Molecular Form of Theophylline Responsible for Positive Inotropic Activity

A comparison of the responses of the dog heart-lung, cat papillary muscle and perfused turtle heart preparations to equimolar doses of theophylline and 8-chlorotheophylline indicates that theophylline is a considerably more potent cardiac inotropic agent. This difference in activity has been related to the ionization characteristics of the two drugs. Studies performed on the isolated turtle heart over a pH range of 7.5 to 9.5, in which the ratio of ionized to nonionized theophylline is varied greatly, indicate that positive inotropic activity is determined by the concentration of nonionized theophylline presented to the heart in the perfusion medium. Similar studies with caffeine, which does not ionize to any appreciable degree over this pH range and thus exists almost exclusively in the nonionized form, indicate that positive inotropic activity is also determined by the concentration of nonionized caffeine presented to the heart in the perfusion medium. No significant difference in the positive inotropic activity of these two agents is discernible when they are compared on the basis of equimolar doses of nonionized drug at pH 7.5 and 8.5. No correlation was observed between the concentration of theophylline anion or cation in the extracellular or intracellular aqueous phase and positive isotropic activity over a wide range of drug concentration in the perfused turtle heart. The positive inotropic activity of theophylline and caffeine is influenced by the pH of the perfusion medium when the pH of this solution is less than 7.5. 8-Chlorotheophylline has been shown to be a potent positive inotropic agent, equivalent to theophylline in pharmacological response, when the concentration of nonionized drug is only one-fifteenth that required for an equivalent response from theophylline. The thesis is presented that the nonionized form of theophylline is the active form of the drug at its final site of action as a positive inotropic agent in the perfused turtle heart. It is suggested that a similar conclusion for the activity of this drug in mammalian cardiac tissue should be considered on the basis of the results obtained in the turtle heart and the indirect evidence obtained in mammalian tissues.