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The energetic state within hibernating myocardium is normal during dobutamine despite inhibition of ATP-dependent potassium channel opening with glibenclamide

¹Veterans Affairs Medical Center-University of Minnesota and ²Magnetic Resonance Unit, University of Minnesota, Minneapolis, Minnesota

Submitted 4 January 2007 ; accepted in final form 16 August 2007

Within hibernating myocardium, it is uncertain whether a normal energetic state is present at baseline and whether maintaining that energy state during a catecholamine challenge is dependent on ATP-dependent potassium channel opening. In this study, 16 swine underwent a thoracotomy with placement of an external constrictor on the left anterior descending coronary artery (LAD) (hibernation model). Seven additional swine underwent a sham operation. At 10 wk, the myocardial energetic state in the LAD region was assessed by ³¹P-NMR spectroscopy, and the ratio of phosphocreatine to ATP (PCr/ATP) was determined at baseline, during glibenclamide treatment (0.5 mg/kg bolus with 50 µg/min iv), and during addition of dobutamine (40 µg·kg^–1·min^–1 iv). At baseline, transmural blood flow in the LAD and remote region was 0.75 ± 0.11 and 0.88 ± 0.09 ml·min^–1·g^–1, respectively (P < 0.01), in hibernating hearts and 0.83 ± 0.12 and 0.88 ± 0.15 ml·min^–1·g^–1, respectively (not significant), in sham-operated hearts. Under basal conditions, PCr/ATP in the LAD region of hibernating and sham pigs was 2.15 ± 0.04 and 2.11 ± 0.05, respectively (not significant). In sham pigs, addition of dobutamine to glibenclamide increased the double product from 10.4 ± 0.8 to 23.9 ± 4.0 mmHg·beats·min^–1 x 1,000 (P < 0.05) and decreased transmural PCr/ATP from 2.06 ± 0.06 to 1.69 ± 0.06 (P < 0.05). Dobutamine increased the double product in hibernating pigs in a similar fashion and, despite a 40% lower blood flow response, induced an equivalent decrease in PCr/ATP from 2.04 ± 0.04 to 1.73 ± 0.08 (P < 0.05). In conclusion, we found that, in chronic hibernating swine myocardium with reduced basal blood flow and perfusion reserve, the transmural energetic state, defined by PCr/ATP, is normal during addition of dobutamine, despite inhibition of ATP-dependent potassium channel opening with glibenclamide. These data suggest that important adaptations other than the ATP-dependent potassium channel opening allow hibernating myocardium to operate over a lower range of the oxygen supply-demand relationship to protect against myocardial ischemia.

myocardial ischemia; high-energy phosphates; preconditioning; hibernation; mitochondrial adaptations

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