THE IMPORTANCE OF POTASSIUM CHANNELS IN THE MECHANISM OF THE RELAXING EFFECT OF PENTOXIFYLLINE ON ISOLATED RAT UTERI

Background. Pentoxifylline, used for treating peripheral vascular deceases is a derivate of methylxanthines. One way of pentoxifylline action is by causing vasodilatation of blood vessels. In this study, the effect of increasing concentrations of pentoxifylline, in the presence of potassium channel antagonist, on contractility of isolated rat uterus was examined. Methods . Uteruses were isolated from virgin Wistar rats (180-220 g) and suspended in an isolated organ bath chamber containing De Jalon's solution and aerated with 95% O 2 and 5% CO 2 . Temperature was maintained at 37oC. Isometric contractions were recorded using an isometric force transducer (Ugo Basile). The preload of the preparation was about 1g. Uteri were allowed to contract spontaneously or in the presence of Ca 2+ (0.018 and 0.36 mM ) and acetylcholine and treated with pentoxifylline. Results. Pentoxifylline caused concentration-dependent inhibition of spontaneous rhythmic uterine activity and uterine activity caused by calcium Ca 2+ (0.018 mM and 0,36 mM). We showed that the inhibitory effect of pentoxifylline depends on type of muscle contraction activation, and that it is significantly stronger in spontaneous rhythmic activity and contraction of isolated rat uterus induced by Ca 2+ . The relaxing effect of pentoxifylline depends on calcium concentration of in the medium. Pentoxifylline exerted the weakest relaxant effects on contractions induced by acetylcholine (Ach). As opposed to methylene blue, tetraethylammonium, and 4-aminopyridine, glibenclamide did not antagonize the relaxing effect of pentoxifylline on the isolated rat uterus. Conclusion. Results obtained suggest that the mechanism of action of pentoxifylline did not lead to the opening of K ATP channels. However, the opening of BKCa and of voltage dependent Ca 2+ channel had some significance, but to varying degrees, in the mechanism of the relaxing effect of pentoxifylline on spontaneous rhythmic activity and contraction of the isolated rat uterus induced by calcium. Our results are additional confirmation of the dominance of the NO/cGMP signaling pathway in the mechanism of the relaxing effect of pentoxifylline (because the presence of methylene blue significantly antagonizes its effect) in relation to the opening of potassium channels, especially K ATP channels. These results indicate that pentoxifylline could be a potential tocolytic drug. Keywords: pentoxifylline, rat uterus, potassium channel blockers, glibenclamide (GLB), tetraethylammonium (TEA), 4-aminopyridine (4-AP ), methylene blue (MB) Running title: Potassium Channels in Action of Pentoxifylline