Neuromuscular Relaxants as Antagonists for M sub 2 and M sub 3 Muscarinic Receptors

Background: Neuromuscular relaxants such as pancuronium bind to M sub 2 and M3 muscarinic receptors as antagonists. Blockade of muscarinic receptors in atria of the M2 subtype mediates tachycardia. In the lung, blockade of M2 receptors on parasympathetic nerves potentiates vagally induced whereas blockade of M sub 3 receptors on bronchial smooth muscle inhibits bronchospasm. The current study was designed to quantify the affinity of a series of neuromuscular relaxants for the M2 and M3 muscarinic receptors, which were individually stably transfected in Chinese hamster ovary cell lines.

Methods: Competitive radioligand binding assays determined the relative binding affinities of the neuromuscular relaxants pancuronium, succinylcholine, mivacurium, doxacurium, atracurium, rocuronium, gallamine, and pipecuronium for the muscarinic receptor in the presence of a muscarinic receptor antagonist (sup 3 H-QNB) in membranes prepared from cells individually expressing either the M2 or M3 muscarinic receptor.

Results: All muscle relaxants evaluated displaced3 H-QNB from muscarinic receptors. The relative order of potency for the M2 muscarinic receptor (highest to lowest) was pancuronium, gallamine, rocuronium, atracurium, pipecuronium, doxacurium, mivacurium, and succinylcholine. The relative order of potency for the M3 muscarinic receptor (highest to lowest) was pancuronium, atracurium, pipecuronium, rocuronium, mivacurium, gallamine, succinylcholine, and doxacurium.     

A mechanism for rapacuronium-induced bronchospasm: M2 muscarinic receptor antagonism

BACKGROUND: A safe and effective ultra-short-acting nondepolarizing neuromuscular blocking agent is required to block nicotinic receptors to facilitate intubation. Rapacuronium, which sought to fulfill these criteria, was withdrawn from clinical use due to a high incidence of bronchospasm resulting in death. Understanding the mechanism by which rapacuronium induces fatal bronchospasm is imperative so that newly synthesized neuromuscular blocking agents that share this mechanism will not be introduced clinically. Selective inhibition of M2 muscarinic receptors by muscle relaxants during periods of parasympathetic nerve stimulation (e.g., intubation) can result in the massive release of acetylcholine to act on unopposed M3 muscarinic receptors in airway smooth muscle, thereby facilitating bronchoconstriction. METHODS: Competitive radioligand binding determined the binding affinities of rapacuronium, vecuronium, cisatracurium, methoctramine (selective M2 antagonist), and 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP; selective M3 antagonist) for M2 and M3 muscarinic receptors. RESULTS: Rapacuronium competitively displaced 3H-QNB from the M2 muscarinic receptors but not from the M3 muscarinic receptors within clinically relevant concentrations. Fifty percent inhibitory concentrations (mean +/- SE) for rapacuronium were as follows: M2 muscarinic receptor, 5.10 +/- 1.5 microm (n = 6); M3 muscarinic receptor, 77.9 +/- 11 microm (n = 8). Cisatracurium and vecuronium competitively displaced 3H-QNB from both M2 and M3 muscarinic receptors but had affinities at greater than clinically achieved concentrations for these relaxants. CONCLUSIONS: Rapacuronium in clinically significant doses has a higher affinity for M2 muscarinic receptors as compared with M3 muscarinic receptors. A potential mechanism by which rapacuronium may potentiate bronchoconstriction is by blockade of M2 muscarinic receptors on prejunctional parasympathetic nerves, leading to increased release of acetylcholine and thereby resulting in M3 muscarinic receptor-mediated airway smooth muscle constriction.     

Neuromuscular Blocking Agents' Differential Bronchoconstrictive Potential in Guinea Pig Airways

Background: Neuromuscular blocking agents are designed to antagonize nicotinic cholinergic receptors on skeletal muscle but also antagonize muscarinic receptors. Several muscle relaxants have the potential to promote bronchoconstriction due to unintended effects exemplified by histamine release of atracurium or mivacurium and detrimental interactions with muscarinic receptors by rapacuronium. Although interactions of muscle relaxants with muscarinic receptors have been extensively characterized in vitro, limited information is available on their potential interactions with airway tone in vivo.

Methods: Changes in pulmonary inflation pressures and heart rates induced by vagal nerve stimulation and intravenous acetylcholine were measured in the absence and presence of increasing doses of gallamine, pancuronium, mivacurium, vecuronium, cisatracurium, rocuronium, or rapacuronium in guinea pigs. Mivacurium's and rapacuronium's potential of inducing bronchoconstriction by histamine release was also evaluated.

Results: Rapacuronium potentiated both vagal nerve-stimulated and intravenous acetylcholine-induced increases in airway pressures, which were totally blocked by atropine but not pyrilamine. Vecuronium, rocuronium, mivacurium, and cisatracurium were devoid of significant airway effects. Mivacurium, at high doses, increased pulmonary inflation pressures, which were attenuated by pyrilamine.     

Rapacuronium preferentially antagonizes the function of M2 versus M3 muscarinic receptors in guinea pig airway smooth muscle

BACKGROUND: Rapacuronium, a nondepolarizing muscle relaxant that was proposed as a replacement for succinylcholine for rapid intubation, was withdrawn from clinical use as a result of fatal bronchospasm, but the mechanism of this effect is not known. Preferential antagonism of presynaptic M2 muscarinic receptors versus postsynpatic M3 muscarinic receptors can facilitate bronchoconstriction. The authors questioned whether rapacuronium preferentially antagonized M2 versus M3 muscarinic receptors in intact airway. METHODS: Guinea pig tracheal rings were suspended in organ baths and muscle relaxants' antagonism of prejunctional M2 muscarinic autoreceptors was evaluated by augmentation of muscle contraction elicited by electrical field stimulation. Muscle relaxants' antagonism of postjunctional M3 muscarinic receptors was assessed by attenuation of muscle contraction elicited by acetylcholine. RESULTS: Rapacuronium displayed a 50-fold higher affinity for antagonism of the M2 versus M3 muscarinic receptor. Moreover, its affinity for the M2 but not the M3 receptor was within concentrations achieved clinically. In addition, rapacuronium caused an increase in baseline tone of airway smooth muscle that was antagonized by atropine but not by previous depletion of nonadrenergic noncholinergic neurotransmitters or by inhibitors of histamine receptors, tachykinin receptors, leukotriene receptors, or calcium channels. CONCLUSION: These findings are consistent with the hypothesis that rapacuronium may precipitate bronchoconstriction by selective antagonism of the M2 muscarinic receptor on parasympathetic nerves, enhancing acetylcholine release to act upon unopposed M3 muscarinic receptors on airway muscle. An additional mechanism of rapacuronium-induced bronchoconstriction is suggested by increases in baseline muscle tension.     

Neuromuscular blocking agents' differential bronchoconstrictive potential in Guinea pig airways

BACKGROUND: Neuromuscular blocking agents are designed to antagonize nicotinic cholinergic receptors on skeletal muscle but also antagonize muscarinic receptors. Several muscle relaxants have the potential to promote bronchoconstriction due to unintended effects exemplified by histamine release of atracurium or mivacurium and detrimental interactions with muscarinic receptors by rapacuronium. Although interactions of muscle relaxants with muscarinic receptors have been extensively characterized in vitro, limited information is available on their potential interactions with airway tone in vivo. METHODS: Changes in pulmonary inflation pressures and heart rates induced by vagal nerve stimulation and intravenous acetylcholine were measured in the absence and presence of increasing doses of gallamine, pancuronium, mivacurium, vecuronium, cisatracurium, rocuronium, or rapacuronium in guinea pigs. Mivacurium's and rapacuronium's potential of inducing bronchoconstriction by histamine release was also evaluated. RESULTS: Rapacuronium potentiated both vagal nerve-stimulated and intravenous acetylcholine-induced increases in airway pressures, which were totally blocked by atropine but not pyrilamine. Vecuronium, rocuronium, mivacurium, and cisatracurium were devoid of significant airway effects. Mivacurium, at high doses, increased pulmonary inflation pressures, which were attenuated by pyrilamine. CONCLUSION: Rapacuronium was unique among muscle relaxants evaluated in that it potentiated both vagal nerve- and intravenous acetylcholine-induced bronchoconstriction with no evidence of histamine release. The dual detrimental interactions of rapacuronium with muscarinic receptors previously demonstrated in vitro correlate with in vivo muscarinic receptor mechanisms of bronchoconstriction and may account for the profound bronchoconstriction seen with its clinical use. These findings may establish pharmacologic characteristics to avoid with new muscle relaxants intended for clinical use.     

A Mechanism for Rapacuronium-induced Bronchospasm: M2 Muscarinic Receptor Antagonism

Background: A safe and effective ultra-short-acting nondepolarizing neuromuscular blocking agent is required to block nicotinic receptors to facilitate intubation. Rapacuronium, which sought to fulfill these criteria, was withdrawn from clinical use due to a high incidence of bronchospasm resulting in death. Understanding the mechanism by which rapacuronium induces fatal bronchospasm is imperative so that newly synthesized neuromuscular blocking agents that share this mechanism will not be introduced clinically. Selective inhibition of M2 muscarinic receptors by muscle relaxants during periods of parasympathetic nerve stimulation (e.g., intubation) can result in the massive release of acetylcholine to act on unopposed M3 muscarinic receptors in airway smooth muscle, thereby facilitating bronchoconstriction.

Methods: Competitive radioligand binding determined the binding affinities of rapacuronium, vecuronium, cisatracurium, methoctramine (selective M2 antagonist), and 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP; selective M3 antagonist) for M2 and M3 muscarinic receptors.

Results: Rapacuronium competitively displaced 3H-QNB from the M2 muscarinic receptors but not from the M3 muscarinic receptors within clinically relevant concentrations. Fifty percent inhibitory concentrations (mean +/- SE) for rapacuronium were as follows: M2 muscarinic receptor, 5.10 +/- 1.5 [mu]m (n = 6); M3 muscarinic receptor, 77.9 +/- 11 [mu]m (n = 8). Cisatracurium and vecuronium competitively displaced 3H-QNB from both M2 and M3 muscarinic receptors but had affinities at greater than clinically achieved concentrations for these relaxants.     

Rapacuronium Preferentially Antagonizes the Function of M2 versus M3 Muscarinic Receptors in Guinea Pig Airway Smooth Muscle

Background: Rapacuronium, a nondepolarizing muscle relaxant that was proposed as a replacement for succinylcholine for rapid intubation, was withdrawn from clinical use as a result of fatal bronchospasm, but the mechanism of this effect is not known. Preferential antagonism of presynaptic M2 muscarinic receptors versus postsynpatic M3 muscarinic receptors can facilitate bronchoconstriction. The authors questioned whether rapacuronium preferentially antagonized M2 versus M3 muscarinic receptors in intact airway.

Methods: Guinea pig tracheal rings were suspended in organ baths and muscle relaxants' antagonism of prejunctional M2 muscarinic autoreceptors was evaluated by augmentation of muscle contraction elicited by electrical field stimulation. Muscle relaxants' antagonism of postjunctional M3 muscarinic receptors was assessed by attenuation of muscle contraction elicited by acetylcholine.

Results: Rapacuronium displayed a 50-fold higher affinity for antagonism of the M2 versus M3 muscarinic receptor. Moreover, its affinity for the M2 but not the M3 receptor was within concentrations achieved clinically. In addition, rapacuronium caused an increase in baseline tone of airway smooth muscle that was antagonized by atropine but not by previous depletion of nonadrenergic noncholinergic neurotransmitters or by inhibitors of histamine receptors, tachykinin receptors, leukotriene receptors, or calcium channels.     

Do Pipecuronium and Rocuronium Affect Human Bronchial Smooth Muscle?

Background: Muscle relaxants affect nicotinic and muscarinic receptors. Interaction of muscle relaxants with muscarinic receptors of human airways has been studied incompletely.

Methods: The effects of pipecuronium bromide (long-acting, nondepolarizing) and rocuronium bromide (intermediate-acting, nondepolarizing) on prejunctional and postjunctional muscarinic receptors were studied in 96 isolated human bronchial rings from 12 patients. Contractile isometric responses to electric field stimulation of pilocarpine-stimulated and nonstimulated M2 muscarinic receptors were compared before and after incubation with the two muscle relaxants. The effect on postjunctional muscarinic receptors was studied by comparing acetylcholine concentration-response curves before and after incubation with the two muscle relaxants.

Results: Pipecuronium bromide, but not rocuronium bromide, inhibited pilocarpine-stimulated prejunctional M2 muscarinic receptors. Neither pipecuronium bromide nor rocuronium bromide had significant inhibitory effects on nonstimulated M2 muscarinic receptors and on postjunctional M3 muscarinic receptors.     

Do pipecuronium and rocuronium affect human bronchial smooth muscle?

BACKGROUND: Muscle relaxants affect nicotinic and muscarinic receptors. Interaction of muscle relaxants with muscarinic receptors of human airways has been studied incompletely. METHODS: The effects of pipecuronium bromide (long-acting, nondepolarizing) and rocuronium bromide (intermediate-acting, nondepolarizing) on prejunctional and postjunctional muscarinic receptors were studied in 96 isolated human bronchial rings from 12 patients. Contractile isometric responses to electric field stimulation of pilocarpine-stimulated and nonstimulated M2 muscarinic receptors were compared before and after incubation with the two muscle relaxants. The effect on postjunctional muscarinic receptors was studied by comparing acetylcholine concentration-response curves before and after incubation with the two muscle relaxants. RESULTS: Pipecuronium bromide, but not rocuronium bromide, inhibited pilocarpine-stimulated prejunctional M2 muscarinic receptors. Neither pipecuronium bromide nor rocuronium bromide had significant inhibitory effects on nonstimulated M2 muscarinic receptors and on postjunctional M3 muscarinic receptors. CONCLUSIONS: The inhibitory effect of pipecuronium bromide on pilocarpine-stimulated prejunctional M2 muscarinic receptors occurred at clinical concentrations.     

The mechanism of pancuronium potentiation of mivacurium block: use of the isolated-arm technique

The neuromuscular blocking effects of mivacurium are greatly enhanced when mivacurium is preceded by a subparalyzing dose of pancuronium. The mechanism of this potentiation has not been elucidated. This study investigated the effects of the anticholinesterase activity of a small dose of pancuronium on the neuromuscular blocking effects of mivacurium. Forty patients were enrolled in the study. The neuromuscular effects of 7.5 and 15 microg/kg pancuronium, followed by 50 and 100 microg/kg mivacurium, were assessed in Groups PM1 and PM2 (n = 20), respectively. The neuromuscular effects of 65 and 130 microg/kg mivacurium were assessed in Groups M1 and M2 (n = 20), respectively. One arm was excluded from circulation with a tourniquet, which was inflated before the injection of pancuronium and deflated 3 min after the injection of mivacurium. The plasma cholinesterase activity was measured before induction for all patients and 3 min after the injection of pancuronium for Groups PM1 and PM2. The plasma cholinesterase activity was decreased by 16% and 33% after pancuronium administration in Groups PM1 and PM2, respectively. In the nonexcluded arm, pancuronium significantly potentiated the effects of mivacurium. In the excluded arm, no significant block was detected for Groups M1 and M2, whereas the maximal degree of neuromuscular block was 79% and 100% for Groups PM1 and PM2, respectively. Using the isolated-arm technique, we suggest that pancuronium potentiation of the neuromuscular blocking effects of mivacurium is more likely attributable to an increase in the effective plasma concentration of mivacurium than to occupancy of postsynaptic acetylcholine receptors. Implications: Using the isolated-arm technique, we suggest that pancuronium potentiation of the neuromuscular blocking effects of mivacurium is more likely attributable to an increase in the effective plasma concentration of mivacurium than to occupancy of postsynaptic acetylcholine receptors.     

Rapacuronium augments acetylcholine-induced bronchoconstriction via positive allosteric interactions at the M3 muscarinic receptor

BACKGROUND: Neuromuscular blocking agents' detrimental airway effects may occur as a result of interactions with muscarinic receptors, allergic reactions, or histamine release. Rapacuronium, a nondepolarizing muscle relaxant, was withdrawn from clinical use because of its association with fatal bronchospasm. Despite its withdrawal from clinical use, it is imperative that the mechanism by which bronchospasm occurred is understood so that new muscle relaxants introduced to clinical practice do not share these same detrimental airway effects. METHODS: Airway smooth muscle force was measured in guinea pig tracheal rings in organ baths exposed to muscle relaxants with or without subthreshold concentrations of acetylcholine. Antagonism of muscarinic, histamine, neurokinin, leukotriene receptors, or blockade of L-type calcium channels or depletion of nonadrenergic, noncholinergic neurotransmitters was performed. Muscle relaxants' potentiation of acetylcholine-stimulated inositol phosphate synthesis and allosteric interactions on the kinetics of atropine-induced [3H]N-methylscopolamine dissociation were measured in cells expressing recombinant human M3 muscarinic receptors. RESULTS: Rapacuronium, within clinically achieved concentrations, contracted tracheal rings in the presence but not in the absence of subthreshold concentrations of acetylcholine. This effect was prevented or reversed only by atropine. The allosteric action of rapacuronium was demonstrated by the slowing of atropine-induced dissociation of [3H]N-methylscopolamine, and positive cooperativity was demonstrated by potentiation of acetylcholine-induced inositol phosphate synthesis. CONCLUSION: Many muscle relaxants have allosteric properties at muscarinic receptors; however, positive cooperativity at the M3 muscarinic receptor within clinically relevant concentrations is unique to rapacuronium. These findings establish novel parameters that should be considered in the evaluation of airway safety of any newly synthesized neuromuscular blocking agents considered for clinical practice.     

Rapacuronium Augments Acetylcholine-induced Bronchoconstriction via Positive Allosteric Interactions at the M3 Muscarinic Receptor

Background: Neuromuscular blocking agents' detrimental airway effects may occur as a result of interactions with muscarinic receptors, allergic reactions, or histamine release. Rapacuronium, a nondepolarizing muscle relaxant, was withdrawn from clinical use because of its association with fatal bronchospasm. Despite its withdrawal from clinical use, it is imperative that the mechanism by which bronchospasm occurred is understood so that new muscle relaxants introduced to clinical practice do not share these same detrimental airway effects.

Methods: Airway smooth muscle force was measured in guinea pig tracheal rings in organ baths exposed to muscle relaxants with or without subthreshold concentrations of acetylcholine. Antagonism of muscarinic, histamine, neurokinin, leukotriene receptors, or blockade of L-type calcium channels or depletion of nonadrenergic, noncholinergic neurotransmitters was performed. Muscle relaxants' potentiation of acetylcholine-stimulated inositol phosphate synthesis and allosteric interactions on the kinetics of atropine-induced [3H]N-methylscopolamine dissociation were measured in cells expressing recombinant human M3 muscarinic receptors.

Results: Rapacuronium, within clinically achieved concentrations, contracted tracheal rings in the presence but not in the absence of subthreshold concentrations of acetylcholine. This effect was prevented or reversed only by atropine. The allosteric action of rapacuronium was demonstrated by the slowing of atropine-induced dissociation of [3H]N-methylscopolamine, and positive cooperativity was demonstrated by potentiation of acetylcholine-induced inositol phosphate synthesis.     

Train-of-Four recovery after pharmacologic antagonism of pancuronium-, pipecuronium-, and doxacurium-induced neuromuscular block in anaesthetized humans

Previous studies have suggested that the increased duration of action of long-acting neuromuscular relaxants may make their pharmacologic antagonism more difficult and, thus, increase the likelihood of residual block. This hypothesis was tested in healthy, adult humans who received a background of isoflurane/N₂O/fentanyl anaesthesia.
Study subjects were paralyzed with either pancuronium (N=8), pipecuronium (N=8), or the longer-acting relaxant, doxacurium (N=8). Neuromuscular function was monitored, and, using a blinded, randomized study design, the relaxants were titrated to identify the ED₉₅ dose in each patient. Thereafter, spontaneous recovery was observed until there was 25% ofbaseline response to the first supramaximal twitch (Tl) in a train-of-four (TOF). At this time, the block was antagonized with neostigmine 0.07 mg/kg and glycopyrrolate 0.014 mg/kg i.v., and recovery of TOF was recorded.
Spontaneous recovery to 25% of the baseline Tl response occurred at 52± 14 min (mean±SD) following administration of either pancuronium and pipecuronium, and 85 ±33 min following doxacurium ( P <0.05 for doxacurium versus pancuronium and pipecuronium). In doxacurium-rreated patients, reversal of block with neostigmine was less predictable and less complete than with the other two relaxants. For example, the ratio of the fourth to first twitch (T4/T1) of the TOF at 10 and 15 min after reversal was significantly less with doxacurium (59 ±14% and 61±16%, respectively) than with either pancuronium (75±6% and 75±10%) or pipecuronium (76±9% for both). At 30 min post-neostigmine, the incidence of residual block (i.e. T4/T1 <0.70) was: pancuronium 2 patients, pipecuronium 1 patient, and doxacurium 5 patients.
These studies support the hypothesis that incomplete reversal of neuromuscular block is more likely with longer-acting neuromuscular relaxants.     

Effect of halothane on galphai-3 and its coupling to the M2 muscarinic receptor

BACKGROUND: Halothane is an effective bronchodilator and inhibits airway smooth muscle contraction in part by inhibiting intracellular signaling pathways activated by the M2 muscarinic receptor and its cognate inhibitory heterotrimeric guanosine-5'-triphosphate (GTP)-binding protein (G protein), Gi. This study hypothesized that halothane inhibits nucleotide exchange at the alpha isoform-3 subunit of Gi (Galphai-3), but only when regulated by the M2 muscarinic receptor. METHODS: GTP hydrolysis by Galphai-3 and the Galphai-3beta1gamma2HF heterotrimer expressed in Spodoptera frugiperda cells was measured using a phosphohydrolase assay with [gammaPi]-labeled GTP. Anesthetic binding to Galphai-3 was measured by saturation transfer difference nuclear magnetic resonance spectroscopy. Galphai-3 nucleotide exchange was measured in crude membranes prepared from COS-7 cells transiently coexpressing the M2 muscarinic receptor and Galphai-3. A radioactive analog of GTP, [S]GTPgammaS, was used as a reporter for Galphai-3 nucleotide exchange. RESULTS: Although spectroscopy demonstrated halothane binding to Galphai-3, this binding had no effect on [gammaPi]-labeled GTP hydrolysis by the Galphai-3beta1gamma2HF heterotrimer expressed in Spodoptera frugiperda cells, nor basal Galphai-3 nucleotide exchange measured in crude membranes when the muscarinic receptor agonist acetylcholine was omitted from the assay. Conversely, halothane caused a concentration-dependent inhibition of Galphai-3 nucleotide exchange with acetylcholine included in the assay. CONCLUSION: These data indicate that despite halothane binding to Galphai-3, halothane has no direct inhibitory effect on the intrinsic activity of the Galphai-3beta1gamma2HF heterotrimer but inhibits M2 muscarinic receptor regulation of the heterotrimer. This novel effect is consistent with the ability of halothane to inhibit airway smooth muscle contraction and bronchoconstriction induced by acetylcholine.     

The myocardial effects of pancuronium.

The effect of pancuronium on myocardial contractility was studied in three different animal preparations. Pancuronium produced no change in isometric contraction of rabbit atrial or cat papillary muscle but displaced the acetylcholine dose-response curve to the right in the papillary muscle preparations, verifying a muscarinic blocking effect of this drug. In atropinized dogs in vivo pancuronium produced no significant change in the cardiovascular parameters studied. These studies show that pancuronium exerts its cardiovascular effects primarily by blocking muscarinic receptors in the heart.     

Presynaptic M1, M2, and A1 receptors play roles in tetanic fade induced by pancuronium or cisatracurium

Purpose

We investigated whether presynaptic facilitatory M1 and/or inhibitory M2 muscarinic receptors contributed to pancuronium- and cisatracurium-induced tetanic fade.

Methods

Phrenic nerve-diaphragm muscle preparations of rats were indirectly stimulated with tetanic frequency (75 ± 3.3 Hz; mean ± SD). Doses of pancuronium, cisatracurium, hexamethonium, and d-tubocurarine for producing approximately 25% fade were determined. The effects of pirenzepine and methoctramine, blockers of presynaptic M1 and M2 receptors, respectively, on the tetanic fade were investigated.

Results

The concentrations required for approximately 25% fade were 413 µM for hexamethonium (26.8 ± 2.4% 4% fade), 55 nM for d-tubocurarine (28.7 ± 2.55% fade), 0.32 µM for pancuronium (25.4 ± 2.2% fade), and 0.32 µM for cisatracurium (24.7 ± 0.8% fade). Pirenzepine or methoctramine alone did not produce the fade. Methoctramine, 1 µM, attenuated the fade induced by hexamethonium (to 16.0 ± 2.5% fade), d-tubocurarine (to 6.0 ± 1.6 fade), pancuronium (to 8.0 ± 4.0% fade), and cisatracurium (to 11.0 ± 3.3% fade). 10 nM pirenzepine attenuated only the fades produced by pancuronium (to 5.0 ± 0.11% fade) and cisatracurium (to 13.3 ± 5.3% fade). Cisatracurium (0.32 µM) showed antiacetylcholinesterase activity (in plasma, 14.2 ± 1.6%; 6%; in erythrocyt 17.2 ± 2.66%) similar to that of pancuronium (0.32 µM). The selective A1 receptor blocker, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 2.5 nM), also attenuated the fades induced by pancuronium and cisatracurium.

Conclusion

The tetanic fades produced by pancuronium and cisatracurium depend on the activation of presynaptic inhibitory M2 receptors; these agents also have anticholinesterase activities. The fades induced by these agents also depend on the activation of presynaptic inhibitory A1 receptors through the activation of stimulatory M1 receptors by acetylcholine.     

Rocuronium-induced Neuromuscular Block Is Affected by Chronic Carbamazepine Therapy

Background: Patients on chronic anticonvulsant drugs are relatively resistant to certain nondepolarizing neuromuscular blockers such as pancuronium, vecuronium, pipecuronium, doxacurium, or metocurine, but not resistant to mivacurium and atracurium. This study investigated the influence of chronic carbamazepine therapy on the neuromuscular block induced by the new muscle relaxant rocuronium.

Methods: Twenty-two otherwise healthy individuals scheduled for neurosurgical operations were studied: 11 of them were on chronic treatment with carbamazepine; the others served as control subjects. The median duration of carbamazepine therapy was 9 weeks (range, 4-312 weeks). After premedication with oral diazepam, anesthesia was induced with fentanyl and thiopental and maintained with nitrous oxide/oxygen and 0.5% inspired isoflurane. Rocuronium, 0.6 mg/kg (2 x ED95), was given for intubation. The ulnar nerve was stimulated, and the evoked electromyogram recorded using a Datex NMT monitor.

Results: Based on the response to the first of four stimuli, neither the lag time nor the onset-time differed between the two groups. However, the intervals of recovery to 10%, 25%, 50%, and 75% of the baseline response and the recovery index (RI, 25%-75%) were significantly shorter in patients on chronic carbamazepine therapy.     

EFFECTS OF PIPECURONIUM AND PANCURONIUM ON THE ISOLATED RABBIT HEART

We have studied the effects of pipecuronium and pancuroniumon myocardial contractility and heart rate in two differentanimal preparations. Pipecuronium and pancuronium produced nochange in isometric contraction of rabbit atria. The chronotropiceffects of pipecuronium, pancuronium and vecuronium were investigatedusing acetylcholine as an agonist in isolated perfused rabbitheart. Pancuronium but not pipecuronium or vecuronium, produceda significant degree of antagonism to the bradycardia producedby acetylcholine.     

Effects of non-depolarizing neuromuscular blocking agents on norepinephrine release from human atrial tissue obtained during cardiac surgery

We have studied the effect of non-depolarizing neuromuscular blocking agents, at concentrations present in serum during anaesthesia, on release of [3H]-norepinephrine ([3H]NE) from superfused atrial appendage obtained during cardiac surgery from 48 patients. Three of the neuromuscular blocking agents (pancuronium, gallamine and rocuronium), which are known to cause an increase in heart rate during anaesthesia, increased stimulation-evoked release of [3H]NE. In contrast, (+)tubocurarine and pipecuronium, neuromuscular blocking agents that do not cause tachycardia, did not affect release of NE. Org 9487 significantly enhanced release while SZ1677 was ineffective, even at concentrations higher than those expected after administration of a 2 x ED95 dose. Atropine enhanced release. These data suggest that the axon terminals of sympathetic nerves in human heart have muscarinic heteroreceptors whose activation by acetylcholine (ACh) released from the vagal nerve reduces release of NE. This action contributes to lowering of heart rate. Therefore, any neuromuscular blocking agent with antimuscarinic actions and capable of increasing the release of NE may produce tachycardia.      

Actions of enflurane, isoflurane, vecuronium, atracurium, and pancuronium on pulmonary resistance in dogs

The effects of enflurane, isoflurane, vecuronium, atracurium, and pancuronium on pulmonary resistance and heart rate were studied in 30 vagotomized dogs lying supine and anesthetized with chloralose-urethane. None of the five drugs affected pulmonary resistance when the airway was unstimulated. Enflurane and isoflurane significantly attenuated the increase in pulmonary resistance induced by electrical stimulation of the vagus nerves. This effect was dose-dependent and similar for both anesthetics at equivalent multiples of their minimum alveolar concentration. Atracurium significantly (P less than 0.05) enhanced the increase in pulmonary resistance induced by vagus nerve stimulation; vecuronium had no significant effect. Pancuronium, up to a cumulative dose of 0.14 mg/kg, also significantly (P less than 0.05) enhanced the increase in pulmonary resistance induced by vagus nerve stimulation; but this effect was reversed by further increasing the dose. Pancuronium also attenuated the cardiodecelerator response to vagus nerve stimulation in a dose-dependent fashion. The underlying mechanisms for the attenuation of responses to vagus nerve stimulation by enflurane or isoflurane or for the increase in response with atracurium are unknown. Pancuronium at lower doses increases the response most likely by blocking prejunctional muscarinic receptors (M2) that physiologically inhibit vagally mediated increases in pulmonary resistance.