Opposite modulation of ouabain cardiotoxicity by hexamethyleneamiloride and phenylephrine

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 μmo1/l), an inhibitor of Na/H exchange, ouabain (1 mmol/l) caused a sustained positive inotropic effect without toxicity. By contrast, phenylephrine (100 μmol/ 1) an α-adrenoceptor agonist reported to stimulate the antiporter, hastened the development of ouabain's toxicity. Neither ouabain, at a subtoxic concentration (650 μol/l), nor phenylephrine (100 μmol/l) affected diastolic force, but in their combined presence, a substantial contracture developed and twitch contractions disappeared. Phenylephrine (30 or 100 μmol/l) or adrenaline (30 μmol/l), in the presence of a β-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 μmol/l). Consistent with phenylephrine's ability to stimulate Na⁺ influx via the Na/H antiporter, phenylephrine (100 μmol/l) increased intracellular Na⁺ activity by about 3 mmol/l in ouabain (650 μmol/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 α-adrenoceptors may aggravate digitalis toxicity.