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Method: Male mice (20-30 g) were humanely killed and each hemi-diaphragm with its phrenic nerve was placed on a tissue holder in a tissue bath filled with a modified Krebs-Henseleit buffer at 37°C, bubbled with 95% oxygen and 5% carbon dioxide. The phrenic nerve was stimulated continuously using a Grass S88E stimulator (rectangular pulses of 0.2 ms every 20 s at a supra-maximal voltage of 2.5 V) and isometric force was recorded using Grass FT03 transducers and a Grass 79D recorder. In preliminary studies, the ED90 doses for all NMBs had been determined and no spontaneous reversal was observed after administration of the NMBs.
After a stimulation period of at least 30 min, a 90% blocking dose of NMB was administered. Twenty minutes later, increasing doses of Org 25969 were administered at intervals of 10 min. The results are summarized in Table 1.
Results: All steroidal NMBs could be effectively reversed. Org 25969 was more effective against rocuronium and rapacuronium than against vecuronium and pancuronium. In contrast, the reversal of the block, induced by non-steroidal NMBs, was less effective, within the concentration range of Org 25969 used. We also studied the effects of Org 25969 and neostigmine on 90% block and profound block induced by rocuronium (3.6 and 10.8 μmol, ED90 and 3 × ED90 dose, respectively). Twenty min after induction of a 90% block, both Org 25969 (3.6 μmol) and neostigmine (7.0 μmol) caused reversal of neuromuscular blockade (97.9 ± 2.8% and 74.4 ± 9.5%, respectively, n=4). However, after obtaining profound block with 3 × 90% blocking dose of rocuronium, only Org 25969 (10.8 μmol) was able to reverse the block (61.9±8.8%), whereas neostigmine was ineffective, even at higher concentrations (7.0-9.0 μmol).
Conclusion: Org 25969 is a novel reversal agent, which effectively reverses neuromuscular blockade induced by steroidal NMBs. Org 25969 is less effective against non-steroidal NMBs. In contrast to neostigmine, Org 25969 can reverse profound block induced by steroidal NMBs.
