Histamine/peptide leukotriene

The peptide leukotrienes 99,100, and 101 cause contraction of the bronchial smooth muscle and probably play an important role as mediators in allergic reactions (e.g. asthma) and inflammations. Antagonistic blockade of the leukotriene action of 99,100, and 101, by analogy with histamine Hj-reccptor antagonists, would therefore be an important principle in the treatment of allergic symptoms. A number of selective peptide leukotriene antagonists have in fact been synthesized by Smith Kline ... 

Figure 4.1. Model of neurogenic inflammation. Stimulation at the skin initiates orthodromic impulses in sensory nerve receptors which elicit antidromic impulses in branching collaterals. The release of neuropeptides such as calcitonin gene-related peptide (CGRP), substance P (SP), and somatostatin (SOM) from nerve terminals ensues and they in turn stimulate the release of histamine (H) and the generation of leukotrienes (LT) from nearby mast cells. These mediators then produce vasodilatation and an increase in vascular permeability. In addition, they act on the nerve terminal to produce further...

Figure 4.8. Hypothesis for the local generation of mast-cell-stimulating peptides by the action of neutrophil-derived enzymes on albumin. Initial stimulation of the mast cell by any of a variety of agents causes the release of preformed histamine (H) neutrophil and eosinophil chemotactic factors (NCF, ECF) and enzymes and the de novo synthesis of prostaglandins (PG) and leukotrienes (LT). These agents increase vascular permeability and vessel diameter. As a result, albumin and later neutrophils (PMN) enter the tissue space where the latter undergo phagocytosis and the secretion of proteolytic enzymes to the extracellular space where they act on albumin to generate NRP (neurotensin-related peptide) and HRP (histamine-releasing peptide). These newly formed peptides then act as a second stimulus to the mast cell. In addition NRP and HRP may affect other immunocompetent celt such as monocytes, macrophages or eosinophils.

Histamine is released from mast cells in antigen-antibody reactions, as in anaphylaxis and allergy, which are the most widely known physiological reactions to histamine. However, these potentially fatal reactions are not caused by histamine alone. Other agents present in mast cells, such as serotonin, acetylcholine, bradykinin (a nonapeptide), and a slow-reacting substance or leukotriene (see chapter 8) also contribute. In the stomach, where histamine induces acid secretion, its release seems to be regulated by the peptide hormone pentagastrin. 

The mediators probably most important in causing asthmatic bronchoconstriction are leukotrienes LTC and LTD. Another leukotriene (LTB ), prostaglandins, peptides, some enzymes, and histamine probably also play a role. 

Originally isolated after stimulation of lung tissue by histamine and snake venom and named over 70 years ago as slow reacting substance of anaphylaxis, (SRS-A), leukotrienes are a family of bioactive peptide-conjugated eicosanoid lipids produced by mast cells, basophils, eosinophils, and macrophages. The name cysteinyl leukotrienes is derived from the facts that the com-... 

The theory behind the inclusion of histamine Hi antagonists in the premedication is obvious but the mode of action of corticosteroids is not completely understood so some beheve its inclusion cannot be explained and justified. Corticosteroids ultimately inhibit kaUikrem, a peptide that lowers blood pressure and liberates bradykinin. Corticosteroids also act in the arachidonic acid cascade to inhibit the production of prostaglandins and leukotrienes, so there does seem to be some rationale for their use. There are some indications that premedication prevents the recurrence of many minor reactions. Some, or even many, of these reactions may not be immune mediated, proceeding instead via a nonspecific and low-level histamine release. In the case of severe inunediate reactions, IgE antibody-mediated explosive histamine release from mast cells may overwhelm the potential effectiveness of premedication. 

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