Effects of the KIR7.1 Blocker VU590 on Spontaneous and Agonist-Induced Contractions of Human Pregnant Myometrium

Denis J. Crankshaw, David A. Crosby, John J. Morrison

KIR7.1, an inwardly rectifying K(+) channel, plays a critical role in regulating uterine excitability during pregnancy and has been suggested as a potential new target for the treatment of conditions arising from dysfunctional uterine contractility, for example, atonic postpartum hemorrhage. The aim of this study was to investigate the effects of the selective KIR7.1 blocker, VU590, on both spontaneous and agonist-stimulated contractions of human pregnant myometrium in vitro. At a concentration of 20 µmol/L, VU590 significantly increased the mean contractile force and the frequency of spontaneous contractions ( P < 0.05) when compared to vehicle-treated tissues. However, there was a significant ( P < 0.0001) monoexponential decay in amplitude with time of exposure. When VU590 was coadministered with EC50 concentration of the uterotonics oxytocin, ergometrine, or carboprost, the only significant changes were an immediate decrease in the amplitude of oxytocin- and carboprost-induced contractions and a delayed reduction in amplitude and an increase in the frequency of ergometrine-induced contractions. Amplitude to all 3 agents in the presence of VU590 showed a monoexponential decay with time of exposure ( P < 0.0001). We conclude that VU590 modifies the contractility of pregnant human myometrium in support of a role for KIR7.1 in regulating that process. However, VU590 in vitro does not produce the types of contraction, either alone or in combination with other uterine stimulants that would suggest its usefulness as a first- or second-line clinical uterotonic agent.