Myocardial stunning is characterized not only by a decreased regional postischemic function but also by a relatively high oxygen consumption (ie, decreased mechanical efficiency). Several lines of evidence suggest that the underlying mechanism may involve a decreased sensitivity of the myofibrils to
calcium, but in vivo evidence is lacking. We therefore evaluated this hypothesis in vivo using
EMD 60263, a
calcium-sensitizing agent, which is devoid of any
phosphodiesterase-inhibiting properties.
METHODS AND RESULTS: We first established the effect of two consecutive doses of
EMD 60263 (0.75 and 1.5 mg/kg i.v., n = 7), administered at 15-minute intervals, on segment length shortening (SLS), external work index (EW; the area inside the left ventricular pressure-segment length loop), myocardial oxygen consumption (MVO2), and mechanical efficiency (EW/MVO2) in anesthetized pigs with normal myocardium. After the highest dose of
EMD 60263, SLS in the distribution area of the left anterior descending coronary artery (LADCA) increased from 13 +/- 1% at baseline to 17 +/- 1% (P < .05). However, EW, MVO2, and EW/MVO2 were not significantly affected (123 +/- 10%, 98 +/- 9%, and 85 +/- 13% of baseline, respectively). In 14 other anesthetized pigs,
myocardial stunning was induced by two sequences of 10 minutes of LADCA occlusion and 30 minutes of myocardial reperfusion. After induction of stunning, the two doses of
EMD 60263 (n = 7) or saline (3 and 6 mL, n = 7) were infused. In the distribution area of the LADCA, the stunning protocol caused decreases in SLS from 16 +/- 1% to 8 +/- 1% (P < .05) and in EW to 49 +/- 5% of baseline (P < .05), whereas MVO2 was only minimally affected (P > .05). Consequently, mechanical efficiency decreased to 59 +/- 8% of baseline (P < .05). Saline infusion did not affect any of these regional myocardial variables, but after administration of
EMD 60263 SLS recovered dose-dependently to 15 +/- 2% after the highest dose of the
drug. EW and mechanical efficiency also recovered dose-dependently to 89 +/- 4% (P < .05 versus stunning) and to 88 +/- 7% (NS versus baseline) of baseline, respectively. In the not-stunned segment, SLS increased from 15 +/- 2% (at baseline) to 18 +/- 2% (after the highest dose), and EW per beat was not changed significantly. An
adrenergic mode of action of
EMD 60263 was excluded by blocking the alpha- and
beta-adrenergic receptors with
phentolamine and
propranolol, respectively, 15 minutes before administration of
EMD 60263 (ie, 15 minutes into the second reperfusion period) in five additional experiments. In these experiments the EMD 60263-induced increases in SLS and EW were not attenuated. Because
EMD 60263 decreased heart rate from 106 +/- 4 to 76 +/- 3 beats per minute (P < .05) in the animals with
stunned myocardium, we performed five experiments with the specific negative chronotropic compound
zatebradine (
UL-FS 49, 0.1 to 0.5 mg/kg) to rule out
bradycardia as
a factor contributing to the effects of
EMD 60263. These
zatebradine doses lowered heart rate from 116 +/- 5 to 55 +/- 1 beats per minute (P < .05) but had no effect on SLS of stunned and not-
stunned myocardium.
CONCLUSIONS: