The importance of potassium channels in the mechanism of the relaxing effect of pentoxifylline on isolated rat uteri

Abstract

Background. Pentoxifylline is a methylxanthine derivative that is used to treat peripheral vascular disease. One of the mechanisms of action of pentoxifylline is the vasodilatation of blood vessels. This study examined the effect of increasing pentoxifylline concentrations on the contractility of isolated rat uteri in the presence of a potassium channel antagonist. Methods. The uteri 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% O2 and 5% CO2. The temperature was maintained at 37єC. Isometric contractions were recorded using an isometric force transducer (Ugo Basile). The preload of the preparation was approximately 1 g. The uteri were allowed to contract spontaneously or in the presence of Ca2+ (0.018 and 0.36 mM) and acetylcholine (ACh) and were treated with pentoxifylline. Results. Pentoxifylline caused concentration-dependent inhibition of spontaneous rhythmic uterine activity and uterine activity caused by calcium Ca2+ (0.018 mM and 0,36 mM). We showed that the inhibitory effects of pentoxifylline depend on the type of muscle contractions activated and that the inhibitory effect is significantly stronger for spontaneous rhythmic activity and forin Ca2 -induced contractions of isolated rat uteri+. The relaxing effect of pentoxifylline depends on the calcium concentration in the medium. Pentoxifylline exerted the weakest relaxant effects on contractions induced by acetylcholine. In contrast to methylene blue, tetraethylammonium, or 4-aminopyridine, glibenclamide did not antagonise the relaxing effect of pentoxifylline on isolated rat uteri. Conclusion. The results obtained suggest that the mechanism of action of pentoxifylline does not lead to the opening of KATP channels. However, the opening of BKCa and voltage-dependent Ca2+ channels had some role, but to varying degrees, in the mechanism of the relaxing effect of pentoxifylline on the spontaneous rhythmic activity and calcium-induced contractions of isolated rat uteri. Our results provide 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 antagonised this effect) in relation to the opening of potassium channels, especially KATP channels. These results indicate that pentoxifylline could be a potential tocolytic drug.