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

Patai, Z. and Guttman, A. and Mikus, E. G. (2016) Potential L-Type Voltage-Operated Calcium Channel Blocking Effect of Drotaverine on Functional Models. Journal of Pharmacology and Experimental Therapeutics, 359 (3). pp. 442-451. ISSN 1521-0103

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Abstract

Drotaverine is considered as an inhibitor of cyclic-3′,5′-nucleotide-phophodiesterase (PDE) enzymes. However, published receptor binding data supports the potential Ltype Voltage Operated Calcium Channel (L-VOCC) blocking effect of drotaverine too. Hence, in this work we are focusing on the potential L-VOCC blocking effect of drotaverine using L-VOCC associated functional in vitro models. Accordingly, drotaverine and reference agents were tested on KCl-induced guinea pig tracheal contraction. It was found that 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 the Ca2+ replenishment of Ca2+ depleted preparations detected by agonist-induced contractions in post Ca2+ replenishment Ca2+ free medium. Theophylline didn’t modify the Ca2+ store replenishment following contraction. It seems that drotaverine but not theophylline inhibit the inward Ca2+ flux. 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 withCa2+ 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.

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