Effect of meclofenamic acid and other cyclo-oxygenase inhibitors on mouse uterine contractility

Jack Sugrue1, Yosef Mansour1, Rachel Tribe2, Iain Greenwood1. 1St George’s, University of London, London, United Kingdom, 2St Thomas’s Hospital, London, United Kingdom.

Meclofenamic acid (MFA) is a nonspecific inhibitor of cyclo-oxygenases and is often prescribed for dysmenorrhoea. Recently, meclofenamic acid has been shown to activate K+ channels generated by the heterologous expression of the KCNQ2/3 genes. These genes express proteins that form the Kv7 family of ion channels. Activation of Kv7 channels has been shown to relax segments of pre-contracted aorta. As Kv7 channels have been identified in murine uterine tissue the aim of the present study is to see whether meclofenamic acid and other cyclo-oxygenase inhibitors could relax smooth muscle through activation of these Kv7 channels.

Uterine horns were dissected from BALB-C mice (6-8 weeks) killed by cervical dislocation, at all oestrous stages. Transverse segments of uterine horn were excised of all blood vessels and connective tissue before mounting in a myograph (DMT, Denmark) in Krebs’s solution aerated with 95% O2/5% CO2, at 37oC, at a passive tension of 12 mN. Spontaneous contractions developed within 10mins and agents were applied after an equilibrium period of 60mins. Statistical analysis consisted of calculating the average frequency and amplitudes of spontaneous contractions in a 10min period prior to addition of MFA compared with the period 40-50mins after addition of MFA.

In 53% of tissue applications of 10μM MFA, spontaneous contractions were completely abolished, and a significant reduction in frequency of contraction was seen in another 35% (n = 17). By prior addition of 10μM Xe991, a blocker of all Kv7 isoforms this tocolytic effect was greatly reduced. Complete abolition was only observed in 15% of the samples (n = 17). Application of MFA caused an average reduction in individual contraction amplitude of 61.79%, an effect which is reduced to 16.77% in the presence of 10uM Xe991 (n = 17).

This data shows that MFA is an effective relaxant of murine uterus that appears to be dependent upon Kv7 channels, which may underlie the therapeutic effect of this agent.

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