Abstract

Mebutamate (2-methyl-2-sec-butyl-1,3-propanediol dicarbamate) has been shown by pharmacodynamic studies in cats and dogs to be a spinal interneuronal blocking agent that selectively inhibits spinal vasoconstrictor tracts. It is distinguished sharply in this action from meprobamate (2-methyl-2-n-propyl-1,3-propanediol dicarbamate) for no inhibition of spinal vasomotor tracts could be demonstrated for this drug. This inhibition of spinal vasomotor tracts by mebutamate clearly differed from its action on spinal motor tracts affecting skeletal muscle. In suppressing spinal interneuronal arcs concerned with skeletal muscle motor function, mebutamate approximated meprobamate in activity. The present experiments confirm the previously reported centrally acting mechanism for the blood pressure lowering activity of mebutamate, and link this hypotensive effect to a direct action on spinal vasomotor tracts as well as the brain stem vasomotor centers. Mebutamate greatly increased vascular limb flow when injected intrathecally in dogs whereas meprobamate was ineffective. This concurred with cross-circulation experiments demonstrating a marked vasodilatation of the isolated perfused limb as evidenced by increased blood flow and reduced peripheral resistance. In similar trials, phenobarbital was found to be ineffective. The drop in peripheral resistance which followed the intrathecal mebutamate simulated that observed during spinal anesthesia. By direct comparison with lidocaine, it has been shown that the spinal action of mebutamate was not due to a local anesthetic property of the drug. Infiltration of mebutamate into the sciatic nerve failed to paralyze the limb or to block sensation. By contrast, lidocaine caused profound paralysis and loss of sensation.

Physiologically the discovery of a highly selective action by mebutamate on the spinal vasomotor pathways rather than on spinal motor tracts emphasizes that small changes in molecular structure can sharply alter the pattern of nerves inhibited by closely related neuronal blocking agents. Furthermore, the data suggest that the spinal cord may play an important role in modulating the predominantly vasoconstrictor output from the medullary vasomotor regions.