The Malpighi lecture. From 'Porositates carnis' to cellular microcirculation.

After Malpighi's discovery of the capillaries almost 200 years elapsed before clear concepts about their main function, solute transport between blood and tissue, were formulated. The German physiologist Carl Ludwig played a significant role in this development because of his will to seek physico-chemical explanations of physiological phenomena. Ludwig's pupil Christian Bohr formulated the first (and almost definitive) mathematical model of transcapillary diffusion, later extended by Bohr's pupil August Krogh, to describe blood-tissue exchange in peripheral tissues. In the 1950s the two-pore model of transcapillary transport became the main paradigm (Pappenheimer, Grotte). The morphological substrate for this concept is found in tortuous pathways in the interendothelial junctions together with a small number of 'leaks' or focal openings in the capillary wall. The concept makes transcapillary transport of hydrophilic molecules a paracellular phenomenon. Recent studies in the author's laboratory based on electrophysiological methods on single capillaries have disclosed the rapidity of changes in microvascular permeability in response to many different substances--indicating reactions elicited in the endothelial cells. It is almost certain that in many cases, these changes are mediated via a transitory increase in cytosolic free calcium concentration. The overlap between permeability-increasing substances and agents that induce formation of endothelial-derived relaxing factor, EDRF, is so striking that a possible connection between vasodilatation and subtle increase in permeability should be considered. It is likely that the endothelial system of plasmalemmal invaginations ('vesicles') plays a role in the control of cytosolic calcium concentration.