Effects of guanethidine on electron transport and proton movements in rat heart, brain and liver mitochondria.
Guanethidine at 5-25 mM concentrations was found to induce up to 79% inhibition of ADP-stimulated (state III) oxygen consumption in isolated rat heart, brain or liver mitochondria, when the added substrate was glutamate or succinate, but the inhibition was considerably lower (24% or less) when respiration was supported by ascorbate plus tetramethylphenylenediamine (TMPD). Comparable results were seen regarding ADP-stimulated proton uptake, where even greater inhibition (up to 94% with glutamate or succinate, but not ascorbate plus TMPD) was found. Similar but somewhat less marked effects were also seen in resting (state IV) respiration and on the acceptor control ratio (state III/state IV respiration). 2,4-Dinitrophenol was unable to relieve guanethidine-induced inhibition of electron transport. These results indicate that guanethidine inhibits primarily mitochondrial electron transport itself, and that the site where such inhibition is more marked is located in the span between ubiquinone and cytochrome c of the respiratory chain. It is, therefore, suggested that active guanethidine uptake by noradrenergic neurons can lead to a high drug concentration in their cytoplasm and hence to mitochondrial alterations that can contribute to the pharmacological effect of this drug. Our results demonstrate the interaction between guanethidine and the electron transport chain of mitochondria derived from different tissues and, therefore, support this hypothesis.
Ferreira
J
J
Gil
L
L
Stutzin
A
A
Orrego
F
F
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism*; D004140:Dinitrophenols / Q000494:pharmacology; D004579:Electron Transport / Q000187:drug effects; D005260:Female; D006145:Guanethidine / Q000494:pharmacology*; D066298:In Vitro Techniques; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D011522:Protons; D051381:Rats; D011919:Rats, Inbred Strains
D004140:Dinitrophenols; D011522:Protons; D000244:Adenosine Diphosphate; D006145:Guanethidine