Opposite modulation of ouabain cardiotoxicity by hexamethyleneamiloride and phenylephrine.

Abstract

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.

• Authors: A Terzic, T Anagnostopoulos, S M Vogel
• Journal: Naunyn-Schmiedeberg's archives of pharmacology (Naunyn Schmiedebergs Arch Pharmacol) Vol. 343 Issue 5 Pg. 511-8 (May 1991) ISSN: 0028-1298 [Print] Germany
• PMID: 1652698 (Publication Type: Journal Article)

Chemical References

• Antiporters
• Carrier Proteins
• Sodium Channels
• 5-(N,N-hexamethylene)amiloride
• Phenylephrine
• Ouabain
• Amiloride

Topics

• Amiloride (analogs & derivatives, pharmacology)
• Animals
• Antiporters
• Carrier Proteins (drug effects)
• Hydrogen-Ion Concentration
• In Vitro Techniques
• Membrane Potentials (drug effects)
• Microelectrodes
• Myocardial Contraction (drug effects)
• Ouabain (toxicity)
• Phenylephrine (pharmacology)
• Rats
• Rats, Inbred Strains
• Sodium Channels (drug effects)