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