Abstract 3726: ATP Sensitive K+ Channels Are Critical for Maintaining Myocardial Perfusion and High Energy Phosphates in the Failing Heart
Congestive heart failure (CHF) is associated with intrinsic alterations in mitochondrial oxidative phosphorylation which are independent of ischemia and manifest as an increase in myocardial cytosolic free ADP. ATP sensitive K+ channels (KATP) act as metabolic sensors that are important for maintaining coronary blood flow (CBF) 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 >25 mmHg) was produced in adult mongrel dogs (n=6) by rapid ventricular pacing (220–250) for 4 weeks. CBF was measured with radiolabeled microspheres in open chest dogs during baseline (BL), AdR blockade with 8-Phenyltheophylline (8-PT; 5mg/kg iv) and KATP blockade with Glibenclamide (GLB; 20 μg/kg/min ic), while high energy phosphates were examined with 31P magnetic resonance spectroscopy (MRS). Myocardial oxygenation was examined from the deoxymyoglobin signal using 1H MRS (Mb-δ). During basal conditions Mb-δ was undetectable while phosphocreatine (PCr)/ATP (1.73±0.15) was significantly lower than in previously studied normal dogs (2.21±0.11). 8-PT caused a ≈ 21% increase in CBF (0.71±0.07 at BL vs 0.90±0.15 ml/min-g with 8-PT) with no change in PCr/ATP (1.65±0.17 with 8-PT vs 1.73±0.15 at BL, p=NS). GLB resulted in a 32.7±0.1% decrease in CBF (to 0.58±0.07 ml/min-g, p<0.02) that was associated with a decrease in PCr/ATP (1.11±0.11 with GLB vs 1.65±0.17 with 8-PT, p<0.0001). The pseudo-first-order rate constant of ATP production via CK (kf) did not change during GLB. However, the ATP production rate via CK was reduced by 35±0.08% during GLB, and this was accompanied by a significant increase in Pi/PCr and a Mb-δ signal indicating tissue hypoxia. Thus, in the failing heart without coronary artery disease, the balance between myocardial ATP demands (or oxygen demands) and delivery are critically dependent on functioning KATP channels but not AdR.
This research has received full or partial funding support from the American Heart Association, National Center.