Systemic considerations circulatory system

Vertebrates contain several proteins that maintain the integrity of the blood plasma circulatory system. These contain domains that are specific to vertebrates (Gla, FN1, FN2) (Patthy, 1985), domains that are found in different contexts in invertebrates and/or protists (FBG, APPLE, KR) (Xu and Doolittle, 1990 Eschenbacher et al., 1993 Wilson et al., 1993) and a domain that is found in all cellular life (trypsin-like serine protease, Tryp SPc). The invertebrate versions of these domains, however, are found in molecular contexts that differ considerably from their vertebrate extracellular counterparts, indicating that although these nonenzy-... 

The circulatory system of fish is also unique structurally and functionally. Structurally, the membranous nature of the vasculature makes for a friable high-capacitance system under low pressure. Low blood flows result in somewhat longer distributional phases for many drugs. Processes such as heart rate and stroke volume that influence drug distribution are themselves influenced by external factors such as temperature and stress. In addition, total plasma protein content differs in fish as compared to mammals. Total plasma protein in the trout and flounder is approximately one-half that of mammals such as dogs and cats. For many compounds protein binding is considerably lower in fish than their mammalian counterparts (19, 20). 

An advantage of this sort of test is that it is much easier and more rapid than dominant-lethal tests, chromosomal-aberration studies, and specific-locus mutation experiments. Because the test is done in vivo, activation of the test chemical is possible in the germ cells themselves or in other organs that might then release the active compound to the circulatory system and thereby cause an interaction with the germ cells. For most of the chemicals looked at, the measurement of DNA repair in mouse germ cells appears to be a considerably more sensitive biologic end point than measurement of dominant lethals or translocations. 

Considerable losses of body water may occur rather suddenly via hemorrhage or more slowly via severe diarrhea or vomiting. Excessive losses of blood volume cause shock, which may set in when 25-30% of the blood volume is lost. The physiologic mechanism to correct for blood loss involves the rapid movement of interstitial fluid into the circulatory system, into which as much as 50% of the interstitial fluid may thus be transferred within a matter of a few hours. The interstitial fluid is, in turn, partially replaced by intracellular fluid however, this is a much slower process, and 1 or 2 days is required to reestablish a fluid equilibrium in the organism. The lost fluids and electrolytes must eventually be replaced through diet or intravenous feeding. 

The squalestatins, e.g. 6.28, also known as the zaragozic adds, have attracted considerable interest as inhibitors of squalene synthase and hence of cholesterol biosynthesis and lipid deposition in the circulatory system. They are also inhibitors of farnesyl protein transferase and thus they may have other potentially useful biological applications. They are formed by Phoma spedes and also by Setosphaeria khartoumensis. The squalestatins are characterized by a dioxabicyclo-octane core bearing three carboxyl groups and two polyketide chains, one of which is attached as an ester. The biosynthetic incorporation of succinic acid into part of the bicyclo-octane, together with its oxygenation pattern, indicate that it may be derived via oxaloacetic acid. Both the polyketide chains have several pendant methyl groups attached to them, which arise from methionine, whilst benzoic add ads as a starter unit for one of the chains. These complex structures are thus the summation of several biosynthetic pathways. 

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