Final Discussion

Abstract

Dr. Robison: I thought I might start by mentioning an interesting experiment relating to the action of theophylline. I believe this is pertinent because a number of people who have done experiments with theophylline or caffeine noted an effect, and assumed that the effect was probably secondary to the inhibition of phosphodiesterase. We have recognized for a long time that theophylline and other phosphodiesterase inhibitors probably have a variety of other mechanisms of action, and Schwabe and Ebert recently did a very interesting experiment pointing to an additional mechanism involving cyclic nucleotides. They incubated cyclic AMP with isolated rat fat cells at different cell densities. When they incubated the cells at a high density, as I recall, about 100,000 rat cells per milliliter, and then added isoproterenol, a beta adrenergic agonist, they produced what a lot of people had seen before, a relatively small increase in the level of cyclic AMP. When they did the same experiment in the presence of theophylline, they saw a much more striking rise. But, when they reduced the density of the cells down to something like 20,000 per milliliter, then isoproterenol by itself produced a large effect, and theophylline did not increase the response much above that. They interpreted the experiment as suggesting that at high cell densities, theophylline was acting as an antagonist of some inhibitory substance produced by the cell, an inhibitor of adenyl cyclase. Thus, at a high cell density, there is a lot of inhibitor and, therefore, a large effect of theophylline. But when the cells are reduced in number, the inhibitor is not present in high concentration, and isoproterenol by itself produces a good response.