Effect of Calmodulin Antagonists on Contraction and ⁴⁵Ca Movements in Rat Aorta

Abstract

To study the selectivity of calmodulin antagonists it was assumed that they should inhibit noradrenaline (NA)- and K⁺-induced contractions similarly without an accompanying inhibition of ⁴⁵Ca uptake. Therefore, in isolated rat aorta the effects of W-7, calmidazolium and trifluoperazine on contraction and ⁴⁵Ca uptake elicited by K⁺ and NA were investigated. Calmidazolium (10^–5–10^–4 mol/l) elicited an incomplete inhibition of K⁺-and NA-induced contraction and ⁴⁵Ca uptake. Trifluoperazine inhibited the NA-induced contractions at lower concentrations (10^–8–10^–6 mol/l) than the K⁺-induced contraction (10^–6–10^–4 mol/l). The K⁺- and NA-induced ⁴⁵Ca uptake was blocked by trifluoperazine (10^–5 mol/l). W-7 (10^–5–10^–4 mol/l) inhibited the K⁺- and NA-induced contraction, however, in the same concentration range W-7 diminished the K⁺- and NA-induced 45Ca uptake. In conclusion, the results indicate that calmidazolium and trifluoperazine are hardly useful as calmodulin antagonists because of their additional properties, whereas W-7 seems to be the least unspecific of the calmodulin antagonists studies.

Regulation of apical transporter of L‐DOPA in human intestinal Caco‐2 cells

“…2001). Alternatively, it could be hypothesized that calmidazolium and trifluoperazine were acting non‐specifically (Klockner & Isenberg 1987, Wermelskirchen et al . 1989).…”

Role of Ca2+-calmodulin dependent phospholamban phosphorylation on the relaxant effect of ?-adrenergic agonists

“…With regards to the former, cAMP-dependent phosphorylation of cardiac SR vesicles was found to be independent of [Ca 2+] variations in a broad range (0.1 to 100 gM) [6]. On the other hand, W7, a rather selective calmodulin inhibitor [34][35][36], at high concentrations has several side effects [36][37][38]. In our experimental conditions, the concentration of W7 used (ten times lower than the reported K d for calmodulin [39]), failed to affect either myocardial contractility and relaxation, phospholamban phosphorylation or cAMP levels under basal conditions.…”

Calmodulin Antagonist W‐7 Prevents Sparfloxacin‐Induced Early Afterdepolarizations (EADs) in Isolated Rabbit Purkinje Fibers: Importance of Beat‐to‐Beat Instability of the Repolarization

“…28,44 At high concentrations, W-7 is a nonspecific antagonist of the CaM kinase II and has a direct effect on ionic currents such as K + , Ca 2+ , and Na + . [45][46][47] The concentrations of W-7 (5 × 10 −7 M, 5 × 10 −6 M, and 5 × 10 −5 M) used in the present study are within the range of its IC 50 values for inhibiting calmodulin-dependent enzymes. W-7 at these concentrations limited sparfloxacin-induced prolongation of the APD and increase in the triangulation of the action potential.…”

“…W‐7 is a water‐soluble, cell‐membrane‐permeant competitive antagonist that inhibits calmodulin‐dependent enzymes with IC 50 values of 2.5 × 10 −6 M to 5 × 10 −5 M and is a less potent protein kinase A or protein kinase C antagonist (Ki: 1.2 × 10 −4 M) 28,44 . At high concentrations, W‐7 is a nonspecific antagonist of the CaM kinase II and has a direct effect on ionic currents such as K + , Ca 2+ , and Na + 45–47 . The concentrations of W‐7 (5 × 10 −7 M, 5 × 10 −6 M, and 5 × 10 −5 M) used in the present study are within the range of its IC 50 values for inhibiting calmodulin‐dependent enzymes.…”