Does amrinone inhibition of stimulated bone resorption involve Na⁺-Ca⁺⁺ exchange?

Amrinone, a new cardiotonic agent, inhibits stimulated bone resorption in vitro. Pretreatment of neonatal mouse calvaria or fetal rat limb bones in culture with 2 x 10^-4 M amrinone for 6 hr reduces the response to a stimulatory agent added after washing out amrinone. This irreversible inhibition by amrinone could be blocked if the stimulatory agent was present together with amrinone during the pretreatment. To determine whether the early interaction of amrinone with this system involved an effect on a Na⁺-Ca⁺⁺ exchange that may be required for stimulated calcium release from bone, the pretreatment effect of amrinone was examined under conditions of altered medium calcium or sodium concentration. If the calcium concentration was lowered during the 6 hr pretreatment, the inhibitory effect of amrinone was partially overcome; conversely increasing the calcium concentration during the pretreatment potentiated the effect of a submaximal concentration of amrinone. Although these results were consistent with amrinone blocking the Na⁺-Ca⁺⁺ exchange mechanism, the effects of altering the medium sodium concentration during the 6 hr pretreatment were inconclusive. Therefore sodium-independent effects of amrinone on calcium transport cannot be ruled out. Amrinone also inhibited macromolecular synthesis in bone but this effect does not account for its ability to inhibit stimulated resorption.