Tissue receptors

Hurst (19) discusses the similarity in action of the pyrethrins and of DDT as indicated by a dispersant action on the lipids of insect cuticle and internal tissue. He has developed an elaborate theory of contact insecticidal action but provides no experimental data. Hurst believes that the susceptibility to insecticides depends partially on the cuticular permeability, but more fundamentally on the effects on internal tissue receptors which control oxidative metabolism or oxidative enzyme systems. The access of pyrethrins to insects, for example, is facilitated by adsorption and storage in the lipophilic layers of the epicuticle. The epicuticle is to be regarded as a lipoprotein mosaic consisting of alternating patches of lipid and protein receptors which are sites of oxidase activity. Such a condition exists in both the hydrophilic type of cuticle found in larvae of Calliphora and Phormia and in the waxy cuticle of Tenebrio larvae. Hurst explains pyrethrinization as a preliminary narcosis or knockdown phase in which oxidase action is blocked by adsorption of the insecticide on the lipoprotein tissue components, followed by death when further dispersant action of the insecticide results in an irreversible increase in the phenoloxidase activity as a result of the displacement of protective lipids. This increase in phenoloxidase activity is accompanied by the accumulation of toxic quinoid metabolites in the blood and tissues—for example, O-quinones which would block substrate access to normal enzyme systems. The varying degrees of susceptibility shown by different insect species to an insecticide may be explainable not only in terms of differences in cuticle make-up but also as internal factors associated with the stability of oxidase systems. 

Novel modalities of cell/tissue/receptor exposure... 

The benzene ring per se does not impart any particular pharmacological response to a drug. It is widely held that its planarity, its ability to bind to tissue receptors by Van der Waals and charge transfer mechanisms, and, particularly, its ability to serve as a conductor of electrons within a substance serve as modulators, enhancing or diminishing the intensity of response to a molecule that is otherwise inherently bioactive. 

The answer is b. (Hardman, p 1507. Katzung, pp 723-724J Three proposed mechanisms for sulfonylurea action are (1) the release of insulin from pancreatic cells, (2) reduction of serum glucagon levels, and (.3) increased binding of insulin to tissue receptors. On binding to a specific receptor that is associated with a K channel in cell membranes, sulfo-nylureas inhibit K efflux, which causes influx of Ca followed by release of preformed insulin. 

IgE binds to tissue receptor sites through its F region, leaving the Fab region free to react with the allergen. The half-life of IgE is 2 days... 

By now you will be comfortable with the idea that the body treats drugs as just another set of chemicals to cope with, and also the idea that drugs interact with many molecules in many sites - with gastric acid, with chemicals in food, with enzymes in the gut and others in the gut wall and liver, with plasma proteins in the blood, and (often transiently) with their tissue receptor once they have got that far. 

Some adrenomimetic drugs act both directly and indirectly that is, they release some norepinephrine from storage sites and also directly activate tissue receptors. Such drugs are called mixed-action adrenomimetics. However, most therapeutically important adrenomimetic drugs in humans act either directly or indirectly. 

E) Anesthetics bind more readily to tissue receptors when hypotension and poor oxygenation occur. With which hypothetical anesthetic would you expect anesthetic partial pressure to be achieved relatively quickly ... 

Glucagon is extensively degraded in the liver and kidney as well as in plasma and at its tissue receptor sites. Because of its rapid inactivation by plasma, chilling of the collecting tubes and addition of inhibitors of proteolytic enzymes are necessary when samples of blood are collected for immunoassay of circulating glucagon. Its half-life in plasma is between 3 and 6 minutes, which is similar to that of insulin. 

Advances have been made in the localization of the cellular sites of l,25-(OH)2D3 in target tissue. Receptor proteins have been extracted, and, in the case of the chick intestinal receptor, purified to homogeneity.451 The ability of l,25-(OH)2D3 to stimulate absorption of calcium is blocked reversibly by inhibitors of RNA and protein synthesis. This suggests that l,25-(OH)2D3 functions by a nuclear mechanism. 

Holmgren, J. Lonnroth, I. Svennerholm, L. Tissue receptor for cholera exotoxin Postulated structure from studies with GMl-ganglioside and related glycolipids. Infect. Immun.,... 

Release of Transmitter Species and Tissue Receptor Type References... 

Transferrin is a single-chain glycoprotein that binds 2 g-atoms of ferric iron per mole of protein. The iron is chelated via tyrosyl and histidyl residues, and the complex is extremely stable at physiologic pH. The function of transferrin is to transport iron throughout the human organism, especially to the immature red cells, which cannot effectively acquire iron for the biosynthesis of hemoglobin unless it is presented to them in combination with transferrin. Specific transferrin receptors are present on the surface of such immature red cells as well as in all other tissues. Receptor-mediated endocytosis (see Chapter 9) is believed to be the main means of transferrin-bound iron entry into cells. Transferrin is also believed to be antimicrobial because it withholds iron from microorganisms. 

All hormones, other than the steroids and thyroid hormones, as well as many neurotransmitters, act on cellular metabolism by interacting with membrane receptors. The extent of hormone action in a cell line or tissue depends on both the number of receptors per cell as well as the affinity of the receptor for the hormone. Very often, the circulating hormone concentration (e.g., for insulin) regulates the number of its tissue receptors in an inversely proportional manner. 

Type I lipoproteinemia is generally caused by the inability of the organism to clear chylomicrons. The problem may be defective ApoC-II or a defective lipoprotein lipase. Very often, chylomicron clearance may be affected by injection of heparin, which apparently releases hepatic lipase from the liver into the circulation. ApoE disorders may be associated with type III lipoproteinemia, in which clearance of IDL is impeded. Increases in circulatory LDL are usually caused by a decrease in tissue receptors specific for ApoB-100. An extreme case of type Ha hyperlipoproteinemia is familial hypercholesterolemia, in which serum cholesterol levels may be as high as 1000 mg/dL and the subjects may die in adolescence from cardiovascular disease. There is total absence of ApoB-100 receptors. Mild type Ila and lib lipoproteinemias are the most commonly occurring primary lipoproteinemias in the general population. 

Protein blocks are applied to the tissues prior to application of the primary antibody to reduce nonspecific staining. Nonspecific staining is non-CDR-mediated staining. Protein blocks often contain serum, which contain immunoglobulins that bind to the Fc receptors in the tissues, blocking Fc attachment to those tissue receptors. Other proteins such as casein or BSA may be added to block nonspecific protein-protein interactions. 

The maleimidoacetamide 6c differed from /3-FNA in showing considerably greater irreversible /x-antagonism in the MVD relative to p,-blockade in the GPI. It was proposed, on this basis, that different proportions of p,-receptor subtypes (/xM and pa) exist in the two tissues. Receptor models were advanced in which /x-receptors are subject to regulatory subunits p, which differ in the two muscle preparations. 

The mechanism by which the action of a hormone on its tissue receptor leads to stimulation of adenylate cyclase is not known. Studies concerning the relationship of hormone binding to enzyme stimulation are in their infancy, and there may not be a direct relation between the number of receptors occupied and the extent of enzyme stimulation. The problems involved in the identification of the glucagon [24] and catecholamine receptors [25-27] have been discussed elsewhere. 

At steady state, the distribution of any drug in the body is dependant upon its binding to plasma proteins, blood cells and tissue receptors. Only unbound drug is capable of entering and exiting from plasma and tissue compartments. Therefore, an apparent volume of distribution can be expressed as follows,... 

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