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

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 Ca²⁺- 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 Ca²⁺ flow. Drotaverine was also tested on the L-VOCC-mediated resting Ca²⁺ refill model. In this model, the extracellular Ca²⁺ enters the cells to replenish the emptied intracellular Ca²⁺ stores. Drotaverine and L-VOCC blocker reference molecules inhibited Ca²⁺ replenishment of Ca²⁺-depleted preparations detected by agonist-induced contractions in post-Ca²⁺ replenishment Ca²⁺-free medium. Theophylline did not modify the Ca²⁺ store replenishment after contraction. It seems that drotaverine, but not theophylline, inhibits inward Ca²⁺ flux. The addition of CaCl₂ to Ca²⁺-free medium containing the agonist induced inward Ca²⁺ flow and subsequent contraction of Ca²⁺-depleted tracheal preparations. Drotaverine, similar to the L-VOCC blockers, inhibited inward Ca²⁺ flow and blunted the slope of CaCl₂-induced contraction in agonist containing Ca²⁺-free medium with Ca²⁺-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.