, ACE inhibitors also increase kinin concentrations. Furthermore, it has recently been shown that these drugs potentiate kinin effects by modulating a direct interaction between the ACE protein and the kinin B2 receptor, which is independent from the enzymatic activity of ACE. Kinin potentiation may be involved in the beneficial action of ACE inhibition since kinins are known to exert cardio- and renoprotective actions. 

Complete C-fibre inhibitions can be produced under normal conditions but opiates do not always produce a complete analgesia in some clinical situations, especially when the pain arises from nerve damage. Reasons for this are suspected to be excessive NMDA-mediated activity which is hard to inhibit and the mobilisation of cholecysto-kinin in the spinal cord which can act as a physiological antagonist of opiate actions. The idea that pre-emptive analgesia aids post-operative pain relief by preventing the pain-induced activation of these systems is becoming popular. 

Involvement of complement activation in the etiology of the acute byssinotic reaction could explain the pathogenic mechanism of histamine release, non-histamine-mediated bronchoconstriction, chemotaxis, endotoxin and bacterial proteolytic enzyme action. Bronchoconstriction experienced in the acute byssinotic reaction might be attributed to the combined action of C3a and C5a mediated histamine release and non-histamine mediated kinin activity. The presence of PMN in the nasal airways of byssinotics might be explained by the chemotactic action of C5a and the C567 complex. 

Lowering of an elevated blood pressure is predominantly brought about by diminished production of angiotensin 11. Impaired degradation of kinins that exert vasodilating actions may contribute to the effect... 

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. 

Peptides are used by most tissues for cell-to-cell communication. As noted in Chapters 6 and 21, they play important roles in the autonomic and central nervous systems. Several peptides exert important direct effects on vascular and other smooth muscles. These peptides include vasoconstrictors (angiotensin II, vasopressin, endothelins, neuropeptide Y, and urotensin) and vasodilators (bradykinin and related kinins, natriuretic peptides, vasoactive intestinal peptide, substance P, neurotensin, calcitonin gene-related peptide, and adrenomedullin). This chapter focuses on the smooth muscle actions of the peptides. 

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. 

Each kinin is formed from a kininogen by the action of a different enzyme. Bradykinin is released by plasma kallikrein, lysylbradykinin by tissue kallikrein, and methionyllysylbradykinin by pepsin and pepsin-like enzymes. The three kinins have been found in plasma and urine. Bradykinin is the predominant kinin in plasma, whereas lysylbradykinin is the major urinary form. 

The biologic actions of kinins are mediated by specific receptors located on the membranes of the target tissues. Two types of kinin receptors, termed Bj and B2, have been defined based on the rank orders of agonist potencies. (Note that here stands for bradykinin, not for -adrenoceptor.) Bradykinin displays the highest affinity in most B2 receptor systems, followed by lys-bradykinin and then by met-lys-bradykinin. One exception is the B2 receptor that mediates contraction of venous smooth muscle this appears to be most sensitive to lys-bradykinin. Recent evidence suggests the existence of two B2-receptor subtypes, which have been termed B2A and B2B. 

The synthesis of kinins can be inhibited with the kallikrein inhibitor aprotinin. Actions of kinins mediated by prostaglandin generation can be blocked nonspecifically with inhibitors of prostaglandin synthesis such as aspirin. Conversely, the actions of kinins can be enhanced with ACE inhibitors, which block the degradation of the peptides. Indeed, as noted above, inhibition of bradykinin metabolism by ACE inhibitors contributes significantly to their antihypertensive action. 

Another kinin, Lys-bradykinin (also known as kallidin), is produced via the action of the tissue-kallikrein enzyme on LMWK. This enzyme is found in many tissues, either in the form of a precursor requiring activation or as an active enzyme. In contrast to plasma kallikrein, which preferentially acts upon HMWK, tissue kallikrein can release kallidin from either HMWK or LMWK. Through the action of aminopeptidases, kallidin can subsequently be converted directly into bradykinin. This enzyme is present in both the plasma and on the surface of epithelial cells. 

When injected intravenously, kinins produce a rapid fall in blood pressure that is due to their arteriolar vasodilator action. The hypotensive response to bradykinin is of very brief duration. Intravenous infusions of the peptide fail to produce a sustained decrease in blood pressure prolonged hypotension can only be produced by progressively increasing the rate of infusion. The rapid reversibility of the hypotensive response to kinins is due primarily to reflex increases in heart rate, myocardial contractility, and cardiac output. In some species, bradykinin produces a biphasic change in blood pressure—an initial hypotensive response followed by an increase above the preinjection level. The increase in blood pressure may be due to a reflex activation of the sympathetic nervous system, but under some conditions, bradykinin can directly release catecholamines from the adrenal medulla and stimulate sympathetic ganglia. Bradykinin also increases blood pressure when injected into the central nervous system, but the physiologic significance of this effect is not clear, since it is unlikely that kinins cross the blood-brain barrier. 

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. 

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