Myocardial oxygenation and high-energy phosphate levels during K_ATP channel blockade

Abstract

.-Inhibition of ATP-sensitive K ϩ (KATP) channel activity has previously been demonstrated to result in coronary vasoconstriction with decreased myocardial blood flow and loss of phosphocreatine (PCr). This study was performed to determine whether the high-energy phosphate abnormality during KATP channel blockade can be ascribed to oxygen insufficiency. Myocardial blood flow and oxygen extraction were measured in open-chest dogs during KATP channel blockade with intracoronary glibenclamide, whereas high-energy phosphates were examined with 31 P magnetic resonance spectroscopy (MRS), and myocardial deoxymyoglobin (Mb-␦) was determined with 1 H MRS. Glibenclamide resulted in a 20 Ϯ 8% decrease of myocardial blood flow that was associated with a loss of phosphocreatine (PCr) and accumulation of inorganic phosphate. Mb-␦ was undetectable during basal conditions but increased to 58 Ϯ 5% of total myoglobin during glibenclamide administration. This degree of myoglobin desaturation during glibenclamide was far greater than we previously observed during a similar reduction of blood flow produced by a coronary stenosis (22% of myoglobin deoxygenated during stenosis). The findings suggest that reduction of coronary blood flow with an arterial stenosis was associated with a decrease of myocardial energy demands and that this response to hypoperfusion was inhibited by KATP channel blockade. blood flow; myoglobin; oxygen saturation ATP-SENSITIVE POTASSIUM (K ATP ) channels have the potential to influence energy metabolism in the heart. Opening of K ATP channels on vascular smooth muscle cells allows efflux of potassium; the resultant membrane hyperpolarization closes voltage-gated calcium channels to result in vasodilatation with an increase of blood flow (25). K ATP channels on coronary arterioles open in response to hypoxia and appear to be critical for metabolic vasoregulation by which coronary blood flow is regulated in response to myocardial metabolic requirements (11,20). We previously observed that in intact awake dogs, K ATP channel blockade with intracoronary glibenclamide resulted in vasoconstriction with a 17-20% decrease in coronary blood flow (4, 5).This decrease in coronary flow was associated with a parallel reduction of myocardial oxygen consumption (MV O 2 ) and a significant decrease of systolic wall thickening. These findings suggested that glibenclamide resulted in coronary vasoconstriction with a decrease in myocardial blood flow sufficient to result in ischemic contractile dysfunction. However, an alternative possibility is that glibenclamide caused a primary decrease of MV O 2 so that the reduction of coronary flow occurred secondary to the decreased oxygen uptake. This possibility is based on studies of K ATP channels located on the inner mitochondrial membrane where they have the potential to influence respiration and ATP synthesis (10, 15). If blockade of mitochondrial K ATP channels by glibenclamide caused a decrease of MV O 2 , then the consequent reduction of ATP synthesis could lead to decreased ...

Myocardial Energy Transport and Heart Failure

“…In the porcine model KATP inhibition with glibenamide does interfere with modulation of myocardial respiration that normally occurs during hypoperfusion. [94] This finding in vivo supports the hypothesis that KATP activity coordinates with phosphotransfer; and prolonged disruption of these systems would lead to contractile dysfunction and heart failure.…”

ATP sensitive K+ channels are critical for maintaining myocardial perfusion and high energy phosphates in the failing heart

“…Mitochondrial K ATP channel activity can also be cardioprotective, presumably because the influx of K + across the mitochondrial inner membrane reduces the mitochondrial membrane potential (Δψm), matrix swelling, and the production of reactive oxygen species (ROS) 11 . Nevertheless, we have shown that the decrease in MVO 2 produced by glibenclamide administration is caused by coronary vasoconstriction and the accompanying decline in oxygen availability, rather than by a direct effect on mitochondrial respiration 10, 12 .…”

“…A similar catheter was inserted into the left atrium through the atrial appendage. A homemade intra coronary catheter was placed into left anterior descending coronary artery (LAD) as previously described in details 10 . A 28 mm diameter MRS surface coil was sutured onto the epicardium of LV anterior wall.…”

“…We have previously shown that the decrease in MBF produced by glibenclamide also reduced the ratio of phosphocreatine (PCr) to ATP (PCr/ATP), increased inorganic phosphate (Pi) levels, and led to the appearance of a prominent deoxymyoglobin peak in the magnetic resonance spectrum. Furthermore, these changes in high energy phosphate (HEP) levels were substantially greater than the changes observed when coronary flow was reduced to a similar extent by stenosis 10 . Collectively, our findings suggested that the decrease in coronary blood flow produced by an arterial stenosis was accompanied by a decrease in myocardial energy demand, and that this response to hypoperfusion was inhibited by K ATP channel blockade 10 .…”

“…Furthermore, these changes in high energy phosphate (HEP) levels were substantially greater than the changes observed when coronary flow was reduced to a similar extent by stenosis 10 . Collectively, our findings suggested that the decrease in coronary blood flow produced by an arterial stenosis was accompanied by a decrease in myocardial energy demand, and that this response to hypoperfusion was inhibited by K ATP channel blockade 10 . Mitochondrial K ATP channel activity can also be cardioprotective, presumably because the influx of K + across the mitochondrial inner membrane reduces the mitochondrial membrane potential (Δψm), matrix swelling, and the production of reactive oxygen species (ROS) 11 .…”