Internal milieu

As multicellular life forms reached a sufficient degree of complexity, they improved their physical separation from the water medium, allowing migration to land and continued evolution in novel environments. In terrestrial plants and animals, water is no longer both external and internal, but solely the internal milieu, the milieu interieur, in constant flux with the environment yet carefully separated from it Such, in a nutshell, is the biophysical role of water as a medium. 

The lipid bilayer forms a barrier to transport of matter into and out of the cell. This barrier function is essential since cells need to be able to control their internal milieu, regardless of the external environment. (Some antibiotics work by disrnpting the barrier function of bacterial membranes see Chapter 23). At the same time, some communication of signals and materials across the bilayer must occur. Special mechanisms to do this are a key property of biological membranes. More specifically, these mechanisms are the province of proteins that one finds in these membranes. 

Prior to its uptake into the blood (i.e during absorption), a drug has to overcome barriers that demarcate the body from its surroundings, i.e separate the internal milieu from the external milieu. These boundaries are formed by the skin and mucous membranes. 

Regulated transport of substances, which determines the internal milieu and is a precondition for homeostasis—i.e., the maintenance of constant concentrations of substances and physiological parameters. Regulated and selective transport of substances through pores, channels, and transporters (see p. 218) is necessary because the cells and organelles are enclosed by membrane systems. 

The blood is the most important transport medium in the body. It serves to keep the internal milieu constant (homeostasis) and it plays a decisive role in defending the body against pathogens. 

III Central conditioner Compounds that act mainly to improve the internal milieu of the CNS so that penile erection is enabled or enhanced, they do not on their own initiate an erection (e.g. trazodone)... 

FIGURE 10-28. Cellular events occurring during excitotoxicity (part 2). The internal milieu of a neuron is very sensitive to calcium, as a small increase in calcium concentration will alter all sorts of enzyme activity, as well as neuronal membrane excitability. If calcium levels rise too much, they will begin to activate enzymes that can be dangerous for the cell owing to their ability to trigger a destructive chemical cascade. 

The major ions in different organs and body fluids of euryhaline fish have been studied by a number of authors. The concentrations of sodium, potassium, magnesium and chloride were usually more concentrated in fish taken from sea water than in those from fresh water, the effect being shown in blood, kidney, liver, various secondary muscles and urine. The trend was less clear in the case of swimming muscle, as were the values for calcium (reviewed by Love, 1970, Table 30). All the ions mentioned above were much more concentrated in the urine of the fish from the sea, urine being one channel by which these salts are excreted. A fish with remarkable ability to control its internal milieu is the tilapia, in which the total sodium in the body increases by only 30% when it is transferred from fresh water to doublestrength sea water (Potts et al., 1967). 

An interesting mechanism for the establishment of a pH gradient in growing fatty acid vesicles was recently shown by Chen and Szostak [62], Fatty acid vesicles are usually very permeable to cations, including H+. Maintenance of a gradient thus requires a non-permeant cation, such as arginine. Incorporation of protonated (neutralised) fatty acid molecules from the external medium results in acidification of the internal milieu, by a flip-flop mechan-... 

The successful development of oral nucleic acid delivery systems is challenged by a variety of barriers encountered with the GI tract. The intestinal mucosa is both a physical and a biochemical barrier, separating the external environment from the internal milieu of the body. 

Our treatment of basic principles of water-solute relationships involves a bottom-up approach that begins with a basic physical-chemical analysis of how fundamental water solute interactions have set many of the boundary conditions for the evolution of life. We discuss how the properties of macromolecules and micromolecules alike reflect selection based on such fundamental criteria as the differential solubilities of different organic and inorganic solutes in water, and the effects that these solutes in turn have on water structure these are two closely related issues of vast importance in cellular evolution. With these basic features of water-solute interactions established, we will then be in a position to appreciate more fully why regulation of cellular volume and the composition of the internal milieu demands such precision. We then can move upwards on the reductionist ladder to consider the physiological mechanisms that have evolved to enable cells to defend the appropriate solutions conditions that are fit for the functions of macromolecular systems. This multitiered analysis is intended to help provide answers to three primary questions about the evolution and regulation of the internal milieu ... 

Which solutes are selected as constituents of the internal milieu ... 

These concepts and definitions provide the vocabulary and theoretical framework for much of the analysis that follows, as we explore one of the most interesting and important aspects of life, the evolution and regulation of the internal milieu. We begin this exploration by considering a primary way in which life depends on water, namely, the role of water as a reactant in metabolic chemistry. 

EVOLUTION OF THE INTERNAL MILIEU PATTERNS OF SOLUTE ACCUMULATION... 

The different facets of water-micromolecule-macromolecule interactions discussed up to this point involve several of the most important ways in which water has shaped the characteristics of living systems and the ways in which the internal milieu is defended in the face of water stress. Because of water s pervasive influence on the evolution of virtually all properties of organisms, there are many other imprints of water on biological design that remain to be discussed. Below, we present in somewhat abbreviated manner several of these issues. This discussion will help us to understand more clearly how water establishes the boundary conditions for life and dictates many of the engineering principles that are found in the designs of cells. Of particular importance is the issue of packaging how to accommodate tens of thousands of chemical systems in a minute volume of water. 

Somero, G.N. (1986). Protons, osmolytcs, and fitness of the internal milieu for protein function. Am. J. Physiol. 252 (Regulatory Integrative and Comp. Physiol. 20) R197-R213. 

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