Agonist-induced responses

Activation of platelets is counteracted by biochemical processes which prevent agonist-induced responses. These are mainly mediated by the signaling molecules cAMP and cGMP, and all substances that induce an increase in one or both of diese are defined as platelet antagonists some of these are listed in table 9.5.1. 

Bray, K.M., Weston, A.H., Duty, S., Newgreen, D.T., Long-more, J., Edwards, G. and Brown, T.J. (1991). Differences between the effects of cromakalim and nifedipine on agonist-induced responses in rabbit aorta. Br. J. Pharmacol. 102, 337-344. 

In related studies, norepinephrine action was studied on isolated strips of thoracic aorta (Simpson, 1982). It was found that the toxin neither altered agonist-induced responses nor the high affinity reuptake... 

The data of Table 1 reveal very clearly that some tissues (aorta, trachea) show a clear distinction in sensitivity between agonist- and K+-induced responses whilst other tissues (ileum) show equisensitivity of K+-and agonist-induced responses. Similarly, marked differences in sensitivity to responses induced by the same agonist in different tissues are found (5-HT responses of rabbit saphenous and basilar arteries). 

The basis of the operational model is the experimental finding that the experimentally obtained relationship between agonist-induced response and agonist concentration resembles a model of enzyme function presented in 1913 by Louis Michaelis and Maude L. Menten. This model accounts for the fact that the kinetics of enzyme reactions differ significantly from the kinetics of conventional chemical reactions. It describes the reaction of a substrate with an enzyme as an equation of the form reaction velocity = (maximal velocity of the reaction x substrate concentration)/(concentration of substrate A a... 

Figure 10 Effects of ligands with different modes of action on an agonist-induced response. By comparing the level of inhibition at full receptor occupancy with the baseline, a distinction can be made between an orthosteric antagonist (ortho anta), orthosteric inverse agonist (ortho inv ago), negative allosteric modulator (NAM), and positive allosteric modulator (PAM).

FIGURE 9.21 Changes in heart rate (ordinates) for agonist-induced changes in cardiac inotropy (changes in rate of ventricular pressure) in anesthetized cats. Responses shown to isoproterenol (filled circles) and dobutamine (open circles), (a) Response in normal cats shows inotropic selectivity (less tachycardia for given changes in inotropy) for dobutamine over isoproterenol, (b) The inotropic selectivity of dobutamine is reduced by previous a-adrenoceptor blockade by phentolamine. From [61],... 

Surmountable antagonism, an antagonist-induced shift to the right of an agonist dose-response curve with no diminution of the maximal response to the agonist (observed with simple competitive antagonists and some types of allosteric modulators). 

G-proteins are trimeric, signal-transducing, guanine nucleotide-binding proteins. They constitute the first step in transducing the agonist-induced activation of a G-protein-coupled receptor (see Chapter 2) to a cellular response. 

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