Diethyldithiocarbamate potentiates the effects of protamine sulphate in the isolated rat uterus.
Protamine sulphate causes potassium ion channel-mediated relaxation of spontaneous and calcium ion-induced contractions of the isolated rat uterus. Diethyldithiocarbamate (DDC) potentiated the effect of protamine sulphate. A mechanism for DDC's action was postulated on the basis of its interactions with divalent iron ions and Cu,Zn-SOD. DDC chelates divalent iron ions creating DDC-iron (Fe-DDC) complexes. Fe-DDC forms stable NO-Fe-DDC(2) complexes by NO scavenging and de-nitrosylation processes, which in combination with DDC (5 mM) provoke inhibition of Cu,Zn-SOD resulting in specific oxidative conditions culminating in potassium ion channel opening, membrane hyperpolarisation, inhibition of calcium ion influx and subsequent muscle relaxation. As Fe-DDC and NO-Fe-DDC(2) complexes exclude divalent iron ions from participating in the hydroxyl radical generating Fenton reaction, DDC can also prevent iron-related pathophysiological manifestations. Such permissive roles of DDC open the possibility for application of its pharmacological form (disulfiram) to a wider spectrum of pathophysiological conditions related to smooth muscles.
Orescanin-Dusić
Zorana
Z
Department of Physiology, Institute for Biological Research, Sinisa Stanković, Bulevar Despota Stefana 142, Belgrade, Serbia.
Milovanović
Slobodan
S
Blagojević
Dusko
D
Nikolić-Kokić
Aleksandra
A
Radojicić
Ratko
R
Spasojević
Ivan
I
Spasić
Mihajlo
M
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002614:Chelating Agents / Q000378:metabolism / Q000494:pharmacology; D004050:Ditiocarb / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006494:Heparin Antagonists / Q000378:metabolism / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010084:Oxidation-Reduction; D011479:Protamines / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000378:metabolism; D014599:Uterus / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism
D002614:Chelating Agents; D006494:Heparin Antagonists; D007527:Isoenzymes; D011479:Protamines; D004050:Ditiocarb; D013482:Superoxide Dismutase; D002118:Calcium