PORCINE MALIGNANT HYPERTHERMIA. Sir,â4-Aminopyridine (4-AP) has been introduced recently to Hiniml practice for the antagonism of neuromuscular.
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CORRESPONDENCE Hall, L. W., Trim, C. M., and Woolf, N. (1972). Further studies on porcine malignant hyperthermia. Br. Med. J., 2, 145. Harrison, G. G. (1973). Althesin and malignant hyperpyrexia. Br. J. Anaesth., 45, 1019. Honda, N., Konno, K., Itohda, Y., Nishino, M., Matsushima, S., Haseba, S. Honda, Y., and Gotoh, Y. (1977). Malignant hyperthermia and Althesin. Can. Anaesth. Soc.J., 24, 514. McNeill, H. G., Clarke, R. S. J., and Dundee, J. W. (1979). Minaxolone—a new water-soluble steroid anaesthetic.. Lancet, 2, 73.
the results indicate that porcine MH cannot be induced by a compound the effect of which is mediated, at least partly, by a direct action on the muscle membrane to increase the intracellular Ca'+ concentration. This suggests that the recent emphasis on the sarcolemma or sarcolemma-sarcoplasmic reticulum junction as the site of the primary defect in MH may not be valid. G. M. HALL G. M. COOPER
London J. N. LUCXB D. LISTER
Bristol 4-AMINOPYRIDINE FAILS TO INDUCE
ACKNOWLEDGEMENTS
PORCINE MALIGNANT HYPERTHERMIA
We thank Professor W. C. Bowman for helpful advice, and the Muscular Dystrophy Group of Great Britain for financial support.
Sir,—4-Aminopyridine (4-AP) has been introduced recently to Hiniml practice for the antagonism of neuromuscular blockade produced either by curare-like agents (Stoyanov et al., 1976), or antibiotics (Booij, Miller and Crul, 1978), and for the treatment of myasthenia gravis (Lundh, Nilsson and Rosen, 1979), and the Eaton-Lambert syndrome (Lundh, Nilsson and Rosen, 1977). 4-AP facilitates neuromuscular transmission by a pre-synaptic effect on the motor nerve terminal in which both the spontaneous and the evoked output of acetylcholine is increased, and also by a direct effect on muscle to increase contractility (Bowman, Khan and Savage, 1977). The mode of action of 4-AP is thought to be an increase in the intracellular Ca1+ concentration either as a result of blockade of the potassium channel in the cell membrane with prolongation of the action potential (Molgo, Lemeignan and Lechat, 1977), or by a direct effect on the calcium channel in the membrane (Lundh and Thesleff, 1977). There are, therefore, good grounds for suggesting that 4-AP may trigger porcine malignant hyperthermia (MH), since this syndrome is caused by an increase in the Ca1+ concentration within the striated muscle cell. This contention is supported by studies which have shown that the effects of 4-AP on striated muscle are antagonized by dantrolene (Bowman, Khan and Savage, 1977) and Mg 1+ (Marshall, Lambert and Durant, 1979), both of which have been used successfully to treat porcine MH (Hall, Lucke and Lister, 1980). We have investigated the effects of the administration of 4-AP in four MH-susceptible Retrain pigs, anaesthetized with increments of thiopentone, the lungs being ventilated artificially with nitrous oxide in oxygen. 4-AP was administered i.v. in a total dose of 3-4 mg kg"1 body weight. In a preliminary experiment we demonstrated that 4-AP had a marked direct effect on the muscle at this dose as it was possible to reduce only partially the coarse muscle twitching by the administration of large doses of pancuronium. The ability of 4-AP to trigger MH was assessed by frequent estimations of arterial blood-gas tensions, muscle temperature, plasma potassium and blood lactate concentrations for 1-2 h. 4-AP failed to induce MH in all the pigs studied and their susceptibility was proven at the end of the experiment by ventilating with 1% halothane. The inability of 4-AP to trigger porcine MH suggests that this compound is unlikely to induce MH in susceptible patients. The dose of 4-AP used in this study was 10 times greater than the 0.35 mg kg"1 body weight recommended for use with neostigmine for the antagonism of neuromuscular blockade in man) Miller, 1979). Furthermore,
REFERENCES
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Sir,—We were most interested to see the paper on lumbar extradural injection pressures in pregnant women (Husemeyer and White, 1980), since it confirmed our findings of some years ago (Burn, Guyer and Langdon, 1973). Using epidurograms to study the spread of solutions in the extradural space we too concluded that the rate of injection
