Pharmacological Profile of the Selective Mitochondrial F₁F₀ ATP Hydrolase Inhibitor BMS‐199264 in Myocardial Ischemia

Abstract

The mitochondrial F 1 F 0 ATP synthase is responsible for the majority of ATP production in mammals and does this through a rotary catalytic mechanism. Studies show that the F 1 F 0 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. Oligmycin and aurovertin cannot be used for treating myocardial ischemia as they will reduce ATP production in healthy tissue. We generated a focused structureactivity relationship, and several compounds were identified that selectively inhibited the F 1 F 0 ATP hydrolase activity while having no effect on synthase function. One compound, BMS-199264 had no effect on F 1 F 0 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. IntroductionMyocardial ischemia is caused by an oxygen supply/demand imbalance. The degree of coronary occlusion will give differential clinical presentations and different therapeutic modes of treatment. Chronic stable angina is myocardial ischemia seen only upon increased oxygen demand (increased exertion) as the coronary stenosis alone will not cause pain or ST-segment abnormalities at rest. Resolution of symptoms often occurs after cessation of the increased exertion. Numerous therapeutics can resolve the symptoms of stable angina pectoris and these include nitrates, calcium antagonists, and β-adrenoceptor blockers [1][2][3].Severe myocardial ischemia causing necrosis or infarction has been difficult to effectively treat pharmacologically. Surgical intervention is the most commonly employed treatment because of its efficacy, along with agents such as aspirin, which are efficacious in secondary prevention of myocardial infarction. Many types of agents are efficacious in reducing infarct size or showing cardioprotection in animal models such as in dog and rat infarct size models and isolated rat hearts [1][2][3][4][5][6]. These agents include calcium antagonists, β-adrenoceptor blockers, preconditioning, and ATPsensitive potassium channel (K ATP ) openers. These agents are associated with preservation of ATP in ischemic myocyt...

ATP synthase: from single molecule to human bioenergetics

“…86) The complex regulation of HF o F 1 has been shown to be essential for daily human activity that is triggered by the brain (Fig. 10), thus human bioenergetics is also applicable to emergency medicine 113,118) and obesity/diabetes 23,116) and mitochondrial diseases. 87,97) …”

“…BMS-199264 selectively inhibits ATPase activity during ischemia while having no effect on ATP synthesis, and enhances the recovery of contractile function following reperfusion. 118) IF 1 , ectopic HF o F 1 and the opener of mitochondrial ATP-sensitive K + channel 113) protect cardiomyocytes from ischemic/reperfusion damage.…”

“…The degree of ATP inefficiently hydrolyzed during ischemia may be as high as 50–90%. 118) At the start of F o F 1 study, oligomycin was shown to inhibit F o , 3,39–42) and this portion of F o F 1 was therefore designated “oligomycin sensitivity conferring factor”. Oligomycin cannot be used to treat myocardial ischemia, as it would reduce ATP synthesis in normal tissue.…”

“…As HF o F 1 supplies most ATP needed for human activity, further study will provide useful insight for emergency medicine, 118) mitochondrial cardiomyopathy 22,87) and obesity-related chronic diseases. 23,115,116) …”

Nanotechnology inspired tools for mitochondrial dysfunction related diseases

“…Excessive ATP hydrolysis decreases the cardiac energy reserve leading to HF (151). Grover et al reported selective F 1 F 0 -ATPase inhibitor BMS-199264 with significant cardio-protective profile by reducing ATP hydrolysis (152). Thus, the F 1 F 0 -ATPase can be a target for nanotechnology-based tools against HF and IR.…”