Extracellular Mg++ manipulation prevents the proarrhythmic activity of cromakalim in ischemic/reperfused diabetic hearts

Arpad Tosaki, Dipak K. Das

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Cromakalim, an adenosine triphosphate-sensitive potassium channel opener, shows proarrhythmic activity at moderate doses (1-10 μmol/liter) in the reperfused myocardium. We studied the effects of extracellular Mg++ ([Mg++](o)) on the incidence of reperfusion-induced ventricular fibrillator and ventricular tachycardia in isolated working hearts (n = 12 in each group) subjected to 20 min of global ischemia followed by 30 min of reperfusion, a modeling eliciting a low incidence of reperfusion arrhythmias, obtained from 8-wk streptozotocin-induced diabetic rats. Cromakalim, at a concentration of 3 μmol/liter, perfused 5 min before the induction of ischemia and throughout reperfusion increased the incidence off ventricular tachycardia from their drug-free diabetic control values of 25 an 42% ([Mg++](o) = 1.2 mmol/liter to 92% (P<.05) an 100% (P<.05), respectively. Glibenclamide at a concentration of 3 μmol/liter prevented the proarrhythmiac activity of cromakalim. Increasing concentration off [Mg++](o) to 2.4, 3.6 and 4.8 mmol/liter in the perfusion buffer, the arrythmogenic effect of cromakalim was also abolished. Thus, with 2.4, 3.6 and 4.8 mmol/liter of [Mg++](o) perfused before the administration of cromakalim and the onset of ischemia, the incidence of reperfusion-induced ventricular tachycardia was reduced from 92% (in cromakalim treated group) to 67%, 42% (P<.05), and 25% (P<.05), respectively. The incidence of reperfusion-induced ventricular tachycardia showed the same pattern. Elevated [Mg++](o) prevented the cromakalim- induced cellular Na+ gain and K+ loss, measured by atomic absorption spectrophotometer. [Mg++](o) could prevent the proarrhythmic activity of cromakalim, and the use of cromakalim as an antihypertensive or antiischemic agent may be of particular concern in the population of postischemic diabetic subjects who are known to be at high risk of sudden coronary death.

Original languageEnglish
Pages (from-to)309-317
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume282
Issue number1
Publication statusPublished - Jul 1 1997

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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