Many other inflammatory mediators of anaphylaxis are also involved, including cytokines, basophil kallikrein, prekallikrein activator, and Hageman factor activator.
The exact role of the kinin system is unclear; however, bradykinin is a potent activator of vascular endothelium, releasing both endothelium-derived relaxing factor (nitric oxide) and prostacyclin (Fig 1).
Fig. 1 The action of any mediator on vascular responses is the result of effects on vascular endothelial cells and direct responses on vascular smooth muscle. Leukotrienes (LT), thromboxane A2 (TxA2), and histamine (H-, receptor effects) produce vascular contraction by increasing calcium release or entry in vascular smooth muscle. Bradykinin, substance P, histamine (H-, receptor effects), and other mediators stimulate endothelial cells to release both endothelium-derived relaxing factor (EDRF) and prostacyclin (PGI2), which produce vasodilation by vascular relaxation. EDRF, like nitroglycerin (TNG) or sodium nitroprusside (SNP), generates nitric oxide (NO), which activates guanylate cyclase. Guanylate cyclase generates cGMP, which causes calcium uptake into the sarcoplasmic reticulum and extrusion from the cell to produce vascular relaxation and vasodilation. PGI2, PGE-,, and other prostaglandins directly stimulate receptors on vascular smooth muscle that are coupled to adenylate cyclase. Stimulation of these prostaglandin receptors increases cAMP, which also increases calcium uptake into the sarcoplasmic reticulum and extrusion from the cell to produce vascular relaxation and vasodilation. The cyclic nucleotides in vascular smooth muscle cytoplasm are broken by various phosphodiesterase enzymes (PDE) as shown.
Multiple mediators produce shock during anaphylaxis via the direct and indirect effects that they have on vascular endothelium, smooth muscle, and the cardiopulmonary system (Fig 1). However, most of the symptoms and signs of anaphylaxis can be produced by histamine alone. Histamine may be released by a spectrum of non-specific stimuli including drugs, neuropeptides, anaphylatoxins, and antibody-induced release. Allergic and non-allergic histamine release are initiated by different mechanisms.
Histamine exhibits diverse endorgan effects including increased capillary permeability, increased exocrine gland secretion, smooth muscle contraction, increased prostaglandin synthesis, modulation of eosinophil migration, bradycardia, the release of endogenous catecholamines, and the suppression of T-cell function. Capillary permeability is a complex pathophysiological event produced in part by contracting cells on postcapillary venules and the stimulation of terminal arteriolar dilatation which opens intercellular gaps.
The precise role of individual mediators is difficult to assess, as they are usually only able to be studied in isolation. Infusion of any mediator into animal or man will produce some of the effects of clinical anaphylaxis. Possible mediators in anaphylactic shock include platelet activating factor, bradykinin, and cytokines.
The endpoints of mediator release in anaphylaxis are vasodilatation, smooth muscle contraction, increased capillary permeability, and increased exocrine secretion.
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