Surgical exposure induces formation of an arteriovenous permeability gradient for macromolecules in the microcirculation of muscle

Rous and his colleagues ( P. Rous, H. P. Gilding, and F. Smith, 1930, J. Exp. Med. 51, 807–830, F. Smith and P. Rous, 1931, J. Exp. Med. 53, 195–217) uncovered evidence for an arteriovenous gradient of permeability in exchange vessels of muscle. After injecting vital dyes intravenously in laboratory animals, including mice and rats, they examined escape of the dyes from exchange vessels of abdominal muscles, prepared for observation by reflection of the overlying skin. They noted that a particular class of dyes, termed “poorly diffusible,” escapes from venules but not from arterioles and capillaries a few minutes after injection. We now assume that the “poor” diffusibility of the dyes stems from their binding to plasma proteins. We repeated similar experiments in mice and rats, using Evans blue as tracer, and also observed leakage of Evans blue from venules but not from other exchange vessels. We made three additional observations. (1) Evans blue leaks from venules only after the skin overlying the abdominal muscles is reflected. (2) Reflection of the skin initiates degranulation of mast cells in the muscles. (3) Leakage of Evans blue from venules is inhibited by administration of promethazine, a histamine and serotonin antagonist, to the animals prior to reflection of the skin. On the basis of our observations, we conclude that the arteriovenous permeability gradient for poorly diffusible dyes in the microcirculation of muscle represents response to tissue injury resulting from reflection of overlying skin.