Train‐of‐four Fade During Neuromuscular Blockade Induced by Tubocurarine, Succinylcholine or Α‐bungarotoxin in the Rat Isolated Hemidiaphragm

Abstract

1. Nerve-evoked maximal twitches (T1, T2, T3, T4) of the rat isolated hemidiaphragm to train-of-four (TOF) stimulation (2 Hz X 2 s) were recorded continuously in the absence or presence of tubocurarine (1.5 mumol/l), succinylcholine (40 mumol/l) or alpha-bungarotoxin (1 mumol/l). The T1 and T4 response-time profiles for the three drugs were analysed with respect to amplitude depression and the TOF ratio (T4/T1) during the development of and recovery from neuromuscular blockade. 2. Tubocurarine produced T1 block accompanied by intense TOF fade; for the same degree of T1 block, the TOF ratio was lower during the recovery from blockade after washing out tubocurarine from the bath than during the onset of blockade. There was also a correspondingly slower recovery of the TOF ratio from 90% T1 block to control levels when compared with the time for complete T1 recovery. Fade and twitch tension depression were shown clearly to be separate responses, each with its own response-time profile. Fade is therefore not simply a consequence of postjunctional cholinoceptor blockade. 3. Succinylcholine produced T1 block with only moderate TOF fade; similar recovery rates from 90% T1 block to control levels were obtained for T1 and the TOF ratio. 4. alpha-Bungarotoxin produced irreversible and complete neuromuscular blockade during which TOF fade was virtually absent. 5. The results obtained in this study closely resemble those from other similar studies in animals and in humans and clearly demonstrate that the rat isolated hemidiaphragm is a suitable in vitro model for time course studies on TOF fade.

Presynaptic snake β-neurotoxins produce tetanic fade and endplate potential run-down during neuromuscular blockade in mouse diaphragm

“…These snake α-neurotoxins cause the blockade of postjunctional nicotinic receptors without inducing fade or marked rundown (Gibb and Marshall 1984;Bowman et al 1986) but upon washout fade becomes prominent and persists after the complete recovery from the postjunctional inhibitory effect (Bradley et al 1987(Bradley et al , 1990Chang and Hong 1987;Cheah and Gwee 1988). This indicates that tetanic fade or EPP run-down, can be dissociated from the blockade of postjunctional nicotinic receptors suggesting that snake α-neurotoxins bind at a prejunctional receptor with slow association/dissociation kinetics (Bradley et al 1987(Bradley et al , 1990Chang and Hong 1987;Cheah and Gwee 1988;Hong and Chang 1991). Interestingly however 3 H-acetylcholine release is unaffected by these agents arguing that snake α-neurotoxins do not block prejunctional nicotinic autoreceptors (Apel et al 1995).…”

Difference of train-of-four fade induced by nondepolarizing neuromuscular blocking drugs: a theoretical consideration on the underlying mechanisms

“…These reported orders of the degree of TOF fade were almost in inverse relation to the order of the potencies of the drugs. The difference of TOF fade induced by nondepolarizing neuromuscular blocking drugs has been attributed to a presynaptic action of the drugs [8][9][10]. At the presynaptic level, the drugs inhibit the feedback control of ACh release and reduce the ACh output at the fourth stimulu s in a train in comparison with that at the first stimulus.…”

“…The TOF ratio (T4/T1) at a certain degree of T1 depression varies depending on the drugs [3][4][5]. It has been considered that the difference of TOF fade among the drugs is due to the presynaptic action of the drugs [8][9][10]. Recently, it has been suggested that the TOF fade has no relation with the presynaptic action [11].…”

Neuromuscular effects of candoxin, a novel toxin from the venom of the Malayan krait (Bungarus candidus)

“…In contrast, under the same experimental conditions, erabutoxin‐b, α ‐cobratoxin and α ‐bungarotoxin did not produce such a fade during neuromuscular blockade. It has long been recognized that d‐TC and related compounds, in addition to producing neuromuscular blockade, also produced an independent ‘fade’ phenomenon characterized by rapidly waning tetanic tension or rundown in the successive twitch responses to TOF nerve stimulation (Paton & Zaimis, 1952; Cheah and Gwee, 1988; Gibb & Marshall, 1986; Bowman et al ., 1988). In contrast, curaremimetic α ‐neurotoxins such as α ‐bungarotoxin do not display prominent fade response during TOF stimulation (Gibb & Marshall, 1986; Bowman et al ., 1988; Cheah & Gwee, 1988; Blount et al ., 1992; Wilson & Nicholson, 1997; Oliveira & Oliveira, 1999).…”

“…The effects of candoxin on the maximal twitch responses of the MHD evoked through TOF stimulation were also investigated. TOF stimulation (2 Hz for 2 s every 20 s) of the phrenic nerve was carried out as described by Cheah & Gwee (1988) and continued throughout the experiment. Control TOF twitches (T 1 , T 2 , T 3 , T 4 ) were recorded for 20 min and conditions stabilized before the addition of candoxin (10–100 μ g ml −1 ; 1.36–13.6 μ M ).…”