ENZYME INHIBITION ANE CHANGES IN CELL FUNCTION 467 



tivity of the cells indirectly, since the effect of the agonist will depend 

 primarily on the concentration ]Dresent in the region of the receptors and 

 the ability of the receptors to react with the agonist. The reaction with 

 the receptors is usually represented simply as: 



A + R^AR K^=^^^ (9-14) 



(AR) 



and the effect on the tissue is assumed to be proportional to (AR)/(R;), 

 the fraction of the total receptors combined with agonist: 



(^^) '^^^ (9-15) 



(R,) (A), + Ka 



where (A)^ is the concentration of agonist in the receptor region. Some 

 common agonists would be acetylcholine, epinephrine, norepinephrine, 

 histamine, 5-hydroxytryptamine, and related substances, but the concept 

 could be extended to any substances produced in the preparation and hav- 

 ing an effect on the cellular activity. Even in isolated tissues, such substan- 

 ces may control the functional level. Isolated cardiac tissue or intestine are 

 under the influence of acetylcholine in most cases, as may be readily shown 

 by the effects of the specific antagonist atropine. Thus these tissues are 

 susceptible to effects of inhibitors on any of the reactions determining the 

 concentration of agonist. 



The simplest system in which the agonist is formed and is active and inac- 

 tivated in a discrete region (diffusion either through membranes or away 

 from the region being unimportant), is actually represented by a mono- 

 linear chain (Eq. 7-1) and the concentration of agonist is given by the ex- 

 pressions developed for multienzyme systems. Inhibition of the formation 

 reaction would, of course, lead to a decrease in agonist concentration and 

 a changed level of tissue activity. The agonist is usually formed, not by a 

 single reaction but by a series of enzymically catalyzed steps. The synthe- 

 sis of acetylcholine, for example, requires choline and an acetyl donor 

 (probably acetyl-CoA); hence, the enzymes involved in the formation of 

 the acetyl donor are possible sites for inhibition as well as the choline 

 transacylase, the enzyme catalyzing the final condensation. Inhibitor- 

 induced functional failure in synaptic networks most likely results from 

 depression in the formation of acetylcholine or some other transmitter. 



Inhibition of an Enzyme Inactivating an Agonist 



The potent effects on tissue function of the inhibitors of enzymes in- 

 activating acetylcholine or the sympathomimetic amines are well known. 

 These actions are due to the rise in agonist concentration at the receptor 

 region. The normal balance between formation and inactivation is disturbed. 



