title: ATP sensitive K(+) channels are critical for maintaining myocardial perfusion and high energy phosphates in the failing heart.
abstract: Congestive heart failure (CHF) is associated with intrinsic alterations of mitochondrial oxidative phosphorylation which lead to increased myocardial cytosolic free ADP. ATP sensitive K(+) channels (KATP) act as metabolic sensors that are important for maintaining coronary blood flow (MBF) and in mediating the response of the myocardium to stress. Coronary adenosine receptors (AdR) are not normally active but cause vasodilation during myocardial ischemia. This study examined the myocardial energetic response to inhibition of KATP and AdR in CHF. CHF (as evidenced by LVEDP>20mmHg) was produced in adult mongrel dogs (n=12) by rapid ventricular pacing for 4weeks. MBF was measured with radiolabeled microspheres during baseline (BL), AdR blockade with 8-phenyltheophylline (8-PT; 5mg/kg iv), and KATP blockade with glibenclamide (GLB; 20μg/kg/min ic). High energy phosphates were examined with (31)P magnetic resonance spectroscopy (MRS) while myocardial oxygenation was assessed from the deoxymyoglobin signal (Mb-δ) using (1)H MRS. During basal conditions the phosphocreatine (PCr)/ATP ratio (1.73±0.15) was significantly lower than in previously studied normal dogs (2.42±0.11) although Mb-δ was undetectable. 8-PT caused ≈21% increase in MBF with no change in PCr/ATP. GLB caused a 33±0.1% decrease in MBF with a decrease in PCr/ATP from 1.65±0.17 to 1.11±0.11 (p<0.0001). GLB did not change the pseudo-first-order rate constant of ATP production via CK (kf), but the ATP production rate via CK was reduced by 35±0.08%; this was accompanied by an increase in Pi/PCr and appearance of a Mb-δ signal indicating tissue hypoxia. Thus, in the failing heart the balance between myocardial ATP demands and oxygen delivery is critically dependent on functioning KATP channels.
authors: Department of Medicine, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors: Mohammad N
authors: MN
authors: Jameel
authors: Department of Medicine, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors: Qiang
authors: Q
authors: Xiong
authors: Department of Medicine, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors: Abdul
authors: A
authors: Mansoor
authors: Department of Medicine, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors: Robert J
authors: RJ
authors: Bache
authors: Department of Medicine, University of Minnesota Medical School, Minneapolis, MN 55455, USA; Department of Biomedical Engineering, School of Medicine, School of Engineering, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address: jayzhang@uab.edu.
authors: Jianyi
authors: J
authors: Zhang
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D004285:Dogs; D005905:Glyburide / Q000008:administration & dosage*; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D018047:Receptors, Purinergic P1 / Q000187:drug effects / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
chemical_list: D015221:Potassium Channels; D018047:Receptors, Purinergic P1; C117780:mitochondrial K(ATP) channel; D000255:Adenosine Triphosphate; D005905:Glyburide
keywords: Heart failure; K(ATP) channels; Myocardial blood flow