![]() cAMP was incubated with purified cAMP-PDE at 30☌ for 30 min in the presence of increasing concentrations of methylxanthines. Inhibition of cAMP-PDE activity by methylxanthines. In this same study, PDE was identified as the enzyme capable of inactivating cAMP, and it was shown that this enzyme could be activated by magnesium ions and importantly could be inhibited by caffeine providing a plausible mechanism of action for the diverse activities of this drug (see Figure 1 Sutherland, 1958). The discovery of cAMP was followed 5 years later by the identification of a second intracellular second messenger, cyclic guanosine monophosphate (cGMP), in rat urine ( Ashman et al., 1963). The seminal work by Earl Sutherland and Ted Rall published in 1958, first identified the heat-stable nucleotide, cyclic adenosine monophosphate (cAMP) in liver extracts as a second messenger and suggested that it mediated many of the cellular effects of neurotransmitters and hormones. Subsequently, analogues of caffeine including theophylline were successfully introduced as treatments for airway disease. Although the mechanism of action at the time was unknown, it has since been shown that caffeine was acting as a non-selective, albeit weak, PDE inhibitor. An asthmatic he noted that when he drank a strong cup of coffee on an empty stomach, his breathing eased, an effect attributed to the bronchodilator properties of caffeine. The phosphodiesterase (PDE) story begins with the work of Henry Hyde Salter in 1886. ![]()
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