Abstract
1. WIN 2747 produced complete arrest of nerve-impulse transmission in the dog nerve-muscle preparation at dosages approximately one-half the dose of d-tubocurarine chloride pentahydrate required to produce a similar effect. The muscle was capable of responding to direct stimulation during arrest of nerve-impulse transmission due to either drug.
2. WIN 2747 was one-half as active and one-fourth as toxic as d-tubocurarine by subcutaneous injection in mice.
3. WIN 2747 was approximately five times as active as d-tubocurarine by intravenous injection in rabbits, but it was also approximately four times as toxic so that the margin between the HD50 and the LD50 was very small for both compounds.
4. The dose producing respiratory arrest in the dog nerve-muscle preparation was only slightly larger than the dose which caused arrest of nerve-impulse transmission with both compounds.
5. While d-tubocurarine consistently produced a fall in blood pressure at curarizing dose levels, either no effect or a slight rise in blood pressure was observed at equally active doses of WIN 2747.
6. Amounts of WIN 2747 as great as 1563 times the average dose required to produce neuromuscular blockade were infused into the barbitalized dog without producing cardiac arrest, while total dosages representing 184 and 298 times the curarizing dose of d-tubocurarine resulted in cardiac failure.
7. The duration of curarimimetic activity in mice and rabbits appeared to be the same for both substances but the effect with d-tubocurarine persisted somewhat longer in the dog nerve-muscle preparation.
8. Pretreatment of rabbits with neostigmine was observed to raise the HD50 values by factors of 1.3 and 1.7 times and the LD50 values by factors of 1.6 and 2.1 times for WIN 2747 and d-tubocurarine, respectively. Neostigmine failed to protect the barbitalized dog against more than twice the respiratory paralyzing dose of either drug. Adequate positive intratracheal insufflation, on the other hand, protected the anesthetized dog against many times the minimum dose of either drug required to produce neuromuscular blockade.
9. The use of the quantal response rabbit head-drop assay procedure appears to be a reasonably accurate and satisfactory research tool. The error of the method was approximately 10 per cent.
Footnotes
- Received July 17, 1950.
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