In additional experiments the influence of 1 |j,mol/L AAP10 on intracellular electrophysiology of guinea pig papillary muscles was investigated. No alteration in action potential duration was found at 90% repolarization (165±5 versus 164±6 ms), action potential duration at 20% repolarization (80±4 versus 78±8 ms), resting membrane potential (-84±1 versus -84±3 mV), overshoot potential (29±2 versus 30±4 mV) or maximum upstroke velocity (181±10 versus 190±12 V/s). However, a significant reduction was observed in coupling time between the stimulus and the propagated action potential within 1 min (Figure 3).
To clarify further the mechanism of action of AAP10, 0.01 |J.mol/L 14C-AAP10 (48 |J.Ci) was infused and hearts were processed histologically using autoradiography. Labelled AAP10 was found near the intercalated disks, as shown in Figure 4. Some labelled AAP10 could also be seen at the transversal cell-to-cell connections. For further investigation these experiments were repeated and hearts were processed biochemically according to the protocol reported by Manjunath et al (described above). Radioactive material was extracted with the intracellular and membrane-bound proteins in purification step 21.
Figure 3 Influence ofAAP10on coupling time between the stimulus and the fast upstroke of the propagated action potential in guinea pig papillary muscles. Data are means ± SEM of six experiments. *P<0.05 versus control
Figure 4 Autoradiograph from an unstained section of the left ventricle after perfusion with 10 nmol/L 14C-AAP10 viewed at a magnification of400x with phase contrast. The arrowheads point to the accumulation of activity at cell-to-cell borders
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