Selective blockade of mitochondrial K_ATP channels does not impair myocardial oxygen consumption

Opening of mitochondrial ATP-sensitive potassium (K_ATP) channels has been postulated to prevent inhibition of respiration resulting from matrix contraction during high rates of ATP synthesis. Glibenclamide, which blocks K_ATP channels on the sarcolemma of vascular smooth muscle cells and myocardial myocytes as well as on the inner mitochondrial membrane, results in a decrease of myocardial oxygen consumption (MV_O2) both at rest and during exercise. This study examined whether this represents a primary effect of blockade of mitochondrial K_ATP channels or occurssecondary to coronary resistance vessel constriction with a decrease of coronary blood flow (CBF) and myocardial oxygen availability. MV_O2 was measured at rest and during treadmill exercise in 10 dogs during control conditions, after selective mitochondrial K_ATP channel blockade with 5-hydroxydecanoate (5-HD), and after nonselective K_ATP channel blockade with glibenclamide. During control conditions, exercise resulted in progressive increases of CBF and MV_O2. Glibenclamide (50 μg·kg^-1·min^-1 ic) resulted in a 17 ± 6% decrease of resting CBF with a downward shift of CBF during exercise and a decrease of coronary venous P_O2, indicating increased myocardial oxygen extraction. In contrast with the effects of glibenclamide, 5-HD (0.7 mg·kg^-1·min^-1 ic) had no effect on CBF, MV_O2, or myocardial oxygen extraction. These findings suggest that glibenclamide decreased MV_O2 by causing resistance vessel constriction with a decrease of CBF and oxygen available to the myocardium rather than to a primary reduction of mitochondrial respiration.