Selective blockade of mitochondrial KATPchannels does not impair myocardial oxygen consumption

Abstract
Opening of mitochondrial ATP-sensitive potassium (KATP) channels has been postulated to prevent inhibition of respiration resulting from matrix contraction during high rates of ATP synthesis. Glibenclamide, which blocks KATP 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˙o 2) both at rest and during exercise. This study examined whether this represents a primary effect of blockade of mitochondrial KATP channels or occurs secondary to coronary resistance vessel constriction with a decrease of coronary blood flow (CBF) and myocardial oxygen availability. MV˙o 2 was measured at rest and during treadmill exercise in 10 dogs during control conditions, after selective mitochondrial KATP channel blockade with 5-hydroxydecanoate (5-HD), and after nonselective KATPchannel blockade with glibenclamide. During control conditions, exercise resulted in progressive increases of CBF and MV˙o 2. 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 Po 2, 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˙o 2, or myocardial oxygen extraction. These findings suggest that glibenclamide decreased MV˙o 2 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.