EFFECTS OF CALCIUM ON NEUROMUSCULAR BLOCK BY SUXAMETHONIUM IN DOGS

Brit. J. Anaesth. (1971), 43, 1027

EFFECTS OF CALCIUM ON NEUROMUSCULAR BLOCK BY SUXAMETHONIUM IN DOGS BY

R. P. BADOLA, S. CHATTERJI, K. PANDEY AND S. KUMAR SUMMARY

The importance of calcium in synaptic transmission, particularly in neuromuscular transmission, is well recognized (Locke, 1894; Feng, 1936; Harvey and Macintosh, 1940; del Castillo and Katz, 1954a, b). An anti-curare effect of ionic calcium was reported by del Castillo and Stark (1952). It is also known that calcium effectively antagonizes the myoneural blocking action of an excess of magnesium (del Castillo and Engbaek, 1954) and the neuromuscular block resulting from administration of such antibiotics as streptomycin, neomycin and kanamycin (Brazil and Corrado, 1957; Brazil, Corrado and Berti, 1959; Corrado, Ramos and DeEscobar, 1959; Jindal and Despande, 1960; Pandey, Kumar and Badola, 1964). Little is known, however, about the effect of calcium on the neuromuscular blocking action of depolarizing muscle relaxants, although Irwin, Wells and Whitehead (1956) studied the effect of the removal of ionic calcium by the administration of EDTA (ethylene-diamine-tetra-acetic acid) on the duration of apnoea induced by suxamethonium in dogs and rats. In this paper an investigation into the effect of calcium on the myoneural block produced by suxamethonium is described, and the results are compared with the effect of calcium on the neuromuscular block due to tubocurarine and gallamine, under identical experimental conditions.

METHODS

Experiments were performed on mongrel dogs weighing 5-15 kg. Anaesthesia was produced by pentobarbitone sodium 30 mg/kg, given intravenously. The tibialis anterior muscle-nerve preparation was set up and muscle contraction recorded kymographically according to the method described by Pandey, Kumar and Badola (1964). Indirect stimulation of the muscle was produced by an electronic stimulator which delivered supramaximal square wave pulses. After an initial recording of the response of the muscle to twitch (0.2, 0.4, 0.6, 0.8 and 1/sec) and tetanic (50/sec) rates of stimulation, suxamethonium, tubocurarine or gallamine was injected intravenously. The effect of calcium on the neuromuscular block produced by these agents was studied according to the following plan: (1) In six experiments a small dose of suxamethonium (1-3 mg/kg) was given intravenously. R. P. BADOLA, D.A.(ENC), F.F.A.R.C.S.(ENG.); SUMANTA CHATTERJI,* D.A., M.D.(ANAESTH.); K. PANDEY,! D.A., M.D.(ANAESTH.)J S. KUMAR, M.D., PH.D.; Departments

of Anaesthesiology and Physiology, King George's Medical College, Lucknow, India. Present addresses: •S.M.S. Medical College, Jaipur, India. t College of Medical Sciences, Banaras Hindu University, Varanasi, India.

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The effects of intravenously administered calcium chloride on partial neuromuscular block produced by small and large doses of suxamethonium, tubocurarine and gallamine have been studied in dogs. Calcium chloride brought about an improvement in twitch tension, and this depression lasted for 5-15 minutes. The possible mechanisms of the block produced by small doses of suxamethonium. In the presence of a complete phase II block produced by suxamethonium, however, calcium chloride depressed the twitch tension, and this depression lasted for 5—15 minutes. The possible mechanism of the varying effects of calcium on different types of neuromuscular block are discussed and it is suggested that the depression of twitch by calcium in the presence of desensitization block may be due to a "membrane stabilizing action". It is possible that this observation may prove useful clinically in differentiating desensitization block from other varieties of neuromuscular block.

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type of neuromuscular block during continuous indirect stimulation of the muscle at the rate of 1. or 0.8/sec. After allowing time for the effect of calcium to subside (5-15 min) neostigmine 0.5-1.5 mg was given intravenously with atropine sulphate 0.6 mg. (3) In five experiments calcium chloride 200-400 mg was given after producing a partial neuromuscular block by tubocurarine. In five other experiments a similar dose of calcium chloride was given after producing partial neuromuscular block with gallamine triethiodide. RESULTS

(1) Effect of calcium on neuromuscular block produced by small doses of suxamethonium. The responses of the tibialis anterior, on partial recovery, after suxamethonium 1-3 mg/kg did not show any marked features of a dual type of neuromuscular block except for a mild degree of PTF in six experiments and an ill-sustained tetanus in three experiments. Calcium chloride did not appear to influence the rate of recovery of the muscle response (fig. 1). (2) Effect of calcium when there were features of a dual type of response. The "typical triad" resulted as often after single large doses of suxamethonium (table I, experiments 3,12,14,15 and 16) as after repeated doses (experiments 6, 7, 9, 10 and 13). Repeated doses did not necessarily produce a more intense degree of phase II block (as in experiment 5). The different combinations of myographic characteristics of dual block, after relatively large doses of suxamethonium, which were present at the time of administration of calcium chloride are shown in table II. Table III summarizes the observations on the effects of calcium chloride on the neuromuscular block in the presence of the various myographic features listed in table II. In the presence of a typical triad calcium chloride potentiated the existing neuromuscular block in all of ten experiments (fig. 2). The depressant action of calcium on twitch tension lasted for 5-15 minutes. In two of three experiments in which an atypical triad was present calcium potentiated the block (fig. 3) while in one no such effect was seen. Potentiation of the block after administration of calcium

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This always abolished the twitch response of the muscle. When contractions reappeared, the responses to twitch and tetanus were recorded. Calcium 200-400 mg (2-4 ml of 10 per cent solution calcium chloride) was then injected intravenously while the muscle was being stimulated indirectly at a rate of 1/sec. (2) In sixteen experiments a total of 5.5-13 mg/kg of suxamethonium was given in single or divided doses. The responses to twitch and tetanic rates of stimulation were recorded after each dose, and further doses were given until some or all of the following myographic features of a dual (or phase II) type of block appeared: (i) ill-sustained tetanus (1ST); (ii) post-tetanic facilitation (PTF); (iii) a progressive diminution of the amplitude of the successive responses at twitch rates of stimulation (fade). As the effect of antagonists on dual block has been reported to vary with the degree of PTF and fade (Churchill-Davidson and Wise, 1963b) these were graded as follows: Gradation of PTF: (1) mild when the amplitude of the post-tetanic twitch response was not more than 1.5 times the pre-tetanic response; (2) moderate when the response was greater than 1.5 times but less than twice the pre-tetanic response; (3) marked when the response was two or more times the pre-tetanic response (Churchill-Davidson and Katz, 1966). Gradation of fade: (1) mild if the progressive decline in the amplitude of successive twitch responses was elicited only at some of the relatively fast twitch rates of indirect stimulation; (2) moderate if fade was elicited in the entire range of slow rates of stimulation, but the criterion for its being described as "marked" was not fulfilled; (3) marked if, in addition to being elicited at all the slow rates of stimulation, fade was so marked that the amplitude of the third to sixth response in any particular train of responses was reduced to between two-thirds and half of the first. When 1ST, PTF and fade were observed together, the combination was termed a "triad" which was classified as "typical" when both PTF and fade were moderate or marked, and "atypical" when either of these was only mild. Calcium chloride 200-400 mg was given intravenously in the presence of various combinations of the myographic features of a dual or phase II

BRITISH JOURNAL OF ANAESTHESIA

EFFECTS OF CALCIUM ON NEUROMUSCULAR BLOCK i/s.

s

0.2|S

1029

0.4/S O.6/S 0.8/ST 0 6/S OJ/S

O */%

O 6/S

Sux.

C a O 2 3OOn. 9

FIG. 1 (a) Tibialis anterior contractions (M) and arterial pressure (BP) recordings from an experiment in which suxamethonium 2 mg/kg was given at (S). There is no fade of twitch tension at various slower rates of stimuli. The tetanus at (T) is ill-sustained. There is no PTF. (b) Calcium chloride (200 mg) given during continuous indirect stimulation at the rate of 1/sec produced no effect on the twitch tension. Administration of neostigmine methylsulphate (NMS) also did not influence the rate of recovery of the twitch tension.

suxamethonium

/S

0 6/5

Og/S

FIG. 2 Recording of the tibialis anterior contractions of a dog which was given suxamethonium (Sux) 10.5 mg/kg in a single dose. On partial recovery a marked fade of twitch tensions at slow rates of indirect stimulation (0.2-1/sec) is seen. The tetanic response is hardly discernible (very ill-sustained). There is a marked PTF. This combination of marked fade, marked PTF and ill-sustained tetanus (1ST) was termed the typical triad. Calcium chloride 300 mg given later depressed the twitch tension. Two doses of neostigmine methylsulphate (NMS) had no effect.

O-2/S O4/S M

I/S

in iimuiu niiiumim'roi...

FIG. 3 Tibialis anterior contractions in response to indirect supramaximal stimulation. On partial recovery from suxamethonium 10 mg/kg, mild fade, mild PTF and an ill-sustained tetanus are seen (an atypical triad). Calcium chloride caused a depression of the twitch tension. Neostigmine methylsulphate (NMS) had no effect.

M

FIG. 4 Recordings of tibialis anterior contractions (M), intratracheal pressure excursions (R) and time (T) (10 sec), from an experiment in which a total dose of 10.8 mg/kg of suxamethonium had been given in divided doses. A mild fade of twitch tensions at 0.8 and 1/sec is seen (a). The tetanic response (T) is ill-sustained. There is no post-tetanic facilitation (PTF). Administration of calcium chloride during stimulation of the muscle at 0.8/sec caused depression of twitch tension. Neostigmine methylsulphate produced no effect (b).

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M

NMS 0-51*9

I NMS

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TABLE I

Myographic characteristics after large single or divided doses of suxamethonium and the effects of calcium and neostigmine in presence of these characteristics.

Pre-treatment muscle response

Wt. of Experiment dog No. (kg) Fade 1ST PTF

Initial dose of suxa:

Duration

(mg/kg)

of total unresponsiveness of the muscle (min)

Fade

1ST

PTF

Total dose of suxamethonium (initial and subsequent doses) (mg/kg)

Fade

1ST

+ ++

Yes

Myographic characteristics on recovery

Myographic characteristics on recovery fromj last dose PTF

Combination of myographic characteristics prior to administration of calcium

Dose of calcium chloride (mg)

+

Atypical triad

Effect of Effect of calcium on neuro- Dose of neostigmine muscular neostigmine on twitch tension block (mg)

1

15.00

-

-

-

6.6

80

++

Yes

+

13.3

300

P

2.0

NC

2

9.25

-

-

-

8.1*

60

++

Yes

—

—

Fade and 1ST

300

NC

0.5

NC

3

8.50

-

-

-

5.8*

60

—

Typical triad

300

P

1.5

NC

8.00

-

-

-

9.3*

40

Yes Yes

+++

4

++ ++

-

Fade and 1ST

300

P

1.5

NC

++ +

Yes Yes

-

21.8

++ +++

Yes Yes

Fade and 1ST + + + Typical triad

200

P

-

NC

13.3

300

P

1.0

NC

++ ++ + +

Yes Yes No Yes

+ + ++

19.4

+++

Yes

+++

Typical triad

300

P

1.0

NC

Atypical triad

300

NC

1.0

NC

300

P

0.5

NC

200

P

0.5

NC

Yes Yes

+ ++ +

13.3

+ + + Typical triad + + + Typical triad + Atypical triad

300

P

1.0

NC

Typical triad

400

P

1.0

NC

Yes

++

10.5

Typical triad

400

P

1.0

NC

+++ +++

-

Typical triad

300

P

1.0

NC

-

Typical triad

300

P

1.0

NC

-

Typical triad

400

P

1.0

NC

5

8.00

-

-

-

12.5

45

6

15.00

-

-

+

6.6

60

7

9.00

-

-

-

11.1

45

8

9.00

-

-

+

5.5*

40

9

9.00

-

-

-

5.5

20

10

5.00

-

-

-

5.0

80

11

15.00

-

-

-

6.6

60

12

13.00

-

-

-

7.6*

40

++ ++

13

13.00

-

-

-

7.6

35

+

14

12.00

-

-

-

8.3*

50

15

8.50

5.8* 6.2*

60

16

8.00

- Yes + - - +

40

+++ ++ +++

1ST —ill-sustained tetanus. PTF-post-tetanic facilitation. P — potentiation of the existing neuromuscular block.

Yes Yes Yes

+++

11.1 6.2

+++ +++ +++

Yes Yes Yes

-

+++

Yes

++ +

NC=no change in twitch tension attributable to the treatment. + = mild, + + = moderate and + + + —marked fade or PTF. * Single dose only.

EFFECTS OF CALCIUM ON NEUROMUSCULAR BLOCK

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TABLE II

Incidence of occurrence of various combinations of the myographic characteristics of dual type of neuromuscular block seen after large doses of suxamethonium. Frequency of various combinations of 1ST, PTF and fade Only 1ST ll l i

2 1

PTF and fade 1ii i

ii i i

1ST and fade

Only Only PTF fade i i i i

Dose of No. 1ST suxamethonium of Typical Atypical and dogs triad* triad* PTF (mg/kg) 5 4 5.0-6.0 1 6 4 6.1-8.0 2 3 1 8.1-10.0 2 1 10.1 or more

-

TABLE III

Effects of calcium chloride and neostigmine methylsulphate on neuromuscular block by suxamethonium, showing various combinations of the myographic characteristics of a dual type block. Effect of calcium on the block

Effect of neostigmine methylsulphate on the block

Combination of myographic characteristics

Number of dogs

Potentiation

Reversal

No change

Typical triad* Atypical triad* Fade and 1ST

10 3 3

10 2 2

-

1 1

Potentiation

Reversal

No change

10 3 2**

* See section on method for explanation of the terms typical and atypical triads. ** Neostigmine methylsulphate was not given after calcium in one of these experiments. IST=ill-sustained tetanus.

chloride occurred in presence of 1ST and fade in two of the experiments where this combination was present (fig. 4). The combination of 1ST and fade in three exexperiments reported here conflicts with the statements of previous workers that 1ST and PTF appear in that order much earlier than the fade of the twitch responses (Churchill-Davidson and Christie, 1959; Churchill-Davidson, Christie and Wise, I960; Churchill-Davidson, 1963; Churchill-Davidson and Wise, 1963a, b ; Katz, Wolf and Papper, 1963). In fifteen of sixteen experiments neostigmine given 5-15 minutes after the administration of calcium chloride did not appear to exert any influence on the rate of recovery of the twitch response nor did it potentiate the existing neuromuscular block (table III; figs. 2, 3, 4). (3) Effects oj calcium on the block produced by tubocurarine and gallamine triethiodide. Calcium always brought about an appreciable improvement in the twitch tension in the presence of neuromuscular block produced by either of the

non-depolarizing relaxants (figs. 5, 6). However, this improvement was never as marked as has been reported after administration of calcium chloride in the presence of neuromuscular blockade caused by neomycin (Corrado, Ramos and De Escobar, 1959) or streptomycin (Pandey, Kumar and Badola, 1964). DISCUSSION

The importance of calcium in synaptic transmission and in regulation of effector cell excitability is widely recognized but the mechanism of its effect has not been fully elucidated. A review of the literature (Brink, 1954; Shanes, 1958a, b; Katz and Miledi, 1965; Ritchie and Greengard, 1966; Karczmar, 1967) suggests that ionic calcium could modify muscle twitch tension in three different ways under different conditions. First, ionic calcium might promote acetylcholine (ACh) release by activating the discharge of the contents of the synaptic vesicles after arrival of an action potential (NAP) at the terminal axonal membrane (Koelle, 1965). Secondly, calcium could modify effector cell response through its regulatory action

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1ST=ill-sustained tetanus. PTF=post-tetanic facilitation. * For explanations of typical and atypical triads see description in section on methods.

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BRITISH JOURNAL OF ANAESTHESIA At»opine,o.t5inj dtC(l.25TT.gxz)

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on the permeability of the post-junctional membrane to sodium and potassium ions, the conductance of these ions across the post-junctional membrane varying in inverse proportion to the concentration of ionic calcium in the external medium. Thus an excess of calcium in the external medium would raise the threshold of excitation of the postjunctional membrane in response to the presynaptically released ACh; the endplate potentials following ACh release are not able to attain the threshold value required for the generation of a propagated muscle action potential. This action of calcium has been termed the membrane stabilizing action. Thirdly, calcium has also been stated to be of vital importance in excitation-contraction coupling. It is assumed that after depolarization of the muscle fibre membrane, ionic calcium is released from intracellular binding sites, enters muscle cytoplasm and sets off a chain of as yet unelucidated reactions resulting in the shortening of the contractile protein actomyosin (Sandow, 1965). An explanation for the varying effects of calcium

The depression of the twitch tension by calcium in presence of typical myographic features of dual block induced by suxamethonium requires explanation. The theory of the mechanism of neuromuscular blocking action of suxamethonium envisages that whenever a muscle is exposed to a depolarizing agent the endplate membrane is initially depolarized, and as long as the post-junctional membrane depolarization lasts the muscle fibre remains absolutely unresponsive to presynaptic stimulation (Thesleff, 1955; Paton, 1956; Gissen and Nastuk, 1966; Nastuk, 1966, 1967). The potential difference across the post-junctional membrane is then gradually restored despite the continued presence of the depolarizing agent. This restoration of the potential difference, however, is not accompanied by a parallel restoration of muscle responsiveness to presynaptic stimulation. The continued presence of the depolarizing agent makes the post-junctional membrane increasingly insensitive to the depolarizing action of the natural transmitter, ACh (Thesleff, 1955; Gissen and Nastuk, 1966). It has been shown that during a continuous intra-arterial infusion of suxamethonium at a constant rate the twitch tension

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FIG. 5 Tibialis anterior contractions (M), blood pressure (BP) and time, every 5 sec (T) recordings from an experiment in which two doses of tubocurarine (1.25 mg) were given at arrows. Partial neuromuscular block was produced. Calcium chloride and neostigmine methylsulphate (NMS) both produced improvement of twitch tension.

chloride on the indirectly elicited twitch tension under partial neuromuscular block of different types could be offered in the light of some of these known actions of ionic calcium on junctional transmission and effector cell excitability. A facilitatory action of calcium on the presynaptic release of ACh might overcome any depression of the twitch tension resulting from a competitive receptor blockade or from an interference with the actual process of release of the transmitter. On the basis of this action of calcium the antagonistic action of this ion towards nondepolarizing relaxants was explained by del Castillo and Stark (1952). During the present experiments, however, the reversal of non-depolarization block by calcium was not very prominent, probably because there was little further scope for facilitation of ACh release while using supramaximal stimulation of the motor nerve. On the other hand, if the neuromuscular block is caused by drugs and ions which directly interfere with the process of the release of ACh (e.g., streptomycin and magnesium) the improvement in the twitch tension is very marked (Pandey, Kumar and Badola, 1964; Engbaek, 1952).

1033

EFFECTS OF CALCIUM ON NEUROMUSCULAR BLOCK

GG 1

0 2/5

0.4/S

1

i

0 6/S

i

I/S

T I/S

i

Hi

c

ATR. o 65 mg JNMS 0 5 m9

i

developed by a muscle partially blocked by the agent shows an initial phase of recovery and then undergoes a secondary depression (Gissen et al., 1966; see fig. 7). This secondary depression of the twitch tension has been assumed to be due to the gradually increasing insensitivity of the postjunctional membrane to the depolarizing action of ACh. On this basis it has been suggested that "desensitization block" would be a better term to indicate the later phase of the neuromuscular block by suxamethonium. CONTROL TEST PERIOD OF DRU6 ACTION PERIOD

0

TIME

7 Muscle twitch tension during continuous exposure to a depolarizing agent (e.g., suxamethonium). The tension output shows an initial steep depression followed by partial recovery and a secondary phase of depression. (Modified from Gissen, A. J., and Nastuk, W. L. (1966). Ann. N.Y. Acad. Sci., 135, 185, fig. 1; reprinted by permission of The New York Academy of Sciences.) FIG.

The depression of twitch tension by calcium, observed in this study, can be explained on the assumption that this depression occurred in experiments where there was some desensitization of the post-junctional membrane at most of the endplates due to their continuous exposure to unhydrolyzed suxamethonium. Under such circumstances the membrane stabilizing action of calcium might be expected further to increase the insensitivity of the post-junctional membrane to the depolarizing action of ACh. This assumption is supported by the reported inhibitory action of suxamethonium on the red cell true cholinesterase; this enzyme, it seems, has an important role in removing a proportion of the suxamethonium administered intravenously, by forming a drugenzyme complex thus leaving less available to act on the neuromuscular junction (Lehmann and Liddell, 1962). After administration of a large single dose or repeated small doses of suxamethonium, a large amount of this agent is likely to be available to act on the neuromuscular junction. This would produce insensitivity to the depolarizing action of ACh and such insensitivity might be further aggravated by an increased amount of ionic calcium in the external medium. The work of Nastuk (1966) and Manthey (1966) indicates diat the concentration of calcium in the external medium plays an important role in the develop-

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FIG. 6 Tibialis anterior contractions (M) and blood pressure recordings from an experiment in which neuromuscular block was produced by two consecutive doses (1 mg/kg each) of gallamine triethiodide given at arrows marked G. Typical myographic features of a non-depolarization block are seen. The first dose of calcium chloride (200 mg) given at C did not cause any remarkable change in the twitch tension. The second dose produced an appreciable improvement. Even neostigmine methylsulphate (NMS) did not produce any dramatic change in the twitch tension. Time interval between the end of upper and the beginning of lower tracing=7 minutes.

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del Castillo, J., and Engbaek, L. (1954). The nature of neuromuscular block produced by magnesium. J. Physiol. (Land.), VIA, 370. Katz, B. (1954a). The effect of magnesium on the activity of motor nerve endings. J. Physiol. (Land.), 124, 553. (1954b). Quanta! content of the end-plate potentials. J. Physiol. (Lond.), 124, 560. Stark, L. (1952). Effect of calcium ion on the motor end-plate potential. J. Physiol. (Lond.), 116, 507. Engbaek, L. (1952). The pharmacological actions of magnesium ions with particular reference to the neuromuscular and the cardiovascular system. Pharmacol. Rev., 4, 396. Feng, T. P. (1936). Studies on the neuromuscular junction. I I : The universal antagonism between calcium and curarising agencies. Chin. J. Physiol., 10, 513. Gissen, A. J., Katz, R. L., Karis, J. H., and Papper, E. M. (1966). Neuromuscular block in man during prolonged infusion with succinylcholine. Anesthesiology, 27, 242. Nastuk, W. L. (1966). The mechanism underlying neuromuscular block following prolonged exposure to depolarizing relaxants. Ann. N.Y. Acad. Sci., 135, 184. Harvey, A. M., and Macintosh, F. C. (1940). Calcium synaptic transmission in a sympathetic ganglion. J. Physiol. (Lond.), 97, 408. Irwin, R. L., Wells, J. B., and Whitehead, R. W. (1956). Effect of calcium on the duration of apnea induced by succinylcholine. Anesthesiology, 17, 759. Jindal, M. N., and Despande, V. R. (1960). Neuromuscular blockade by streptomycin and dihydrostreptomycin. Brit. J. Pharmacol., 15, 506. Karczmar, A. G. (1967). Neuromuscular pharmacology; in Annual Review of Pharmacology, Vol. 7, p. 241. California: Annual Rev. Inc. Katz, B., and Miledi, R. (1965). The effect of calcium REFERENCES on acetylcholine release from motor nerve Brazil, O. V., and Corrado, A. P. (1957). Curarifonn terminals. Proc. roy. Soc, Ser. B., 161, 496. action of streptomycin. J. Pharmacol, exp. Ther., Wolf, C. E., and Papper, E. M. (1963). The non120, 452. depolarizing neuromuscular blocking action of Berti, F. A. (1959). Neuromuscular block succinylcholine in man. Anesthesiology, 24, 784. produced by streptomycin and some of its degradation products; in Curare and Curare-like Agents Koelle, G. B. (1965). Neurohumoral transmission and the autonomic nervous system; in The Pharma(eds. Bovet, D., Bovet-Nitti, F., and Marinicological Basis of Therapeutics (eds. Goodman, Bettolo, G. B.). Amsterdam: Elsevier. L. S., and Gilman, A.), 3rd edn., p. 410. New Brink, F. (1954). The role of calcium ions in neural York: Macmillan. processes. Pharmacol. Rev., 6, 243. Churchill-Davidson, H. C. (1963). The succinylcholine Lehmann, H., and Liddell, J. (1962). The cholinesterases; in Modern Trends in Anaesthesia, 2 (eds. story. (Editorial.) Anesthesiology, 24, 761. Evans, F. T., and Gray, T. C ) , p. 189. London: Christie, T. H. (1959). The diagnosis of neuroButterworths. muscular block in man. Brit. J. Anaesth., 31, 290. Wise, R. P. (1960). Dual neuromuscular Locke, F. S. (1894). Notiz uber den Einfluss physiologischer kochsalzlosung auf die electrische Erregblock in man. Anesthesiology, 21, 144. barkeit von Muskel und Nerv. Zbl. Physiol., 6, 166. Katz, R. L. (1966). Dual, phase II or desensitisation block (special communication). Anesthesiology, Manthey, A. A. (1966). The effect of calcium on the desensitisation of membrane receptors at the neuro27, 536. muscular junction. J. gen. Physiol., 49, 963. Wise, R. P. (1963a). Neuromuscular transmission Nastuk, W. L. (1966). Fundamental aspects of neuroin the newborn infant. Anesthesiology, 24, 271. muscular transmission. Ann. N.Y. Acad. Sci., 135, (1963b). Mismanagement of suxamethonium 110. apnoea. (Correspondence.) Brit. J. Anaesth., 35, (1967). Activation and inactivation of muscle post506. junctional receptors. Fed. Proc, 26, 1639. Corrado, A. P., Ramos, A. O., and DeEscobar, C. T. (1959). [Neuromuscular blockade by neomycine, Pandey, K., Kumar, S., and Badola, R. P. (1964). Neuromuscular blocking and hypotensive actions potentiation by ether anesthesia and d-tubocurarine of streptomycin, and their reversal. Brit. J. and antagonism by calcium and prostigmine.] Anaesth., 36, 19. Arch. int. Pharmacodyn., 121, 380. ment of desensitization of the receptors for acetylcholine at the neuromuscular junction. Antagonism of calcium towards pure depolarization block has been claimed to occur by Irwin, Wells and Whitehead (1956) but could not be confirmed in the present study. The rate of recovery of the twitch tension after a small dose of suxamethonium was so fast that a slight degree of antagonism could not possibly be detected with the experimental technique employed by us. The lack of any considerable antagonism to or potentiation of established desensitization block by neostigmine is also noteworthy. The use of this agent in the management of suxamethonium apnoea has been reported to have produced varying effects on the state of neuromuscular transmission (Vickers, 1963). Three factors may account for the failure to demonstrate any reversal of desensitization block by neostigmine in the present study: first, too small a dose of neostigmine; secondly, its administration too late during recovery; or thirdly, the junctional stabilizing action of calcium previously administered. As the doses of neostigmine were considerable and the recovery of twitch tension in most experiments was far from complete at the time of administration of neostigmine, only the last factor appears likely.

1035

EFFECTS OF CALCIUM ON NEUROMUSCULAR BLOCK

EFFETS DU CALCIUM SUR LE BLOCAGE NEUROMUSCULAIRE INDUIT PAR LE SUXAMETHONIUM CHEZ LE CHIEN SOMMAIRE

On a ^tudie chez le chien, les effets de 1'injection intraveineuse de chlorure de calcium sur le blocage neuromusculair partiel induit par des doses minimes et importantes de suxamethonium, de tubocurarine et de gallamine. Le chlorure de calcium entraine une amelioration de la tension spastique en presence d'un blocage non depolarisant, mais n'exerce aucun effet notable sur le blocage induit par de faibles doses de suxamethonium. En presence d'un blocage complet a la phase II, induit par le suxamethonium, le chlorure de calcium a neanmoins exerc£ un effet depresseur sur la tension spastique et cette depression a dur£ 5 a 15 minutes. Le mecanisme possible des effets variables du calcium sur differents types de blocage neuromusculaire fait l'objet d'une discussion et il est sugger^ que la depression du clonus sous l'effet du calcium, en presence d'un blocage d6sensitif, peut etre due a un "effet stabilisant sur la membrane". II est possible que cette observation s'avere etre utile sur le plan clinique, en vue de la differentiation d'un blocage desensitif par rapport aux autres varietes de blocage neuromusculaire.

DIE WIRKUNG VON CALCIUM AUF DEN DURCH SUXAMETHONIUM INDUZIERTEN NEUROMUSKULAREN BLOCK BEI HUNDEN ZUSAMMENFASSUNG

Die Wirkungen von intravenos appliziertem Calciumchlorid auf den partiellen neuromuskularen Block, der durch kleine und grofie Dosen von Suxamethonium, Tubocurarin und Gallamin hervorgerufen wird, wurden an Hunden untersucht. Calciumchlorid fuhrte zu einer Besserung der Muskelzuckungen beim nicht-depolarisierenden Block, blieb aber ohne Wirkung auf den durch kleine Dosen von Suxamethonium hervorgerufenen Block. In Gegenwart eines volligen Blocks im Stadium II durch Suxamethonium jedoch, setzte Calciumchlorid die Muskelspannung herab,und zwar fur 5-15 Minuten. Der mogliche Mechanismus der verschiedenen Wirkungen von Calcium auf die verschiedenen Arten des neuromuskularen Blocks wird diskutiert und die Hypothese aufgestellt, dafi die Herabsetzung der Muskelspannung durch Calcium in Gegenwart eines Depolarisationsblocks durch eine "membranstabilisierende Wirkung" hervorgerufen sein konnte. Es ist mdglich, dafl dieses Beobachtung sich klinisch als niitzlich erweisen wird bei der Unterscheidung eines Depolarisationsblocks von anderen Arten des neuromuskularen Blocks.

EFECTOS DEL CALCIO SOBRE EL BLOQUEO NEUROMUSCULAR POR SUXAMETONIO EN PERROS RESUMEN

Los efectos del cloruro de calcio administrado intravenosamente sobre el bloqueo neuromuscular partial producido por dosis pequefias y grandes de suxametonio, tubocurarina y gallamina fueron estudiados en perros. El cloruro de calcio produjo una mejoria en la tension de contraccion en presencia de un bloqueo no despolarizante, pero no ejercio ningiin efecto evidente sobre el bloqueo producido por pequenas dosis de suxametonio. Sin embargo, en presencia de un bloqueo completo de fase II producido por suxametonio, el cloruro de calcio deprimi6 la tensi6n de contraccidn y esta depresidn dur6 5-15 minutos. Es discutido el posible mecanismo de los efectos variables de calcio sobre tipos diferentes de bloqueo neuromuscular y se postula que la depresi6n de la contraction por el calcio en presencia de bloqueo por desensibilizacion pudiera ser debida a una "accidn estabilizadora de membranas". Es posible que esta observacibn resulte ser clinicamente util para diferenciar el bloqueo de desensibilizacion de otras variedades de bloqueo neuromuscular.

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