PORCINE MALIGNANT HYPERTHERMIA III: ADRENERGIC BLOCKADE

Br.J. Anaesth. (1976), 48, 831

PORCINE MALIGNANT HYPERTHERMIA III: ADRENERGIC BLOCKADE D. LISTER, G. M. HALL AND J. N. LUCRE SUMMARY

Lucke, Hall and Lister (1976) have shown that suxamethonium-induced malignant hyperthermia (MH) in the Pietrain pig is accompanied by a very large increase in the plasma catecholamine concentrations. The stimulatory effects of catecholamines on metabolism are well known (Himms-Hagen, 1967) and the possibility that these hormones may contribute to the malignant nature of MH was discussed by Lister, Hall and Lucke (1975), and by Lucke, Hall and Lister (1976). The purpose of this experiment was to examine the effects of inhibiting the actions of the catecholamines released during porcine MH. Initially reserpine was used to deplete the body stores of noradrenaline and adrenaline before a hyperthermic response was induced, and this was partially successful in protecting the animals against MH. Therefore a further study was undertaken using specific a- and (3-adrenergic blocking drugs to determine the nature of the receptors involved. METHODS

Reserpine experiment

Six Pietrain pigs (mean body weight 43 kg; SEM 3.4 kg) were studied. Reserpine powder ("Serpasil", Gba Laboratories, Horsham, Sussex) was added to the feed in a dose of 10 mg/pig/day for a total of 7 days. When the period of treatment was completed

the pigs were anaesthetized and prepared surgically as described previously (Lucke, Hall and Lister, 1976). Two control arterial samples were analysed for pH and Pco 2 using a Radiometer blood-gas system (Radiometer Ltd, Copenhagen), serum potassium concentration by atomic absorption spectrophotometry (Pye Unicam SP 90A, Series 2), plasma glucose by the method of Werner, Rey and Wielinger (1970) and plasma catecholamine concentrations (McCullough, 1968). The rectal temperature was recorded automatically at 1-min intervals with a Digitec thermometer (Digitec Instruments, Ohio) and the heart rate was derived from the electrocardiogram (M. and I.E. Instruments Ltd). A standard suxamethonium challenge of two 50-mg doses administered at an interval of 15 min was used to induce MH and the progress of the response assessed by changes in the metabolic and physiological factors listed above. A stria protocol for the collection of samples during MH was not observed in this initial experiment so that a statistical evaluation of the results was not possible. Adrenergic blockade experiment

The aim of this study was to block the a- or (3adrenoreceptors before suxamethonium stimulation. The partial protection afforded by oral reserpine suggested that the dose of adrenergic blocking drug used DAVID LISTER, B.SC, PH.D., ARC Meat Research Institute, Langford, Bristol BS18 7DU. G. M. HALL, M.B., B.S., may be critical if complete blockade of the receptors F.F.A.R.C.S., Department of Anaesthetics, Royal Postgraduate was to be achieved. A search of the literature failed Medical School, Hammersmith Hospital, London W12 0HS. to reveal any data on suitable dose regimes in the J. N. LUCKE, B.V.SC, M.R.C.V.S., PH.D., D.V.A., Department pig for the two blocking drugs chosen, namely of Veterinary Surgery, Langford House, Langford, phentolamine and propranolol. Therefore, a preBristol BS18 7DU. liminary study was undertaken to find the effective Correspondence to G. M. H.

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The effects of the establishment of an adrenergic blockade on suxamethonium-induced porcine malignant hyperthermia (MH) were investigated in Pietrain pigs. Six animals were fed reserpine 10 mg daily for 7 days and then challenged with suxamethonium. Three survived but the remainder developed fatal MH. In a further study of 10 pigs, either phentolamine 40 (ig/kg/min or propranolol 50 ng/kg/min were administered for 30 min before suxamethonium stimulation and continued for the duration of the experiment. The five p-blocked pigs all became hyperthermic and died whereas the phentolamine-treated group survived. However, both a-adrenergic blockade and successful reserpinization failed to prevent the abnormal muscle response to the first dose of suxamethonium.

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FIG. 1. Changes in rectal temperature, arterial pH and Pco 2 (mm Hg), serum potassium (mmol/litre), plasma glucose (mg/100 ml) and plasma catecholamines (PI. cats.) ((ig/litre) in a reserpinized pig. Suxamethonium was given at times Sux. I and Sux. II.

fered with the absorption of the drug. Only three out TABLE I. Sequence of sample collection- during the adrenergicof six survived the suxamethonium challenge and the blockade experiment response of one of them (No. 750) is shown in figure 1. Sample no.

Time of collection

Control 1

Immediately before the infusion of the blocking drug, 40 min after induction After 20 min infusion of the blocking drug 1st dose of suxamethonium + 8 min 2nd dose of suxamethonium + 8 min 2nd dose of suxamethonium + 20 min

Control 2 Sux. I. Sux. II. Terminal

The results are expressed as mean values + SEM. The significance of the difference between the mean values of the two groups was assessed using the Student's t test for unpaired data. RESULTS

Some muscle stimulation was present as indicated by a reduction in arterial pH to 7.24 units and an increase in />aC02 to 68 mm Hg and this pattern was present in all three survivors. The mean (+ SEM) rectal temperatures and plasma catecholamine concentrations measured before the suxamethonium challenge in the surviving pigs were 37.2 ± 1.15 °C and 0.14 + 0.04 fig/litre respectively compared with 38.6 + 0.30°C and 1.23 + 0.13 fig/litre in the pigs which succumbed. It is evident that catecholamine depletion had occurred in the survivors whereas the mean plasma concentrations in the pigs which died were similar to those of the untreated control group (Lucke, Hall and Lister, 1976).

Reserpine experiment

The large oral dose of reserpine was well tolerated by the six pigs. The animals were mildly sedated and some developed diarrhoea which may have inter-

Adrenergic blockade experiment

The results of the preliminary study to determine the dose of adrenergic blocking drug indicated that

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or maximally tolerated dose of each drug in the hyperthermic state. This was achieved by the use of a continuous infusion of either phentolamine or propranolol at different doses before and during an episode of suxamethonium-induced MH. Six pigs were studied to derive the doses of phentolamine (50 (J.g/kg body weight/min) and propranolol (40 (J-g/kg body weight/ min) finally used in the definitive experiment. The effects of previous a- or (3-adrenergic blockade on MH were examined in 10 Pietrain pigs taken from two mixed litters. The metabolic and physiological measurements made during this experiment were the same as in the reserpine study. A control sample was collected 40 min after the induction of anaesthesia, then the infusion of an aqueous solution of the adrenergic blocking drug was begun using a calibrated pump (C. F. Palmer Ltd, London). Phentolamine mesylate 50 pig/kg/min (a gift from CIBA Laboratories, Horsham, Sussex, batch No. 1/73) was administered i.v. to five pigs and propranolol hydrochloride 40 (xg/kg/min (approximately) (Sigma Chemical Co., Kingston-upon-Thames) was infused to a further five pigs. The infusion was maintained for the duration of the experiment. A second control sample was taken after the blocking drug had been administered for 20 min and after 30 min a suxamethonium challenge was given. Suxamethonium 50 mg (Sux. I) was injected i.v. and 15 min later a second 50-mg dose (Sux. II) was given. The times at which the arterial and venous blood samples were taken during the suxamethonium stimulation are shown in table I.

PORCINE MH: ADRENERGIC BLOCKADE

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phentolamine was of no benefit in preventing MH when infused at a rate of either 5,10 or 20 (jLg/kg/min. Propranolol was also ineffective at the 10- and 30(xg/kg/min doses and when 50 jxg/kg/min was tried, death occurred in association with profound bradycardia and hypotension shortly after suxamethonium was given. Five pigs received an infusion of phentolamine at a rate of 50 jig/kg/min and survived the suxamethonium challenge; all five of the animals which received propranolol 40 (Ag/kg/min developed typical MH and died. The infusion of phentolamine during the control period was accompanied by the signs of an improved skin circulation and diarrhoea, the latter probably caused by unopposed parasympathetic stimulation of the gastro-intestinal tract (Nickerson, 1970). The amount of the adrenergic blocking drug administered when Sux. I was given and the total quantity infused during the experiment are shown in table II.

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TABLE II. Body weight of pigs and dose of adrenergic blocking drugs infused (means ± SEM)

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Time (.min.)

Amount of blocking drug infused (mg) by Blocking drug

Body weight (kg)

Sux. I

End of experiment

Phentolamine Propranolol

51+3.3 52 + 3.4

78±4.5 62 + 3.5

196 + 13.3 145 + 12.4

FIG. 2. Mean (± SEM) arterial pH and Pco 2 (mm Hg) in the a- and (3-blocked pigs. Suxamethonium was given at times Sux. I and Sux. II. 10

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Blood-gas analysis

Changes in arterial pH and Pco 2 in the a- and (3blocked pigs are shown in figure 2. Eight minutes after Sux. I the pH had decreased to 7.15 in the propranolol group and to 7.19 in the phentolamine group; Paco2 h a d increased to 58mmHg in the (3blocked pigs and to 60 mm Hg in the a-blocked animals. However, the phentolamine group then recovered slowly and by the end of the experiment, the arterial pH had returned to 7.30 and the PaCOii to 45 mm Hg. In the (3-blocked pigs, MH continued to develop and a terminal pH of 6.99 was recorded (P< 0.001).

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Serum potassium and plasma glucose

The results for serum potassium and plasma glucose are shown in figure 3. The serum potassium increased to 5.9 mmol/litre after Sux. I in the propranolol group but only to 5.1 mmol/litre in the phentolamine group. The latter had returned to 4.2 mmol/litre by the end of the experiment, but in

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FIG. 3. Mean ( + SEM) serum potassium and plasma glucose concentrations in o- and (3-blocked pigs. Suxamethonium was given at times Sux. I and Sux. II.

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the propranolol group, serum potassium continued to increase rapidly to 8.7 mmol/litre terminally (P< 0.001). The plasma glucose concentration showed a small increase in the pigs treated with phentolamine and reached a maximum value of 180 mg/100 ml after Sux. II. The propranolol-treated pigs developed a much greater hyperglycaemic response with a plasma concentration of 294 mg/100 ml (P<0.05) following the second dose of suxamethonium.

Heart rate and rectal temperature

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FIG. 4. Mean ( + SEM) plasma catecholamine values in a- and p-blocked pigs. Suxamethonium was given at times Sux. I and Sux. II. Plasma catecholamines

Figure 4 illustrates the changes in plasma catecholamine concentrations in the two groups of pigs. During the establishment of an a-adrenergic blockade in the control period, plasma catecholamines increased from 0.76 fig/litre to 1.36 fig/litre. During the comparable period of (3-blockade, plasma catecholamines decreased slightly from 1.35 ng/litre to 0.99 ng/litre. Plasma catecholamine concentrations increased to 17.6 (xg/litre in the a-blocked pigs after

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FIG. 5. Mean (± SEM) heart rate and rectal temperature in a- and (3-blocked pigs. Suxamethonium was given at times Sux. I and Sux. II.

The administration of phentolamine for 30 min caused a decline in rectal temperature from 39.6 °C to 38.9 °C and a subsequent suxamethonium challenge caused only a small increase to 39.4 °C. The temperature of the propranolol-treated pigs was 39.3 °C when Sux. I was given and reached 41.8 °C terminally (fig. 5).

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The infusion of propranolol in the control period produced a decrease in heart rate from 131/min to 111/min and there was no further change with the development of the hyperthermic response (fig. 5). Phentolamine, on the other hand, caused an increase in heart rate in the control period to 159/min (P < 0.01) and a further increase to 212/min (P<0.001) was recorded after Sux. II.

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Sux. I. This was significantly greater (P<0.05) than the 4.8 (xg/htre observed in the propranolol-treated group. By the end of the experiment, the concentration of plasma catecholamines had decreased to 6.5 u.g/litre in the a-blocked pigs, whereas in the hyperthermic animals a concentration of 27.9 fig/litre was recorded terminally.

PORCINE MH: ADRENERGIC BLOCKADE DISCUSSION

The effectiveness of the (3-blockade produced by the infusion of propranolol 40 (ig/kg/min could be assessed only by the absence of any increase in heart rate during the hyperthermic response (fig. 5) despite the large increase in plasma catecholamines (fig. 4). Heart rate can, however, be controlled at the height of a hyperthermic reaction by only 2-3 mg of propranolol (authors' unpublished observation). Although all the propranolol-treated pigs developed fatal MH some of the metabolic changes were not as severe as those observed in untreated control animals (Lucke, Hall and Lister, 1976). The maximum changes in arterial pH, Pco 2 and rectal temperature were to only 6.99 units, 68 mm Hg and 41.8 °C respectively. This slightly reduced response of muscle metabolism to suxamethonium stimulation may be a

result of the membrane-stabilizing properties of propranolol rather than blockade of the (3-adrenoreceptors. The local anaesthetic activity of propranolol is a result of the ( + ) isomer in the racemic mixture of the compound (Strauss, Bigger and Hoffman, 1970) which causes a delay in the depolarization of cell membranes by decreasing the sodium conductance (Morales-Aguilera and Vaughan Williams, 1965). The use of a (3-blocking drug such as sotalol, which has virtually no local anaesthetic activity, would enable the two effects to be distinguished. The propranolol infusion did not modify the hyperkalaemic and hyperglycaemic response to suxamethonium (fig. 3) which suggests that some of the increase in serum potassium was secondary to hepatic glycogenolysis and not only a result of increased muscle metabolism. Indeed, the presence of a (3-adrenergic blockade might have tended to exacerbate any increase in the serum potassium concentration because of the abolition of the potential hypokalaemic effect produced by stimulation of the p-2 adrenoreceptors (Lockwood and Lum, 1974). These receptors alter the rate of uptake of potassium ions from the extra- to the intracellular fluid. The onset of an oc-adrenergic blockade will be associated with an increase in noradrenaline release from the sympathetic nerve terminals to compensate for the vasodilatation. In the phentolamine study, a small increase in the total plasma catecholamines was recorded during the control period and this was further increased after the initial suxamethonium stimulation to 18.6 (xg/litre (fig. 4). Even at the end of the experiment when the metabolic changes had virtually returned to normal, the plasma catecholamine concentration was still 6.5 i^g/litre. Phentolamine, in addition to its oc-adrenergic blocking properties, also has a direct peripheral vasodilating effect and possibly P-stimulating effects on the myocardium (Gould et al., 1975). A pink, warm, well-perfused skin was a notable feature in the phentolamine-treated animals and this would be of benefit in MH in aiding heat loss. Williams, Houchins and Shanklin (1975) studied heat loss mechanisms in hyperthermic Poland-China pigs and observed that severe peripheral vasoconstriction was associated with the complete abolition of heat loss by radiation. The absence of an increase in the rectal temperature after Sux. I in the a-blocked pigs compared with the propranololtreated group (fig. 5) in the presence of a similar degree of muscle stimulation supports the impression of an improvement in heat dissipation. However, this mechanism cannot explain the effects of a-blockade

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The important finding of this experiment was that although neither reserpine nor phentolamine altered the initial muscle response to suxamethonium, they prevented the further stimulation of muscle metabolism found in fatal MH. The apparently different effects of reserpinization may well have been a result of the practical difficulties associated with the oral administration of drugs to pigs and thus of ensuring that each pig received the same dose. Incomplete catecholamine depletion by reserpine treatment can lead to a supersensitive response to any remaining noradrenaline (Antonaccio and Smith, 1974) and this mechanism may also have contributed to the development of MH in three of these pigs. The very low rectal temperatures (36.5 and 35.7 °C) in two of the successfully reserpinized pigs could have been caused by a disturbance of central temperature regulation in the hypothalamus. Reserpine causes depletion of 5-hydroxytryptamine (5HT) and dopamine (Carlsson, Lindqvist and Magnusson, 1957) in addition to its effects on noradrenaline and adrenaline stores. Feldberg and Myers (1964), Cooper, Cranston and Honour (1965) and Andersson, Jobin and Olsson (1966) have implicated noradrenaline and 5HT as important neurotransmitters in the control of body temperature. The results of the reserpine experiment suggested that the prevention of MH might be a consequence of the decrease in body temperature, but this was not supported by the adrenergic blockade study nor by the survival of a reserpinized pig with a body temperature of 39.5 °C during the control period. The phentolamine infusion decreased the body temperature by 0.7 °C during the 30-min control period to a value only 0.4 °C less than that of the (3-blocked group of pigs (fig. 5).

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the same as that described in other animals. This assumption may not be valid and the recent demonstration that the proportion of a- and (3-receptors in a tissue can vary with the temperature of the preparation (Kunos, Yong and Nickerson, 1973) raises the question of the interconversion of receptor types in the hyperthermic state. Although it is assumed that the form and function of the motor end-plate is the same in all pigs, Swatland and Cassens (1972) described a more extensive end-plate system in Poland-China pigs and our own evidence (Hall, Lucke and Lister, 1976) suggests that individual Pietrain pigs differ in the extent to which a neuromuscular block can be achieved and maintained with standard doses of a blocking drug. Other work in our laboratory has identified important contributions of a-adrenergic stimulation in the hormonal control of lipolysis and lipogenesis in lean pigs such as the Pietrain. In particular, there are clear indications of the impaired release of and insensitivity to insulin in Pietrain pigs, and an increase of thyroid secretion rates (Moss, 1975; Gregory, Wood and Lister, 1976; Lister, 1976). Thus susceptibility to MH in pigs may be a function of body type and in particular the consequence of the physiological mechanisms invoked specifically to induce an extreme mesomorphic conformation. ACKNOWLEDGEMENTS

G. M. Hall received financial support from the Wellcome Trust and the Muscular Dystrophy Group of Great Britain. G. M. Hall and J. N. Lucke are visiting workers at the Meat Research Institute and thank the Director, Professor NorriSj for the use of the Institute's facilities. We are grateful for the technical skills of Mr Roger Lovell and the secretarial assistance of Miss Karen Gorman.

The possibility that the action of phentolamine in REFERENCES porcine MH is a result of other factors in addition to the blockade of the a-adrenoreceptors is supported Andersson, B.3 Jobin, M., and Olsson, K. (1966). Serotonin and temperature regulation. Ada Physiol. Scand., 673 50. by two observations. First, only very high doses of phentolamine were able to prevent MH (table II). Antonaccio, M. J., and Smith, C. B. (1974). Effect of chronic pretreatment with small doses of reserpine upon Second, phentolamine was of no benefit in reversing adrenergic nerve function. J. Pharmacol. Exp. Ther., an established hyperthermic response (Hall, Lucke 188, 654. and Lister, 1975). This suggests that a non-specific Britt, B. A., and Kalow, W. (1970a). Malignant hyperthermia: a statistical review. Can. Anaesth. Soc. J., 17, action of phentolamine could be responsible for the 293. prevention of MH. However, in a separate experi(1970b). Malignant hyperthermia: aetiology ment, phenoxybenzamine infused at 50 (j.g/kg/min for unknown! Can. Anaesth. Soc.J., 17, 316. 1 h before a suxamethonium challenge and for the Bowman, W. C , and Nott, M. W. (1969). Actions of sympathomimetic amines and their antagonists on skeletal duration of the experiment, was found to be as muscle. Pharmacol. Rev., 21, 27. effective as phentolamine. Raper, C. (1966). Effects of sympathomimetic amines It has been assumed that the classification of the on neuromuscular transmission. Br. J. Pharmacol., adrenoreceptors in the muscle of the Pietrain pigs is 27, 313.

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in preventing further muscle stimulation after the first dose of suxamethonium. Catecholamines exert several stimulatory effects on skeletal muscle, such as an increase in twitch tension, prolongation of the active state and increased glycogenolysis. These actions are usually classified as being mediated via stimulation of the (3-adrenoreceptors (Bowman and Nott, 1969; Mayer and Stull, 1971). However, these amines also act presynaptically on the motor nerve terminal to increase acetylcholine release by stimulation of the a-adrenoreceptors (Bowman and Raper, 1966; Kuba, 1970; Miyamoto and Breckenridge, 1974). This a-effect is partially responsible for the defatiguing action of noradrenaline and adrenaline on muscle contraction and also for the anti-curare effects of these compounds (Bowman and Nott, 1969). On the basis of this classification the protection against MH afforded by the phentolamine infusion could be interpreted as an inhibition of the augmentation of transmitter release caused by the increase in circulating catecholamines. This hypothesis is not supported by studies in human MH in which the increase in muscle metabolism has been thought to be a post-junctional effect and unresponsive to non-depolarizing neuromuscular blocking drugs (Britt and Kalow, 1970a, b). As we are not aware of any published studies on the electromyographic activity of muscle in a hyperthermic response in either humans or pigs, the concept of a further increase in muscle activity secondary to an augmentation of transmitter release cannot be discounted. Furthermore, our recent studies (Hall, Lucke and Lister, 1976) show that although nondepolarizing neuromuscular blocking drugs will not reverse an established MH episode in pigs, they may afford some measure of protection against its initiation.

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PORCINE MH: ADRENERGIC BLOCKADE

Nickerson, M. (1970). Drugs inhibiting adrenergic nerves and the structures innervated by them; in The Pharmacological Basis of Therapeutics (eds L. S. Goodman and S. Gilman), 4th edn, p. 559. New York: Macmillan Co. Strauss, H. C , Bigger, J. T., and Hoffman, B. F. (1970). Electrophysiological and beta-receptor blocking effects of MJ 1999 on dog and rabbit cardiac tissue. Circ. Res., 26, 661. Swatland, H. J., and Cassens, R. G. (1972). Peripheral innervation of muscle from stress-susceptible pigs. J. Comp. Pathol., 82, 229. Werner, W., Rey, H.-G., and Wielinger, H. (1970). Uber die Eigenschaften eines neuen Chromogens fur die Blutzuckerbestimmung nach der GOD/POD-Methode. Z. Anal. Chem., 252, 224. Williams, C. H., Houchins, C , and Shanklin, M. (1975). Pigs susceptible to energy metabolism in the fulminant hyperthermic stress syndrome. Br. Med.J., 3, 411.

HYPERTHERMIE MALIGNE DES PORCS. I l l : BLOCAGE SYMPATHICOLYTIQUE RESUME

Les effets de la creation d'un blocage sympathicolytique sur l'hyperthermie maligne (MH) des pores provoquee par le suxamethonium ont ete etudies sur des pores pietrains. On a administre a six animaux une dose journaliere de 10 mg des reserpine pendant sept jours puis on a provoque une reaction a l'aide de suxamethonium. Trois animaux y ont survecu et les autres ont developpe une hyperthermie maligne (MH) dont Tissue a ete fatale. Dans une etude complementaire effectuee sur 10 pores, on a administre soit 40 |xg/kg/min de phentolamine soit 50 (xg/kg/min de propranolol pendant 30 min avant de les stimuler avec du suxamethonium et on a procede ainsi pendant toute la duree de l'experience. Les cinq pores ayant subi un blocage P ont tous souffert d'hyperthermie et en sont morts, alors que le groupe traite a la phentolamine a survecu. Cependant, le blocage sympathicolytique a et la reserpinisation satisfaisante n'ont pas pu empecher une reaction anormale du muscle a la premiere dose de suxamethonium. MALIGNE HYPERTHERMIE BEI SCHWEINEN. I l l : ADRENERGISCHE BLOCKIERUNG ZUSAMMENFASSUNG

Die Auswirkungen der Schaffung einer adrenergischen Blockierung auf durch Suxamethonium hervorgerufene maligne Hyperthermie (MH) wurden bei PietrainSchweinen untersucht. Sechs Tiere erhielten 7 Tage lang taglich 10 mg Reserpin, und nach anschliessender Verabreichung von Suxamethonium blieben drei Tiere am Leben, wahrend der Rest an MH starb. Bei einer weiteren Studie mit 10 Schweinen wurden fur die Dauer des Experiments entweder 40 |ig kg/min Phentolamin oder 50 jig kg/min Propranolol 30 Minuten vor der Stimulierung durch Suxamethonium verabreicht. Die ftinf (3-blockierten Schweine wurden durchwegs hyperthermisch und gingen ein, wahrend die mit Phentolamin behandelte Gruppe uberlebte. Dagegen gelang es weder durch a-adrenergische Blockierung noch durch erfolgreiche Reserpinverabreichung,

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Carlsson, A., Lindqvist, M., and Magnusson, T. (1957). 3, 4-dihydroxyphenylanine and 5-hydroxytryptophan as reserpine antagonists. Nature {Land.), 180, 1200. Cooper, K. E., Cranston, W. I., and Honour, J. A. (1965). Effects of intraventricular and intrahypothalamic injections of noradrenaline and 5-HT on body temperature in conscious rabbits. J. Physiol. (Lond.), 181, 852. Feldberg, W., and Myers, R. D. (1964). Effects on temperature of amines injected into the cerebral ventricles. A new concept of temperature regulation. J. Physiol. (Lond.), 173, 226. Gould, L., Reddy, C. V. R., Blatt, C. J., Gomprecht, R. F., and Hayt, D. B. (1975). Effects of phentolamine on coronary blood flow in patients with recent myocardial infarction. Br. Heart J., 37, 647. Gregory, N. G., Wood, J. D., and Lister, D. (1976). Studies of the role of plasma insulin in controlling body composition and meat quality in pigs. Proc. Br. Soc. Anim. Prod., (in press). Hall, G. M., Lucke, J. N., and Lister, D. (1975). Treatment of porcine malignant hyperthermia. A review based on experimental studies. Anaesthesia, 30, 308. (1976). Neuromuscular blocking drugs in porcine malignant hyperthermia. Br.J. Anaesth., 48,270. Himms-Hagen, J. (1967). Sympathetic regulation of metabolism. Pharmacol. Rev., 19, 367. Kuba, K. (1970). Effects of catecholamines on the neuromuscular junction of the rat diaphragm. J. Physiol. (Lond.), 211, 511. Kunos, G., Yong, M. S., and Nickerson, M. (1973). Transformation of adrenergic receptors in the myocardium. Nature (New. Biol), 241, 119. Lister, D. (1976). Growth and productivity; in Meat Animals (eds D. Lister, D. N. Rhodes, V. R. Fowler and M. F. Fuller), p. 520. New York and London: Plenum Press. Hall, G. M., and Lucke, J. N. (1975). Malignant hyperthermia: a human and porcine stress syndrome? Lancet, 1, 519. Lockwood, R. H., and Lum, B. K. B. (1974). Effects of adrenergic agonists and antagonists on potassium metabolism. J. Pharmacol. Exp. Ther., 189, 119. Lucke, J. N., Hall, G. M., and Lister, D. (1976). Porcine malignant hyperthermia. I: Metabolic and physiological changes. Br. J. Anaesth., 48, 297. Mayer, S. E., and Stull, J. T. (1971). Cyclic AMP in skeletal muscle. Ann. N. Y. Acad. Sci., 185, 433. McCullough, H. (1968). Semi-automated method for the differential determination of plasma catecholamines. J. Clin. Pathol., 21, 759. Miyamoto, M. B., and Breckenridge, B. Mc.L. (1974). A cyclic adenosine monophosphate link in the catecholamine enhancement of transmitter release at the neuromuscular junction. J. Gen. Physiol., 63, 609. Morales-Aguilera, A., and Vaughan Williams, E. M. (1965). The effects on cardiac muscle of (3-receptor antagonists in relation to their activity as local anaesthetics. Br. J. Pharmacol., 24, 332. Moss, B. W. (1975). Some physiological effects of the intensive husbandry of pigs. Ph.D. thesis, University of Bristol.

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838 die abnonnalen Muskelreaktionen nach der ersten Dosis von Suxamethonium zu verhindern. HIPERTERMIA MALIGNA PORCINA. I l l : BLOQUEO ADRENERGICO SUMARIO

Se investigaron en cerdos Pietrain los efectos del establecimiento de un bloqueo adrenergico sobre la hipertermia maligna (HM) porcina inducida con suxametonio (succinilcolina). Se aliment6 a seis animates incorporando a la dieta

10 mg diarios de reserpina durante 7 dias y luego se administro suxametonio como provocation. Tres sobrevivieron, pero los demas desarrollaron HM fatal. En otro estudio con 10 animates se les administro 40 (i.g de pentolamina por kg/min, o propanolol 50 [ig/kg/min, durante 30 minutos antes de la estimulacion con suxametonio y se continuo durante la duration del experimento. Los cinco cerdos con bloqueo-beta se volvieron hipertermicos y fallecieron3 mientras que el grupo tratado con pentolamina sobrevivio. Sin embargo, tanto el bloqueo alfa-adrenergico como la reserpinizacion fructxfera no lograron impedir la respuesta muscular anomala a la primera dosis de suxametonio.

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