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Drotaverine is considered an inhibitor of cyclic-3',5'-nucleotide-phophodiesterase (PDE) enzymes; however, published receptor binding data also support the potential L-type voltage- operated calcium channel (L-VOCC) blocking effect of drotaverine. Hence, in this work, we focus on the potential L-VOCC blocking effect of drotaverine by using L-VOCC-associated functional in vitro models. Accordingly, drotaverine and reference agents were tested on KCl-induced guinea pig tracheal contraction. Drotaverine, like the L-VOCC blockers nifedipine or diltiazem, inhibited the KCl-induced inward Ca 2+ - induced contraction in a concentration- dependent fashion. The PDE inhibitor theophylline had no effect on the KCl-evoked contractions, indicating its lack of inhibition on inward Ca 2+ flow. Drotaverine was also tested on the L-VOCC-mediated resting Ca 2+ refill model. In this model, the extracellular Ca 2+ enters the cells to replenish the emptied intracellular Ca 2+ stores. Drotaverine and L-VOCC blocker reference molecules inhibited Ca 2+ replenishment of Ca 2+ -depleted preparations detected by agonist-induced contractions in post-Ca 2+ replenishment Ca 2+ -free medium. Theophylline did not modify the Ca 2+ store replenishment after contraction. It seems that drotaverine, but not theophylline, inhibits inward Ca 2+ flux. The addition of CaCl 2 to Ca 2+ -free medium containing the agonist induced inward Ca 2+ flow and subsequent contraction of Ca 2+ -depleted tracheal preparations. Drotaverine, similar to the L-VOCC blockers, inhibited inward Ca 2+ flow and blunted the slope of CaCl 2 -induced contraction in agonist containing Ca 2+ -free medium with Ca 2+ -depleted tracheal preparations. These results show that drotaverine behaves like L-VOCC blockers but, unlike PDE inhibitors using L-VOCC associated in vitro experimental models.

Potential L-Type Voltage–Operated Calcium Channel Blocking Effect of Drotaverine on Functional Models