The effects of theophylline and 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (RO 20-1724) on protein secretion from rat parotid gland.

1 The effects of two chemically distinct cyclic nucleotide phosphodiesterase (PDE) inhibitors on protein secretion from superfused rat parotid gland were studied.2 In the presence of 1.0 mM Ca(2+), Ro 20-1724 (10 muM), an imidazolidinone derivative, increased the secretory response to isoprenaline 100% and the isoprenaline-dependent accumulation of adenosine cyclic 3',5'-monophosphate (cyclic AMP) 300-400%. At this concentration Ro 20-1724 alone did not cause protein secretion, accumulation of cyclic AMP or significantly inhibit PDE activity in cell-free preparations from parotid gland.3 In the absence of added Ca(2+) and in the presence of 1.0 mM EGTA, Ro 20-1724 inhibited the secretory response to isoprenaline 65% while increasing isoprenaline-dependent cyclic AMP accumulation 200%.4 In the presence of Ca(2+), theophylline (10 mM) stimulated protein secretion but did not cause the accumulation of cyclic AMP. When combined with isoprenaline the rate of secretion was greater than the sum of the effects of the individual drugs but there was no effect of theophylline on the isoprenaline-dependent accumulation of cyclic AMP.5 Theophylline-stimulated protein secretion is increased by omitting Ca(2+) from the superfusion medium without any detectable change in cyclic AMP accumulation. Under these conditions Ro 20-1724 inhibits theophylline-stimulated protein secretion and the maximum rate of protein secretion in the presence of isoprenaline and theophylline is no greater than that seen with either agent alone.6 It is concluded that the theophylline effects do not result from inhibition of PDE. It is suggested that the primary action of both drugs on parotid gland acinar cells is to alter the distribution of intracellular Ca(2+). Ro 20-1724 may also inhibit Ca(2+)/calmodulin activated enzymes such as PDE.