Physiologic response

Physiological responses to prostaglandins encompass a variety of effects Some prostaglandins relax bronchial muscle others contract it Some stimulate uterine con tractions and have been used to induce therapeutic abortions PGEj dilates blood vessels and lowers blood pressure it inhibits the aggregation of platelets and offers promise as a drug to reduce the formation of blood clots... 

Chlorine gas is a respiratory irritant and is readily detectable at concentrations of <1 ppm in air because of its penetrating odor. Chlorine gas, after several hours of exposure, causes mild irritation of the eyes and of the mucous membrane of the respiratory tract. At high concentrations and in extreme situations, increased difficulty in breathing can result in death through suffocation. The physiological response to various levels of chlorine gas is given in Table 19. 

The biological response to chemical insult may take numerous forms, depending on the physicochemical properties of the material and the conditions of exposure. Listed below are some of the more significant and frequendy encountered types of injury or toxic response they may be defined in terms of tissue pathology, altered or aberrant biochemical processes, or extreme physiological responses. 

Physiological response glycogen breakdown visual excitation histamine secretion in all allergic reactions slowing of pacemaker activity that controls the rate of the heartbeat... 

TABLE 5.1 Thermal Environment and Physiological Responses of Thermoregu lation... 

ISO EN 9886 presents the principles, methods, and interpretation of measurements of relevant human physiological responses to hot, moderate, and cold environments. The standard can be used independently or to complement other standards. Four physiological measures are considered body core temperature, skin temperature, heart rate, and body mass loss. Comments are also provided on the technical requirements, relevance, convenience, annoyance to the subject, and cost of each of the physiological measurements. The use of ISO 9886 is mainly for extreme cases, where individuals are exposed to severe environments, or in laboratory investigations into the influence of the thermal environment on humans. 

By the turn of the century the theory of chemical mediation of physiologic responses had gained some currency. There ensued in some laboratories an intense search for endogenous chemical modifiers of bodily responses. The first such agent to be isolated from mammalian tissue was the ubiquitous hormone, epinephrine—at that time known as adrenaline. This compound has played an important role in pharmacology as well as in medicinal chemistry. 

Efficacy is measured in relative terms (having no absolute scale) and quantifies the ability of a molecule to produce a change in the receptor (most often leading to a physiological response). 

From this equation it can be seen that for a given receptor density systems can spontaneously produce physiological response and that this response is facilitated by high G-protein concentration, high-affinity receptor/ G-protein coupling (low value of KG), and/or a natural tendency for the receptor to spontaneously form the active state. This latter property is described by the magnitude of L, a thermodynamic constant unique for every receptor. 

The most probable mechanism for inverse agonism is the same one operable for positive agonism namely, selective receptor state affinity. However, unlike agonists that have a selectively higher affinity for the receptor active state (to induce G-protein activation and subsequent physiological response) inverse agonists have a selectively higher affinity for the inactive receptor state and thus uncouple already spontaneously coupled [RaG] species in the system. 

It is assumed that the receptor species leading to G-protein activation (and therefore physiological response) are complexes between the activated receptor ([RJ) and the G-protein namely, [ARaG] + [RaG], The fraction of the response-producing species of the total receptor species (([ARaG] + [RaG])/Rtot) is denoted p and is given by... 

Agonist, a molecule that produces physiological response through activation of a receptor. 

Constitutive receptor activity, receptors spontaneously produce conformations that activate G-proteins in the absence of agonists. This activity, referred to as constitutive activity, can be observed in systems in which the receptor expression levels are high and the resulting levels of spontaneously activating receptor species produce a visible physiological response. An inverse agonist reverses this constitutivie activity and thus reduces, in a dose-dependent... 

Cubic ternary complex model, a molecular model (J. Their. Biol 178, 151-167, 1996a 178, 169-182, 1996b 181, 381-397, 1996c) describing the coexistence of two receptor states that can interact with both G-proteins and ligands. The receptor/G-protein complexes may or may not produce a physiological response see Chapter 3.11. 

Extended ternary complex model, a modification of the original ternary complex model for GPCRs (J. Biol. Chem. 268, 4625-4636, 1993) in which the receptor is allowed to spontaneously form an active state that can then couple to G-proteins and produce a physiological response due to constitutive activity. 

Ag, convention for the equilibrium dissociation constant of an antagonist-receptor complex usually determined in a functional assay denoting antagonism of a physiological response, although it can be associated with an antagonist when it is used in other types of experiment. It has units of M and is the concentration that occupies half the receptor population at equilibrium. It also can be thought of as the reciprocal of affinity. 

Operational model, devised and published by James Black and Paul Leff (Proc. R. Soc. Lond. Biol. 220,141-162, 1983), this model uses experimental observation to describe the production of a physiological response by an agonist in general terms. It defines affinity and the ability of a drug to induce a response as a value of x, which is a term describing the system (receptor density and efficiency of the cell to convert an activated receptor stimulus into a response) and the agonist (efficacy). It has provided a major advance in the description of functional effects of drugs see Chapter 3.6 for further discussion. 

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