The contribution of Na-activated K channel, the furosemide-sensitive (Na-K-Cl) cotransport, and Na-K pump to extracellular potassium accumulation during global ischemia was investigated using pharmacological blockade of these pathways. R 56865 (a blocker of the Na-activated K channel), furosemide, or ouabain was included in the perfusate before ischemia in the isolated rat heart preparation, and the extracellular K concentration ([K]e) was monitored during 30 min of global ischemia. In control hearts, [K]e showed an early rise (up to 9.0 +/- 0.2 mM from the baseline of 5.9 mM), a fall (to a minimum of 6.7 +/- 0.2 mM), and a late rise (to 14.1 +/- 0.4 mM by the end of ischemia). R 56865 (0.1 and 1 microM) suppressed the early [K]e rise to 50% of the control level. The late rise in [K]e was also significantly suppressed by the higher dose of R 56865. Furosemide (0.1 and 1 mM) reduced the early K accumulation by 35% but did not affect the rise of [K]e during the late ischemic phase. Blockade of Na-K pump by 10 microM ouabain did not increase [K]e during any phase of ischemia and, in fact, 100 microM ouabain profoundly suppressed the early rise in [K]e. We therefore suggest that the Na-activated K channel, the furosemide-sensitive cotransport, and changes in the activity of the Na-K pump may all contribute to extracellular K accumulation during ischemia. However, in addition to these pathways, it seems likely that other pathways for transsarcolemmal K efflux contribute to cellular K loss during ischemia in the isolated rat heart.(ABSTRACT TRUNCATED AT 250 WORDS)
We examined influences of a blocker (glibenclamide) and an opener (nicorandil) of the ATP-sensitive potassium (KATP) channel on extracellular K concentration [( K+]e), as well as the myocardial function and metabolites during global ischemia and reperfusion in Langendorff-perfused rat heart preparation. In control hearts, [K+]e began to rise 20 s after the onset of ischemia up to an initial peak (8.3 +/- 0.3 mM) at 2.5 +/- 0.7 min, then fell to 6.0 +/- 0.8 mM after 8.2 +/- 0.7 min, and then rose progressively to 14.6 +/- 0.8 mM at the end of 30 min of ischemia. Glibenclamide (50 microM) reduced the initial peak of [K+]e to 7.2 +/- 0.3 mM (P less than 0.01), and nicorandil (200 microM) increased it to 9.4 +/- 0.6 mM (P less than 0.01). There were no significant differences in [K+]e values among all groups at the end of ischemia. During ischemia, nicorandil decreased the time to mechanical arrest from 1.9 +/- 0.1 min to 1.5 +/- 0.1 min, whereas it was increased by glibenclamide to 2.7 +/- 0.4 min. In control hearts, the time to onset of ischemic contracture was 14.7 +/- 1.8 min. Nicorandil delayed onset of contracture and glibenclamide accelerated it. Thus we have confirmed that some part of the early increase in [K+]e during ischemia is attributable to K+ efflux through the KATP channel in our model, and opening of the KATP channel may contribute to a rapid reduction of the contractility of the ischemic myocardium that subsequently protects the myocardium against further ischemic injury.
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