ACUTE AND CHRONIC HYPOKALEMIA SENSITIZE THE ISOLATED HEART TO HYPOXICINJURY

We examined the effects of acute and/or chronic hypokalemia on respons es to 30 min of hypoxia and recovery in the isolated, perfused heart m odel. We found that both acute hypokalemia and chronic hypokalemia imp aired contractility [expressed as maximum slope of pressure increase o ver time (dP/dt): 501 +/- 49 and 529 +/- 48 vs. 1,302 +/- 118 mmHg/s, P < 0.01] and recovery of ATP concentrations (determined with P-31 NMR spectroscopy: 30 +/- 6 and 40 +/- 10 vs. 67 +/- 5% initial, P < 0.05) at 30 min of recovery. Moreover, the combination of acute hypokalemia and chronic hypokalemia had additive effects (dP/dt 166 +/- 15 mmHg/s and ATP 21 +/- 7% initial, both P < 0.01). We also measured cytosolic calcium with surface fluorescence spectroscopy after indo 1 loading. Acute hypokalemia and acute hypokalemia + chronic hypokalemia increase d cytosolic calcium (averaged throughout the cardiac cycle) during and after hypoxia (390- to 460-nm ratio at 30 min of recovery: 0.46 +/- 0 .07 and 0.65 +/- 0.07 vs. 0.18 +/- 0.03, P < 0,01), whereas:control an d chronic hypokalemia hearts had only small changes with hypoxia and r ecovery. Finally, when we examined mitochondria isolated from hearts p erfused under experimental conditions, we found that chronic hypokalem ia-alone mitochondria and chronic hypokalemia + acute hypokalemia mito chondria had marked impairment of state 3 respiration compared with co ntrol hearts (52 +/- 13 and 50 +/- 9 vs. 128 +/- 10 natm.min(-1).mg pr otein(-1) with succinate as substrate, P < 0.01), whereas acute hypoka lemia mitochondria demonstrated only subtle changes. These data sugges t that both acute hypokalemia and chronic hypokalemia impair cardiac r esponses to hypoxia. The mechanism may involve impairment of calcium m etabolism, but cytosolic calcium alterations do not explain all of the metabolic and functional effects of acute hypokalemia and chronic hyp okalemia in the setting of hypoxia.