Mechanism of nafazatrom-induced inhibition of rat uterus contractions in vitro.
Nafazatrom inhibits, in a dose-dependent way, the amplitude and frequency of the rhythmic contractions induced by oxytocin (4 mU/ml), as well as the methacholine (10(-5) M)- and CaCl2 (10 mM)-induced contractions, and the phasic response to KCl (60 mM); similarly, it inhibits the tonic contraction induced by KCl (60 mM) and oxytocin (10 mU/ml). A single concentration of nafazatrom (10(-4) M) also inhibits the uterine contractions caused by carbachol (10(-4) M) and prostaglandin F2 alpha (10(-6) M). CaCl2 (0.1-10 mM) only partially reverses the inhibition produced by nafazatrom on the KCl-induced tonic contractions. Bay K 8644 (3 x 10(-10)-3 x 10(-7) M) reverses the inhibition by 10(-4) M but not by 3 x 10(-4) M of nafazatrom on the CaCl2-induced contractions. Nafazatrom also inhibits, in a dose-dependent way, the calmodulin-dependent phosphodiesterase activity. Our results would suggest that, independently of its 5-lipoxygenase blocking activity, nafazatrom inhibits the contractions of the rat uterus by inhibiting the calmodulin activity and, presumably, by reducing the influx of extracellular calcium and/or the mobilization of intracellular calcium.
Cantabrana
B
B
Departamento de Medicina, Facultad de Medicina, Oviedo, Spain.
Velasco
G
G
Andrès-Trelles
F
F
Hidalgo
A
A
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D000818:Animals; D002122:Calcium Chloride / Q000494:pharmacology; D002147:Calmodulin / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D015237:Dinoprost / Q000494:pharmacology; D005260:Female; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D008688:Methacholine Compounds / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D010121:Oxytocin / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D047069:Pyrazolones; D051381:Rats; D011919:Rats, Inbred Strains; D014590:Uterine Contraction / Q000187:drug effects*
D002147:Calmodulin; D005343:Fibrinolytic Agents; D008688:Methacholine Compounds; D011720:Pyrazoles; D047069:Pyrazolones; D010121:Oxytocin; D011189:Potassium Chloride; D002217:Carbachol; D015237:Dinoprost; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D009543:Nifedipine; C018845:nafazatrom; D002122:Calcium Chloride