RESUMO
A variety of compounds were examined for their capacity to alter RNA synthesis in isolated rat cardiac and hepatic mitochondria. The beta-adrenergic blocking agents propranolol and butoxamine, and the antiarrhythmic agent quinidine, produced a concentration-dependent stimulation of RNA synthesis in cardiac and hepatic mitochondria. In contrast, the antitubercular antibiotic rifampicin produced a concentration-dependent inhibition of RNA synthesis in cardiac and hepatic mitochondria. Propranolol, as a representative compound which stimulated RNA synthesis, was also found to stimulate ATP synthesis in isolated mitochondria, whereas rifampicin inhibited ATP synthesis. Coordinate increases and decreases in RNA and ATP syntheses suggest that agents which stimulate or inhibit RNA synthesis may rapidly alter ATP synthesis. This finding is consistent with the rapid turn-over of mitochondrial RNA with a messenger function (1.4 and 3.3 min in isolated rat cardiac and hepatic mitochondria), and it suggests that mitochondrial RNA must continue to be synthesized to maintain inner membrane systems required for ATP synthesis. Stimulation of RNA and ATP syntheses by propranolol through membrane stabilization or other actions represents a heretofore unrecognized action of propranolol which may contribute to its beneficial therapeutic effects.
Assuntos
Trifosfato de Adenosina/biossíntese , Mitocôndrias/metabolismo , Propranolol/farmacologia , RNA/biossíntese , Rifampina/farmacologia , Animais , Cálcio/metabolismo , Relação Dose-Resposta a Droga , Técnicas In Vitro , Mitocôndrias/efeitos dos fármacos , Ratos , Ratos EndogâmicosRESUMO
Gentamicin injected in vivo, in doses equivalent to those used therapeutically in humans, produced a decrease in the protein synthesizing capacity of microsomes subsequently isolated from rat kidneys, but not of microsomes isolated from rat whole brains. The decreases in eukaryotic cell protein synthesis observed following in-vivo administration of gentamicin were similar to those observed following the addition of gentamicin to microsomes in vitro.
Assuntos
Encéfalo/efeitos dos fármacos , Gentamicinas/toxicidade , Rim/efeitos dos fármacos , Microssomos/metabolismo , Biossíntese de Proteínas , Animais , Encéfalo/metabolismo , Gentamicinas/metabolismo , Técnicas In Vitro , Rim/metabolismo , Ratos , Ratos EndogâmicosRESUMO
The aminoglycoside antibiotics gentamicin, kanamycin and netilmicin produce a dose-dependent inhibition of amino acid incorporation in microsomes isolated from human liver and rat brain, kidney and liver. Inhibitory effects on microsomal protein synthesis occur at concentrations that have been shown to accumulate in rodent and human renal cortex and perilymph following therapeutic administration. Inhibition of translation in those tissues which specifically accumulate aminoglycoside antibiotics may, in part, explain toxicities observed following exposure to aminoglycosides.
Assuntos
Antibacterianos/farmacologia , Microssomos/metabolismo , Biossíntese de Proteínas , Aminoglicosídeos/farmacologia , Animais , Encéfalo/metabolismo , Gentamicinas/farmacologia , Técnicas In Vitro , Canamicina/farmacologia , Rim/metabolismo , Masculino , Microssomos Hepáticos/metabolismo , Netilmicina/farmacologia , Biossíntese de Proteínas/efeitos dos fármacos , RNA/biossíntese , Ratos , Ratos EndogâmicosRESUMO
The ototoxic antibiotic gentamicin, and the ototoxic diuretic ethacrynic acid, both produce inhibitory effects on protein synthesis in microsomes isolated from rat brain. Inhibitory effects appear to be essentially independent of each other. The inhibitory dose-response curve for gentamicin is logarithmic, while that for ethacrynic acid is linear. The dose-response curves make gentamicin the predominant inhibitor when the drugs are combined at low concentrations and ethacrynic acid the predominant inhibitor when the drugs are combined at high concentrations. Accumulation of aminoglycoside by tissues of the inner ear may result in inhibition of protein synthesis in spite of low and transient plasma levels of the drug. Further inhibition of translation by ethacrynic acid could account, in part, for the ototoxic interaction of aminoglycosides and high ceiling diuretics.
Assuntos
Ácido Etacrínico/toxicidade , Gentamicinas/toxicidade , Microssomos/metabolismo , Biossíntese de Proteínas , Animais , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Orelha Interna/efeitos dos fármacos , Técnicas In Vitro , Proteínas do Tecido Nervoso/biossíntese , Ratos , Ratos EndogâmicosRESUMO
In experiments designed to study the mechanism of glucocorticoid hormone induced reductions in rat thymic transcription, adrenalectomized rats were injected with hydrocortisone (50 mg/kg) or control vehicle 12 h prior to sacrifice. Thymic nuclei were used to prepare soluble nuclear extracts containing RNA polymerase II. Nuclear extract RNA polymerases II were then partially purified (600-fold) on DEAE-Sephadex columns and characterized. The responses of partially purified thymic RNA polymerases II from rats treated in vivo with hydrocortisone or vehicle were similar to: pH, temperature, ionic strength, trypsin proteolysis, and inhibition by alpha-amanitin; however, RNA polymerase II from hydrocortisone treated animals was consistently reduced in activity compared to control RNA polymerase II. Determination of the apparent specific activities of peak RNA polymerase II fractions from DEAE-Sephadex columns suggested that the specific activity of RNA polymerase II from hydrocortisone treated animals was reduced compared to RNA polymerase II activity from control animals. The fact that both nuclear extract and partially purified RNA polymerases II from hydrocortisone treated rats were reduced in activity when assayed in reconstituted transcriptive systems suggests a denatured, defective or modified RNA polymerase II molecule acting as a transcription inhibitor. Thermally denatured nucleoplasmic RNA polymerase II fractions were shown to interfere with transcription by native nucleoplasmic RNA polymerase II in vitro, but did not appear to inhibit transcription to he degree observed in vitro following in vivo hydrocortisone administration.