A phospholipase A2 inhibitor (Ro 31-4493) prevents protein loss associated with the calcium paradox in isolated guinea pig hearts without effect on contracture, calcium overload, or the currents through L-type calcium channels.

OBJECTIVE

Although it is widely accepted that the hypercontraction provoked by the influx of Ca2+ on return to normal Tyrode solution after a period of Ca2+ depletion (the calcium paradox) contributes to the damage to the cell membrane, it remains possible that the Ca2+ overload activates intracellular enzymes that are important in the initial degradation of the cell membrane. This possibility was examined in this work.

EXPERIMENTAL DESIGN

The effect of Ro 31-4493, a phospholipase A2 inhibitor, upon protein loss, hypercontracture, and ultrastructural changes in Langendorff perfused guinea pig hearts during the calcium paradox was studied. Because the degree of Ca2+ overload might also be affected, the action of the drug on the resting and action potentials and the whole cell currents through the L-type Ca2+ channels and the changes in [Ca2+]i in isolated guinea pig ventricular myocytes were also studied.

RESULTS

Ro 31-4493, at 10-50 microM, inhibited the release of proteins from guinea pig Langendorff perfused hearts during the calcium paradox in a dose dependent way. This protective effect required preincubation with the agent before the Ca2+ depletion. No significant effect upon the contractile behaviour, as recognised from the sustained increase in intraventricular pressure on Ca2+ repletion, was produced. However, structural changes suggest that the extent of hypercontraction, the disruption of cell membrane and the release of mitochondria was less in treated hearts. Ro 31-4493 produced no change in the resting and action potentials or the behaviour of the L-type Ca2+ channels with either Ca2+ or Na+ as the charge carrier, while measurements of [Ca2+]i indicated a similar Ca2+ overload in both treated and untreated hearts.

CONCLUSION

The effects of Ro 31-4493 are inconsistent with mechanical consequences of hypercontraction upon activation of a Ca2+ dependent phospholipases may be an important step.