Selective blockade of mitochondrial KATP 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 (M(V) over dot O-2) both at rest and during exercise. This study examined whether this represents a primary effect of blockade of mitochondrial K-ATP channels or occurs secondary to coronary resistance vessel constriction with a decrease of coronary blood flow (CBF) and myocardial oxygen availability. M(V) over dot O-2 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 M(V) over dot O-2. Glibenclamide (50 mug . 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 PO2, 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, M(V) over dot O-2, or myocardial oxygen extraction. These findings suggest that glibenclamide decreased M(V) over dot 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.