The mitochondrial F1F0
ATP synthase is responsible for the majority of
ATP production in mammals and does this through a rotary catalytic mechanism. Studies show that the F1F0
ATP synthase can switch to an
ATP hydrolase, and this occurs under conditions seen during
myocardial ischemia. This
ATP hydrolysis causes wasting of
ATP that does not produce work. The degree of
ATP inefficiently hydrolyzed during
ischemia may be as high as 50-90% of the total. A naturally occurring, reversible inhibitor (IF-1) of the
hydrolase activity is in the mitochondria, and it has a pH optimum of 6.8. Based on studies with the nonselective (inhibit both synthase and
hydrolase activity) inhibitors
aurovertin B and
oligomycin B reduce the rate of
ATP depletion during
ischemia, showing that IF-1 does not completely block
hydrolase activity.
Oligomycin and
aurovertin cannot be used for treating
myocardial ischemia as they will reduce
ATP production in healthy tissue. We generated a focused structure-activity relationship, and several compounds were identified that selectively inhibited the F1F0
ATP hydrolase activity while having no effect on synthase function. One compound,
BMS-199264 had no effect on F1F0
ATP synthase function in submitochondrial particles while inhibiting
hydrolase function, unlike
oligomycin that inhibits both.
BMS-199264 selectively inhibited
ATP decline during
ischemia while not affecting
ATP production in normoxic and reperfused hearts. BMS-191264 also reduced cardiac
necrosis and enhanced the recovery of contractile function following reperfusion. These data also suggest that the reversal of the synthase and
hydrolase activities is not merely a chemical reaction run in reverse.