RT Journal Article
SR Electronic
T1 Potential L-Type Voltage–Operated Calcium Channel Blocking Effect of Drotaverine on Functional Models
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 442
OP 451
DO 10.1124/jpet.116.237271
VO 359
IS 3
A1 Zoltán Patai
A1 András Guttman
A1 Endre G. Mikus
YR 2016
UL http://jpet.aspetjournals.org/content/359/3/442.abstract
AB 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.