THE IMPORTANCE OF POTASSIUM CHANELS IN THE MECHANISMS OF THE RELAXING EFFECT OF PENTOXIFYLLINE ON THE ISOLATED RAT UTERUS

Slobodan Milovanovic; Jelena Kordic-Bojinović; Stevanka Djordjevic; Dragana Drakul; Dragana Sokolovic; Natasa Miletic; Dusko Blagojevic

doi:10.5937/sjecr14-3972

Slobodan Milovanovic Department of Pharmacology, Toxicology, and Clinical Pharmacology, School of Medicine, University of East Sarajevo, Foca, Republic of Srpska, Bosnia and Herzegovina
Jelena Kordic-Bojinović High Medical School “Milutin Milankovic”, Belgrade, Serbia
Stevanka Djordjevic Department of Pharmacology, Toxicology, and Clinical Pharmacology, School of Medicine, University of East Sarajevo, Foca, Republic of Srpska, Bosnia and Herzegovina
Dragana Drakul Department of Pharmacology, Toxicology, and Clinical Pharmacology, School of Medicine, University of East Sarajevo, Foca, Republic of Srpska, Bosnia and Herzegovina
Dragana Sokolovic Department of Pharmacology, Toxicology, and Clinical Pharmacology, School of Medicine, University of East Sarajevo, Foca, Republic of Srpska, Bosnia and Herzegovina
Natasa Miletic Department of Pharmacology, Toxicology, and Clinical Pharmacology, School of Medicine, University of East Sarajevo, Foca, Republic of Srpska, Bosnia and Herzegovina
Dusko Blagojevic Department of Physiology, Institute for Biological Research “Sinisa Stankovic”, Belgrade, Serbia

DOI: https://doi.org/10.5937/sjecr14-3972

Abstract

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% O₂ and 5% CO₂. 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 Ca²⁺ (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 Ca²⁺(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 Ca²⁺. 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 Ca²⁺ 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

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