The chemical events of excitation have received considerably less attention than their physical counterparts. This comparative neglect can probably be explained by the remarkable suitability of physical methods for the study of short lasting phenomena, contrasting with the lack of chemical methods capable of detecting rapidly reversible changes.However, the importance of the chemical aspects of the excitation problem is more and more widely recognized, as witnessed by the increasing amount of work devoted to the ionic shift, the energy-yielding reactions, and other chemical changes associated with excitation.The present paper deals with alterations of proteins induced by stimulation of nerves and nerve centers. The over-all problem of the chemistry of cellular excitation will be surveyed in a review to be published (Ungar, 1957).A number of observations indicate a high rate of protein breakdown in nerve structures submitted to prolonged and intense stimulation (Soula, 1912(Soula, , 1913Soula and Faure, 1913; Hydra, 1943 Hydra, , 1955Geiger et al., 1953). More subtle and possibly reversible changes in protein structure have been postulated by Meyer (1937), McElroy (1947), Nassonov (1948), and Segal (1956) without, however, the support of direct experimental evidence. It is believed that the experiments reported in this paper have produced some evidence in favor of reversible molecular rearrangements taking place in the proteins of stimulated structures. MethodsElectrical stimulation was used in all experiments by means of a 60 cycle, 40 volt alternating current from a Harvard stimulator connected to platinum electrodes. Frog and rat sciatic nerves were excised, placed in the appropriate Ringer solution, and stimulated for the specified interval. Stimulation of the cerebral cortex in cats and dogs was produced with the technique described by Geiger, Dobkin, and Magnes (1953) through electrodes placed on the brachial plexus. The unstimulated side was * Some of the results reported in this paper were presented at the International Physiological Congress in Brussels (Ungar et al., 1956). 635

A study was made of the dose-response relationship after injury induced by histamine, an antigen-antibody reaction, and serotonin. The intensity of the inflammatory reaction, as measured by the local clearance of albumin-I131, was found within a certain range to be related to the logarithm of the dose. The relative movements of water and protein were studied by comparing the water increment calculated on the basis of radioactive protein accumulation with the actual increment in the water content of the tissue. At threshold doses of histamine and at the beginning of xylene inflammation, the skin gains more water than protein. Subsequent to this stage and at higher histamine doses, protein is transiently retained by the inflamed skin. After these changes, the ratio of the increments of tissue water and protein approaches that of plasma. Possible mechanisms responsible for these phenomena are examined.

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A method has been developed for following the course of the inflammatory reaction by assaying the radioactivity changes of the skin of rats injected intravenously with radioiodinated human serum albumin (RISA). For this purpose, the term "clearance" has been introduced. It defines the amount of blood, in milliliters, completely cleared of radioactive material by 1 Gm. of dry skin. The initial reaction follows strictly a course described by the formula a = b t c , where (a) is the difference between the average clearance of the inflamed and normal skin samples, (t) is the time in minutes, and (b) and (c) are constants. For normal-, medium-, and large-sized rats, as well as adrenalectomized animals, subjected to Xylene irritation, the (c) value was characteristically constant and equal to 2. Heat injury, on the other hand, is characterized by a lower exponent. The value of the constant (b) varied with the experimental group. The functional or anatomical factors reflected in these constants are not established. Nutritional blood flow was determined at close intervals during the development of the inflammatory reaction. It is postulated that the characteristic kinetics of the transudation of blood proteins into the inflamed skin reflects the changes in nutritional blood flow and vascular-exchange area which accompany the development of the reaction. The view is expressed that the passage of smaller molecules across normal vessel walls is likewise regulated by changes in blood flow and extent of vascular exchange.