Pharmacological modulation of [K+]o accumulation and action potential changes during acute myocardial ischemia is under evaluation as a promising new antiarrhythmic and cardioprotective strategy during myocardial ischemia and reperfusion. We studied the effects of cromakalim, a K+ channel opener that activates ATP-sensitive K+ channels, in isolated arterially perfused rabbit interventricular septa subjected to ischemia and reperfusion and, through use of the patch clamp technique, in inside-out membrane patches excised from guinea pig ventricular myocytes. During aerobic perfusion, 5 microM cromakalim shortened action potential duration (APD) from 217 +/- 7 to 201 +/- 10 msec, had no effect on [K+]o, and reduced tension by 17 +/- 3% (n = 11). During ischemia, pretreatment with 5 microM cromakalim resulted in 1) more rapid APD shortening (71 +/- 9 versus 166 +/- 7 msec at 10 minutes and 63 +/- 12 versus 122 +/- 8 msec at 30 minutes), 2) similar [K+]o accumulation after 10 minutes (8.9 +/- 0.3 versus 9.6 +/- 0.5 mM) but a trend toward increased [K+]o accumulation after 30 minutes (11.0 +/- 1.7 versus 9.6 +/- 1.0 mM), and 3) similar times for tension to decline to 50% of control (2.14 +/- 0.16 versus 2.14 +/- 0.19 minutes) but shorter time to fall to 20% of control (4.34 +/- 0.33 versus 4.90 +/- 0.22 minutes; p = 0.003). After 60 minutes of reperfusion following 30 minutes of ischemia, recovery of function was similar, with a trend toward better recovery of developed tension (to 58 +/- 9% versus 39 +/- 10% of control; p = 0.18) and tissue ATP levels in cromakalim-treated hearts but no differences in APD or rest tension. Thus, 5 microM cromakalim had mild effects in normal heart but greatly accelerated APD shortening during ischemia without markedly increasing [K+]o accumulation, possibly because the more rapid APD shortening reduced the time-averaged driving force for K+ efflux through ATP-sensitive K+ channels. A significant cardioprotective effect during 30 minutes of ischemia plus 60 minutes of reperfusion could not be demonstrated in this model. In excised membrane patches studied at room temperature, the ability of cromakalim to activate ATP-sensitive K+ channels was significantly potentiated by 100 microM but not 15 microM cytosolic ADP, suggesting that in addition to the modest fall in cytosolic ATP during early ischemia, the rapid increases in cytosolic ADP may further sensitize cardiac ATP-sensitive K+ channels to activation by cromakalim.(ABSTRACT TRUNCATED AT 400 WORDS)
BACKGROUND: Lysophospholipids such as lysophosphatidylcholine (LPC) have many direct electrophysiological effects on cardiac muscle and have been implicated as a cause of lethal ventricular arrhythmias during acute myocardial ischemia. Because extracellular K(+) accumulation is also a key arrhythmogenic factor during acute ischemia, we examined the effects of LPC on cellular K(+) balance, including its interaction with adenosine triphosphate-sensitive K(+) (K(ATP)) channels. METHODS AND RESULTS: Isolated rabbit interventricular septa paced at 75 beats/min were loaded with (42)K(+) to measure unidirectional K(+) efflux rate (in (42)K(+) washout experiments) or tissue K(+) content ((42)K(+) uptake experiments) and action potential duration (APD) during exposure to 20 µM LPC for 30 minutes. LPC caused tissue K(+) content to decrease by 15 +/- 2% (n = 4) at a steady rate over 30 minutes, associated with gradual APD shortening and a delayed increase in unidirectional K(+) efflux rate. Pretreatment with 12 µM cromakalim to selectively activate K(ATP) channels shortened APD by 44 +/- 66% and had no effect on net tissue K(+) content during control aerobic perfusion. However, cromakalim increased net K(+) loss during exposure to LPC to 22 +/- 4%, a 47% increase. CONCLUSIONS: LPC induced net K(+) loss in heart, which was potentiated by the K(ATP) channel agonist cromakalim. This ATP finding suggests that if LPC accumulates to similar levels during myocardial ischemia and hypoxia, it may be an important mechanism in net K(+) loss.
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