[Phosphodiesterase inhibition as a therapeutic principle]

A positive inotropic effect can be achieved by an increase in the intracellular concentration of calcium which interacts with the contractile proteins and/or by an increased sensitivity of the contractile proteins towards calcium. An increase in intracellular calcium concentration can be produced by cAMP-increasing agents. An increase in intracellular cAMP levels can result from stimulation of adenylate cyclase which leads to an increase in cAMP formation or from inhibition of the degradation of cAMP by inhibition of phosphodiesterases. The main effect of cAMP is to increase the calcium inward current during the action potential and to enhance the sequestration of calcium by intracellular calcium stores. This leads to an increase in calcium release and hence to an increase in the calcium concentration in the vicinity of the contractile proteins. PDE inhibitors are independent of receptors and also produce vasodilatation ("inodilators"). However, two potential disadvantages of PDEs must be kept in mind: 1) Positive chronotropy and induction of tachyarrhythmias and 2) tolerance which might be due to a down regulation of beta-adrenoceptors and/or to an increase in inhibitory G-proteins.