Opposite modulation of ouabain cardiotoxicity by hexamethyleneamiloride and phenylephrine |
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Authors: | Andre Terzic Takis Anagnostopoulos Stephen M Vogel |
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Institution: | (1) Department of Pharmacology, University of Illinois College of Medicine, 835 South Wolcott Avenue, 60612 Chicago, Illinois, United States of America;(2) INSERM Unité 323, CHU Necker-Enfants Malades, 156 Rue de Vaugirard, 75015 Paris, France |
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Abstract: | Summary To see whether the Na/H antiporter plays a role in digitalis cardiotoxicity, we investigated the influence of modulators of Na/H exchange on the toxic effects of ouabain in isolated, paced (0.4 Hz) rat left atria. Ouabain (1 mmol/l) caused a transient positive inotropic effect followed by toxic events, including a complete loss of developed force and a gradual increase in resting force. In the presence of hexamethyleneamiloride (3 and 10 mo1/l), an inhibitor of Na/H exchange, ouabain (1 mmol/l) caused a sustained positive inotropic effect without toxicity. By contrast, phenylephrine (100 mol/ 1) an -adrenoceptor agonist reported to stimulate the antiporter, hastened the development of ouabain's toxicity. Neither ouabain, at a subtoxic concentration (650 ol/l), nor phenylephrine (100 mol/l) affected diastolic force, but in their combined presence, a substantial contracture developed and twitch contractions disappeared. Phenylephrine (30 or 100 mol/l) or adrenaline (30 mol/l), in the presence of a -adrenoceptor antagonist, increased the intracellular pH by up to 0.15 pH unit, as measured using ion-selective microelectrodes in quiescent preparations. This effect on pH1 was prevented by hexamethyleneamiloride (10 mol/l). Consistent with phenylephrine's ability to stimulate Na+ influx via the Na/H antiporter, phenylephrine (100 mol/l) increased intracellular Na+ activity by about 3 mmol/l in ouabain (650 mol/l)-treated atria. These findings indicate that modulators of Na/H exchange affect the cardiotoxicity of digitalis glycosides and imply that the stimulation of myocardial -adrenoceptors may aggravate digitalis toxicity.This work was conducted in part under the auspices of the Association for US/French Biomedical Cooperation
Send offprint requests to S. M. Vogel at the above address |
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Keywords: | Ouabain cardiotoxicity Na/H antiporter Intracellular Na+ and H+ activity -Adrenoceptor" target="_blank">gif" alt="agr" align="BASELINE" BORDER="0">-Adrenoceptor Hexamethyleneamiloride |
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