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1.
Toxicol Appl Pharmacol ; 82(2): 200-10, 1986 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-3945948

RESUMO

Intact hearts isolated from adult male, Sprague-Dawley rats were perfused under standardized conditions in an apparatus designed for use in a high-resolution nuclear magnetic resonance (NMR) spectrometer system. Myocardial phosphate metabolite concentrations (ATP, PCr, Pi, and phosphomonoesters) and intracellular pH were determined sequentially at timed intervals coincident with the functional assessments of the intact heart by phosphorus-31 (31P) NMR spectroscopic methods. Myocardial functional and metabolic parameters were unaffected by sustained control perfusion (2 hr). The negative inotropic actions of cadmium were associated with significant changes in the chemical environment of inorganic phosphate (Pi) within the cells. This initial cellular response to cadmium, which correlated with the onset and magnitude of the contractile disturbances, appeared to represent the formation of an acidic, intracellular Pi pool (pH, 6.0). This pH compartment reached a steady state during the period in which maximal changes in contractile function were manifested, and before cellular ATP and PCr concentrations were altered. These findings are consistent with the interpretation that the functional deficits caused by cadmium originated primarily from changes in the chemical environment experienced by intracellular metabolites, rather than changes in the amounts of cellular high energy substrates. In contrast, the time-dependent negative inotropic effects of arsenate were proportional to the loss of cellular ATP stores. Intracellular pH was not affected in these hearts. A distinctive metabolic finding associated with the cardiotoxicity of arsenate was the time-dependent accumulation of previously undetected phosphate metabolites in the arsenate-treated hearts. Efforts to chemically identify these metabolites proved inconclusive; however, existing evidence suggests the possibility that these phosphorus-containing compounds may be arsenophosphate derivatives of naturally occurring cellular metabolites. The present findings provide experimental evidence demonstrating that toxicologic assessments in an intact organ model are feasible using whole organ 31P NMR spectroscopic methods and that meaningful, new insights regarding the biochemical mechanisms responsible for the cardiotoxic actions of xenobiotic agents can be obtained by this analytical approach.


Assuntos
Coração/efeitos dos fármacos , Miocárdio/metabolismo , Animais , Arseniatos/toxicidade , Cádmio/toxicidade , Concentração de Íons de Hidrogênio , Espectroscopia de Ressonância Magnética , Contração Miocárdica/efeitos dos fármacos , Perfusão , Fósforo , Ratos , Ratos Endogâmicos , Fatores de Tempo
2.
Toxicol Appl Pharmacol ; 77(2): 303-14, 1985 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-3975902

RESUMO

Barium-supplemented Long-Evans hooded rats were characterized by a persistent hypertension that was evident after 1 month of barium (100 micrograms/ml mineral fortified water) treatment. Analysis of in vivo myocardial excitability, contractility, and metabolic characteristics at 16 months revealed other significant barium-induced disturbances within the cardiovascular system. The most distinctive aspect of the barium effect was a demonstrated hypersensitivity of the cardiovascular system to sodium pentobarbital. Under barbiturate anesthesia, virtually all of the myocardial contractile indices were depressed significantly in barium-exposed rats relative to the corresponding control-fed rats. The lack of a similar response to ketamine and xylazine anesthesia revealed that the cardiovascular actions of sodium pentobarbital in barium-treated rats were linked specifically to this anesthetic, and were not representative of a generalized anesthetic response. Other myocardial pathophysiologic and metabolic changes induced by barium were manifest, irrespective of the anesthetic employed. The contractile element shortening velocity of the cardiac muscle fibers was significantly slower in both groups of barium-treated rats relative to the control groups, irrespective of the anesthetic regimen. Similarly, significant disturbances in myocardial energy metabolism were detected in the barium-exposed rats which were consistent with the reduced contractile element shortening velocity. In addition, the excitability of the cardiac conduction system was depressed preferentially in the atrioventricular nodal region of hearts from barium-exposed rats. Overall, the altered cardiac contractility and excitability characteristics, the myocardial metabolic disturbances, and the hypersensitivity of the cardiovascular system to sodium pentobarbital suggest the existence of a heretofore undescribed cardiomyopathic disorder induced by chronic barium exposure. These experimental findings represent the first indication that life-long barium ingestion may have significant adverse effects on the mammalian cardiovascular system.


Assuntos
Compostos de Bário , Bário/toxicidade , Doenças Cardiovasculares/induzido quimicamente , Cloretos , Hipersensibilidade a Drogas/etiologia , Anestésicos/toxicidade , Animais , Pressão Sanguínea/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Feminino , Contração Miocárdica/efeitos dos fármacos , Miocárdio/metabolismo , Pentobarbital/toxicidade , Ratos , Fatores de Tempo
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