The direct cardioprotective efficacy of the
potassium channel activators
pinacidil and
cromakalim was determined in isolated globally ischemic rat hearts. Isolated
buffer-perfused rat hearts were subjected to 25 min of
ischemia followed by 30 min of reperfusion. These hearts were pretreated with 1 to 100 microM
pinacidil, 1 to 7 microM
cromakalim or vehicle.
Pinacidil resulted in significant improvements in reperfusion function and cardiac compliance, though it did not significantly reduce
lactate dehydrogenase release at any concentration. The protective effects of
pinacidil were greatest at
a 10 microns concentration and were slightly diminished at higher concentrations (30 and 100 microns). Although not affecting the severity of
ischemia alone, 10 microM
glyburide (
potassium channel blocker) completely reversed the protective effects of
pinacidil on reperfusion function and compliance.
Cromakalim (7 microM) resulted in a greater than 50% improvement in reperfusion function and compliance and unlike
pinacidil significantly reduced
lactate dehydrogenase release by approximately 50%. At 1 microM,
glyburide alone did not significantly affect the severity of
ischemia but reversed the protective effects of
cromakalim. Not only did
glyburide reverse the protective effects of
cromakalim, it resulted in a worsening of
ischemia compared to vehicle, an effect not seen with
glyburide alone. Thus, both
pinacidil and
cromakalim appear to have direct cardioprotective efficacy, though some differences between them may be possible. The mechanism of their protective effects appears to be via
potassium channel opening as the
potassium channel blocker glyburide reverses the protective effect of these compounds. Intracellular electrophysiological studies showed that
ischemia-induced depolarization was reversed with
cromakalim, which increased the resting potential nearly back to preischemic levels.(ABSTRACT TRUNCATED AT 250 WORDS)