TY - JOUR
T1 - Effects of glycerol trinitrate, mannitol hexanitrate and erythritol tetranitrate on electron transport and phosphorylation in liver mitochondria
AU - Boime, Irving
AU - Edmund Hunter, F.
N1 - Funding Information:
l This work was supported by United States Public Health Service, National Institute of General Medical Sciences Pharmacology Training Grant 5-TO1-00096, National Heart Institute Research Grant HE-10107-03, and National Institute for Metabolic Diseases and Arthritis Research Grant AM-1 1673-02. t Abbreviations used: GTN, glycerol trinitrate; MHN, mannitol hexanitrate; ETN, erythritol tetranitrate; PETRlN, pentaerythritol trinitrate; DNP, 2,4-dinitrophenol; bovine serum albumin, BSA; ethylenediamine tetraacetate, EDTA; GSH, reduced glutathione. 535
PY - 1971/3
Y1 - 1971/3
N2 - The organic nitrate esters, glycerol trinitrate (GTN), mannitol hexanitrate (MHN) and erythritol tetranitrate (ETN) were tested for effects on the oxygen consumption of rat liver mitochondria. Both MHN and GTN are capable of reducing the respiratory control ratio to 1.0 [rate of O2 consumption with ADP (state 3)/rate without ADP (state 4)] However, this requires 1 mM GTN as compared to 0.1 mM MHN, and the actions are effected through different mechanisms. With the NAD-linked substrate, 3-hydroxybutyrate, GTN inhibits the state 3 rate, whereas MHN markedly increases the state 4 rate. GTN, in concentrations that inhibit 3-hydroxybutyrate oxidation, has little or no effect on respiration with succinate as substrate. MHN, on the other hand, accelerates the state 4 rate with succinate just as it does with 3-hydroxybutyrate. Therefore, the action of GTN appears to be selective for the NADH dehydrogenase region of the electron transport chain. In contrast to the generalized uncoupling activity of MHN, the predominant effect of GTN appears to be inhibition of electron transport. Since DNP relieves this inhibition to a large degree, a considerable part of it must be indirect, by way of an inhibition in energy transfer reactions, as with oligomycin or atractyloside. There also appears to be a small direct inhibition of electron transport by GTN and MHN at low concentrations. This inhibition increases with higher concentrations. Erythritol tetranitrate appears to be intermediate between MHN and GTN in the effects produced. It is suggested that lipid solubility of the organic nitrate esters, location of sulfhydryl groups critical for electron transfer and energy conservation, and reactivity of the organic nitrate esters with sulfhydryl groups determine the selective effects observed.
AB - The organic nitrate esters, glycerol trinitrate (GTN), mannitol hexanitrate (MHN) and erythritol tetranitrate (ETN) were tested for effects on the oxygen consumption of rat liver mitochondria. Both MHN and GTN are capable of reducing the respiratory control ratio to 1.0 [rate of O2 consumption with ADP (state 3)/rate without ADP (state 4)] However, this requires 1 mM GTN as compared to 0.1 mM MHN, and the actions are effected through different mechanisms. With the NAD-linked substrate, 3-hydroxybutyrate, GTN inhibits the state 3 rate, whereas MHN markedly increases the state 4 rate. GTN, in concentrations that inhibit 3-hydroxybutyrate oxidation, has little or no effect on respiration with succinate as substrate. MHN, on the other hand, accelerates the state 4 rate with succinate just as it does with 3-hydroxybutyrate. Therefore, the action of GTN appears to be selective for the NADH dehydrogenase region of the electron transport chain. In contrast to the generalized uncoupling activity of MHN, the predominant effect of GTN appears to be inhibition of electron transport. Since DNP relieves this inhibition to a large degree, a considerable part of it must be indirect, by way of an inhibition in energy transfer reactions, as with oligomycin or atractyloside. There also appears to be a small direct inhibition of electron transport by GTN and MHN at low concentrations. This inhibition increases with higher concentrations. Erythritol tetranitrate appears to be intermediate between MHN and GTN in the effects produced. It is suggested that lipid solubility of the organic nitrate esters, location of sulfhydryl groups critical for electron transfer and energy conservation, and reactivity of the organic nitrate esters with sulfhydryl groups determine the selective effects observed.
UR - http://www.scopus.com/inward/record.url?scp=0015031873&partnerID=8YFLogxK
U2 - 10.1016/0006-2952(71)90140-7
DO - 10.1016/0006-2952(71)90140-7
M3 - Article
C2 - 5004772
AN - SCOPUS:0015031873
VL - 20
SP - 535
EP - 545
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
SN - 0006-2952
IS - 3
ER -