PLASMA KININS AND OTHER VASOACTIVE COMPOUNDS IN ACUTE INFLAMMATION

In order that a substance may be considered as a possible mediator of the inflammatory response, certain conditions must be satisfied. First, it must have physiological or pharmacological actions which resemble, in whole or in part, those effects which characterize the inflammatory response. The plasma kinins satisfy well in this respect: they produce vasodilatation, increased vascular permeability, pain, and in higher concentrations, accumulation and migration of leukocytes (Elliott et al., 1960; Lewis, 1962). These actions are the cardinal signs of the early stages of inflammation. However, severa1 other naturally occurring substances also exert some of these effects. For example, histamine produces vasodilatation, increased vascular permeability, and, perhaps, accumulation of leukocytes. However, unlike the pain produced by plasma kinins, the sensation produced by histamine, when injected intradermally or applied to an area of exposed cutaneous tissue (a blister base), is not the burning sensation one experiences in injury, but is an intense itching sensation. In examining the vascular permeability in animals which had received pontamine blue dye intravenously, there is a marked difference in the response to intradermal histamine and plasma kinins. The response to histamine is more widespread but less intense that the response to plasma kinins. Menkin ( 1936) first observed a similar difference between the response to histamine and that to inflammatory exudates, and it was one of the arguments he used in favor of the view that such exudates contain a permeability-increasing substance other than histamine. However, histamine does produce the triple response which characterizes many forms of minor injury, whereas this response cannot be reproduced by plasma kinins. These peptides do not produce the axon reflex vasodilatation which gives rise to the flare component OI the triple response to mild injury. 5-Hydroxytryptamine is another naturally occurring substance which possesses some of the actions which characterize inflammation. It increases v a s d a r permeability in some species and is particularly potent in rodents which are relatively insensitive to histamine (Rowley & Benditt, 1956; Parratt & West, 1957). Jt is interesting that in these species, 5-hydroxytryptamine, as well as histamine, is present in the mast cells (Benditt et al., 1955; Bhattacharya & Lewis, 1956)cells which are readily degranulated in many forms of injury. 5-Hydroxytryptamine, like plasma kinins and unlike histamine, gives rise to a burning sensation when applied to an area of exposed cutaneous tissue. This substance, however, is not a potent vasodilator and, in fact, in humans behaves rather like adrenaline in constricting skin blood vessels while dilating muscle blood vessels (FOX et al., 1961). Substance P is a naturally occurring peptide but not a plasma kinin, which, at least in crude preparations, causes vasodilatation, increased permeability, and pain (Spector, 1958; Bisset & Lewis, 1962). However, it will be necessary to reexamine this peptide when we have available the pure natural product or the synthetic peptide. A second criterion to be satisfied when a substance is considered for the role of mediator is that it should be evident during inflammation. However, here there