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 mumol/l), an inhibitor of Na/H exchange, ouabain (1 mmol/l) caused a sustained positive inotropic effect without toxicity. By contrast, phenylephrine (100 mumol/l), an alpha-adrenoceptor agonist reported to stimulate the antiporter, hastened the development of ouabain's toxicity. Neither ouabain, at a subtoxic concentration (650 mumol/l), nor phenylephrine (100 mumol/l) affected diastolic force, but in their combined presence, a substantial contracture developed and twitch contractions disappeared. Phenylephrine (30 or 100 mumol/l) or adrenaline (30 mumol/l), in the presence of a beta-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 pHi was prevented by hexamethyleneamiloride (10 mumol/l). Consistent with phenylephrine's ability to stimulate Na+ influx via the Na/H antiporter, phenylephrine (100 mumol/l) increased intracellular Na+ activity by about 3 mmol/l in ouabain (650 mumol/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 alpha-adrenoceptors may aggravate digitalis toxicity.
Terzic
A
A
Department of Pharmacology, University of Illinois College of Medicine, Chicago 60612.
Anagnostopoulos
T
T
Vogel
S M
SM
D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D017920:Antiporters; D002352:Carrier Proteins / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D008839:Microelectrodes; D009200:Myocardial Contraction / Q000187:drug effects; D010042:Ouabain / Q000633:toxicity*; D010656:Phenylephrine / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D015222:Sodium Channels / Q000187:drug effects
D017920:Antiporters; D002352:Carrier Proteins; D015222:Sodium Channels; C057360:5-(N,N-hexamethylene)amiloride; D010656:Phenylephrine; D010042:Ouabain; D000584:Amiloride