Histamine, complexation with heparin

Heparin is biosynthesized and stored (probably as a complex with histamine and other basic species) in basophilic granules of mast cells of many animal tissues. (Mast cells, whose function remains largely obscure, are located in connective tissues, near the capillaries, and in the walls of blood vessels.10 28 27)... 

Histamine is synthesized from the amino acid histidine by an action of the enzyme histidine decarboxylase (Fig. 38.1). Following synthesis, histamine is either rapidly inactivated or stored in the secretory granules of mast cells and basophils as an inactive complex with proteases and heparin sulfate or chondroitin sulfate. 

No Heparin Heparin normally occurs as a macromolecule complexed with histamine in mast cells where its physiologic role is unknown. It is extracted for commercial use from porcine intestine or bovine lung. Heparin is a mixture of straight-chain anionic glycosaminoglycans... 

About the same time Amann and Werle showed the complex of heparin with histamine and other di- and polyamines, and they also suggested a displacement mechanism in the release of histamine from mast cells. Schayer ... 

This was chosen as the first clinical problem to be studied since it presents visible lesions produced by mixtures of inflammation, allergy, and infection, all of which should release histamine. The alkaline antibiotics neomycin, streptomycin, polymyxin, and viomycin were combined with heparin because they could then produce the double-barreled action of an antibiotic complex with the antiinflammatory action of binding the endogeneously released histamine. It is further believed that by releasing the antibiotic slowly, toxic levels might be avoided in the plateau of release. 

The subject of the present review stems from the discoveries of A. Fischer and E. Jorpes. Fischer demonstrated that heparin binds or complexes with proteins and other bases and so modifies their biological activity. As a result, heparin is able to release or activate enzymes such as lipoprotein lipase -, to inhibit hormones such as cortisone and aldosterone , to detoxify toxic agents, and to bind histamine in body cells . Jorpes discovered that heparin is a highly sulphated polysaccharide and that it gives a specific colour reaction with dyes the metachromatic reaction. This resulted in (i) the association of heparin with the naturally occurring mucopolysaccharides ... 

Mast Cells and Basophils. The chief sites of histamine storage are mast cells in the tissues and basophils in blood. These cells synthesize histamine and store it in secretory granules along with a heparin-protein complex. In response to specific antigens, mast cells or basophils are sensitized. Histamine is then secreted from the storage granules. Besides the histamine stores in mast cells and basophils, there is evidence of non-mast cell histamine in some tissues, particularly gastric and intestinal mucosa (60). 

When given rapidly, protamine causes hypotension due to a decrease in vascular resistance, possibly linked to the release of nitric oxide from endothelium. Flypotension can be minimised by slow administration over 10-15 minutes. Protamine does not affect myocardial contractility. In some patients, systemic hypotension occurs in conjunction with pulmonary hypertension and, in severe cases, right ventricular failure. The mechanism is activation of the complement pathways by the heparin-protamine complex leading to release of thromboxane A2, which mediates pulmonary vasoconstriction. Unlike in anaphylaxis, plasma histamine concentrations are not increased. When this syndrome develops protamine administration should be stopped, and some have recommended giving heparin in an attempt to reduce the size of the heparin-protamine complex. 

Synthesis Histamine is an amine formed by the decarboxylation of the amino acid histidine (Figure 40.3). This process occurs primarily in the mast cells, basophils, and in the lungs, skin, and gastrointestinal mucosa—the same tissues in which histamine is stored. In mast cells, histamine is stored in granules as an inactive complex composed of histamine and the polysulfated anion, heparin, along with an anionic protein. If histamine is not stored, it is rapidly inactivated by amine oxidase enzymes. 

DIAMINE OXIDASE INHIBITORS act on the non-selective enzyme diamine oxidase (histaminase), which has as substrate such diverse substances as histamine, cadaverine and putrescine. As with the monoamine-oxidase enzyme, an intermediate complex is formed to yield the aldehyde, and this is then oxidized. The enzyme has been studied in relation to histamine metabolism, and is found to be released in certain circumstances from eosinophils and other tissues, and can be used as a marker in thyroid and ovarian carcinoma. Blood levels are raised in pregnancy, and heparin raises these levels. Amounts of the enzyme are high in the intestinal mucosa, liver and kidney of most species, A preparation of the enzyme itself (Torantil ) was once available for use in therapeutics for conditions in which a deficiency of histamine was implicated. 

The close association of histamine and heparin release in anaphylactic shock and in peptone shock suggests that complexes of histamine and heparin are held in biological systems. Histamine binds heparin in vitro, as shown by displacement tests, by dialysis, and by paper chromatography . Dextran sulphate, polymannuronic acid sulphate, polysulphated xylan and the iV-succinyl derivative of de-W-sulphated heparin give compounds with... 

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