title: The effect of resveratrol on contractility of non-pregnant rat uterus: the contribution of K(+) channels.
abstract: This study was aimed to evaluate resveratrol (1-100 μM) effect on the spontaneous rhythmic contractions (SRC), oxytocin-induced (0.2 nM, POxC) phasic and tonic (20 nM, TOxC) contractions of isolated rat uterus. The SRC and POxC were more sensitive to resveratrol than TOxC (pD2 values: 4.53 and 4.66 versus 4.06). Different blockers of K(+) channels (glibenclamide, tetraethylamonium, iberiotoxin, 4-aminopyridine) antagonized the response to resveratrol on the SRC and phasic contractions, but did not antagonize the effect of resveratrol on the TOxC. In order to compare the relaxant activities of resveratrol on the TOxC with that of potassium channel openers, a separate experiments with NS 1619, a highly specific big Ca(2+)-sensitive K(+) (BKCa) channels opener and pinacidil, a predominant opener of ATP-sensitive K(+) (KATP) channels were done. NS 1619 (10-100 μM) and pinacidil (10-100 μM) produced more potent inhibition of TOxC than resveratrol (pD2 values were 6.00 and 5.29). Iberiotoxin, a highly selective BKCa channels blocker, antagonized the response to NS 1619 and glibenclamide, a highly selective KATP channels blocker, antagonized the response to pinacidil on the TOxC. To test K(+)- and extracellular Ca(2+)- independent mechanism(s) of resveratrol on TOxC, a K(+)-rich, Ca(2+)-free solution was used. Under this condition, only high concentrations (≥30 μM) of resveratrol inhibited TOxC. Western blots analysis confirmed expression of Kir6.1, Kir6.2, KCa1.1, Kv2.1 and Kv4.2. channel proteins in myometrium. Thus, the effect of resveratrol is dependent on the types of contractions. The inhibitory response of resveratrol on the SRC and phasic contractions involves different myometrial K(+)- channels. When applied in high concentrations, resveratrol has an additional K(+)- channels independent mechanism(s) of action. As the effects of NS 1619, pinacidil and resveratrol on the TOxC are different, we can conclud that resveratrol does not behave as a classical potassium channel opener.
authors.affiliation: Institute of Pharmacology, Clinical Pharmacology and Toxicology, Medical Faculty, University of Belgrade, Belgrade, Serbia. l.g.bukarica@sezampro.rs.
authors.forename: R
authors.initials: R
authors.lastname: Novakovic
authors.forename: B
authors.initials: B
authors.lastname: Ilic
authors.forename: B
authors.initials: B
authors.lastname: Beleslin-Cokic
authors.forename: N
authors.initials: N
authors.lastname: Radunovic
authors.forename: H
authors.initials: H
authors.lastname: Heinle
authors.forename: R
authors.initials: R
authors.lastname: Scepanovic
authors.forename: L
authors.initials: L
authors.lastname: Gojkovic-Bukarica
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D007537:Isometric Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010121:Oxytocin / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D020110:Pinacidil / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D019789:Tetraethylammonium / Q000494:pharmacology; D014599:Uterus / Q000187:drug effects* / Q000502:physiology
chemical_list: D001562:Benzimidazoles; D010455:Peptides; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D013267:Stilbenes; C086491:NS 1619; D010121:Oxytocin; D019789:Tetraethylammonium; C064719:iberiotoxin; D020110:Pinacidil; D015761:4-Aminopyridine; D000077185:Resveratrol; D005905:Glyburide