Design and evaluation of artificial receptors for the reversal of neuromuscular block.

Applying patient friendly and cost-efficient medications in healthcare will be a real challenge in the 21st century. Sugammadex is a selective, yet expensive agent used for the post-surgical reversal of neuromuscular block since 2008. A wide library of cyclodextrin-based follow-ups, having potentially similar affinity towards target aminosteroid type neuromuscular blocking agents has been established. Almost 20 compounds were assessed with respect to in vitro affinity against three commonly applied drugs. Based on the capillary electrophoretic screening, carboxymethylated and sulfobutylated gamma-cyclodextrin derivatives have the potential to be promising lead molecules for their affinity towards pipecuronium was identical or even superior to Sugammadex. Carboxymethylated gamma-cyclodextrin showed efficient and complete reversal of the pipecuronium induced neuromuscular block in an ex vivo rat diaphragm experiment.

[CORRECTION OF INTRAABDOMINAL PRESSURE IN RATS IN AN ACUTE PANCREATITIS, USING INFUSION OF MYORELAXANT OF A DURABLE ACTION PIPECURONIUM BROMIDE].

Impact of a durable action of myorelaxant pipecuronium bromide on intraabdominal pressure (IAP) in rats in experimentally simulated acute peritonitis was studied. In the rats in purulent pancreatitis, іnduced by L-аrginin, IAP was in 4,5 times high (p < 0.001), than in intact laboratory animals. Pipecuronium bromide have lowered IAP by 33.4%, witnessing efficacy of application of myorelaxants in treatment of intraabdominal hypertension in purulent pancreatitis.

[Residual neuromuscular blockade after muscle relaxants administration in neurosurgical patients].

The paper analyzes the incidence of residual neuromuscular blockade (NMB) after pipecuronium and rocuronium administration in 124 neurosurgical patients. We analyzed neuromuscular conductance with TOF-Watch SX Residual NMB incidence after neuromuscular blocking agents administration in neurosurgical patients is 87.7%. Use of pipecuronium accompanied by a greater incidence and duration of residual NMB in comparison with rocuronium. Sugammadex administration is effective method of residual NMB reversal and can restore NMC in 3-5 minutes.

Neuromuscular and cardiovascular effects of pipecuronium. A comparative study between different doses.

BACKGROUND AND OBJECTIVES: Pipecuronium is a non-depolarizing neuromuscular blocker with similar properties to pancuronium, but without cardiovascular effects. Neuromuscular effects, conditions of tracheal intubation, and hemodynamic repercussions of two different doses of pipecuronium were evaluated. METHOD: Patients were divided into two groups according to the dose of pipecuronium: Group I (0.04 mg x kg(-1)) and Group II (0.05 mg x kg(-1)). Intramuscular midazolam (0.1 mg x kg(-1)) was administered 30 minutes before the surgery. Propofol (2.5 mg x kg(-1)), preceded by fentanyl (5 microg x kg(-1)) and pipecuronium (0.04 and 0.05 mg x kg(-1) for Groups I and II, respectively), was administered for anesthetic induction. Patients were ventilated with 100% oxygen via a face mask until a 75% reduction in the amplitude of the response to an isolated stimulus (1 Hz) is achieved, at which time laryngoscopy and intubation were carried out. Anesthetic maintenance was achieved with isoflurane (0.5 to 1%) with a mixture of 50% O2 and N2O. Mechanical ventilation was used to maintain P(ET)CO2 between 32 and 36 mmHg. The pharmacodynamics of pipecuronium was evaluated by acceleromyography. RESULTS: Mean times and standard deviation for the onset of action, clinical duration (T1(25%)), and recovery index (T1(25-75%)) were: Group I (122.10 +/- 4.18 sec, 49.63 +/- 9.54 min, and 48.21 +/- 6.72 min), and Group II (95.78 +/- 8.91 sec, 64.84 +/- 13.13 min, and 48.52 +/- 4.95 min). Onset of action, clinical duration, and conditions of tracheal intubation were significantly different for both groups. CONCLUSIONS: Pipecuronium at a dose of 0.05 mg x kg(-1) can be used in prolonged procedures in which cardiovascular changes should be avoided.

Efeitos neuromusculares e cardiovasculares do pipecurônio: estudo comparativo entre diferentes doses / Efectos neuromusculares y cardiovasculares del pipecuronio: estudio comparativo entre diferentes dosis / Neuromuscular and cardiovascular effects of pipecuronium: a comparative study between different dose

JUSTIFICATIVA E OBJETIVOS: O pipecurônio é um bloqueador neuromuscular não-despolarizante, com propriedades similares as do pancurônio, mas desprovido de efeitos cardiovasculares. Foram avaliados os efeitos neuromusculares, as condições de intubação traqueal e as repercussões hemodinâmicas de duas diferentes doses de pipecurônio. MÉTODO: Pacientes foram distribuídos em dois grupos de acordo com a dose de pipecurônio: Grupo I (0,04 mg.kg-1) e Grupo II (0,05 mg.kg-1). A medicação pré-anestésica consistiu em midazolam (0,1 mg.kg-1) por via muscular, 30 minutos antes da operação. A indução anestésica foi obtida com propofol (2,5 mg.kg-1) precedido de fentanil (5 µg.kg-1) e pipecurônio nas doses de 0,04 e 0,05 mg.kg-1 para os Grupos I e II, respectivamente. Os pacientes foram ventilados com O2 a 100 por cento sob máscara até a redução de 75 por cento da amplitude da resposta a estímulo isolado (1 Hz), quando foram realizadas a laringoscopia e intubação traqueal. O isoflurano (0,5 a 1 por cento) em mistura de O2 e N(2)0 a 50 por cento para a manutenção da anestesia, foi introduzido logo após a intubação traqueal. Os pacientes foram ventilados mecanicamente para manter P ET CO2 entre 32 e 36 mmHg. A farmacodinâmica do pipecurônio foi avaliada por aceleromiografia. RESULTADOS: Os tempos médios e desvios-padrão para o início de ação, duração clínica (T1(25 por cento)) e índice de recuperação (T1(25-75 por cento)) foram: Grupo I (122,10 ± 4,18 s, 49,63 ± 9,54 min e 48,21 ± 6,72 min) e Grupo II (95,78 ± 8,91 s, 64,84 ± 13,13 min e 48,52 ± 4,95 min). O início de ação, a duração clínica e as condições de intubação traqueal foram significativamente diferentes entre os grupos. CONCLUSÕES: O pipecurônio na dose 0,05 mg.kg-1 pode ser usado em procedimentos de longa duração, nos quais é desejável evitar alterações cardiocirculatórias.

BACKGROUND AND OBJECTIVES: Pipecuronium is a non-depolarizing neuromuscular blocker with similar properties to pancuronium, but without cardiovascular effects. Neuromuscular effects, conditions of tracheal intubation, and hemodynamic repercussions of two different doses of pipecuronium were evaluated. METHOD: Patients were divided into two groups according to the dose of pipecuronium: Group I (0.04 mg.kg-1) and Group II (0.05 mg.kg-1). Intramuscular midazolam (0.1 mg.kg-1) was administered 30 minutes before the surgery. Propofol (2.5 mg.kg-1), preceded by fentanyl (5 µg.kg-1) and pipecuronium (0.04 and 0.05 mg.kg-1 for Groups I and II, respectively), was administered for anesthetic induction. Patients were ventilated with 100 percent oxygen via a face mask until a 75 percent reduction in the amplitude of the response to an isolated stimulus (1 Hz) is achieved, at which time laryngoscopy and intubation were carried out. Anesthetic maintenance was achieved with isoflurane (0.5 to 1 percent) with a mixture of 50 percent O2 and N2O. Mechanical ventilation was used to maintain P ET CO2 between 32 and 36 mmHg. The pharmacodynamics of pipecuronium was evaluated by acceleromyography. RESULTS: Mean times and standard deviation for the onset of action, clinical duration (T1(25 percent)), and recovery index (T1(25-75 percent)) were: Group I (122.10 ± 4.18 sec, 49.63 ± 9.54 min, and 48.21 ± 6.72 min), and Group II (95.78 ± 8.91 sec, 64.84 ± 13.13 min, and 48.52 ± 4.95 min). Onset of action, clinical duration, and conditions of tracheal intubation were significantly different for both groups. CONCLUSIONS: Pipecuronium at a dose of 0.05 mg.kg-1 can be used in prolonged procedures in which cardiovascular changes should be avoided.

JUSTIFICATIVA Y OBJETIVOS: El pipecuronio es un bloqueador neuromuscular no despolarizador, con propiedades similares a las del pancuronio, pero desprovisto de efectos cardiovasculares. Se evaluaron los efectos neuromusculares, condiciones de intubación traqueal y las repercusiones hemodinámicas de de los diferentes dosis de pipecuronio. MÉTODO: Los pacientes fueron distribuidos en de los grupos de acuerdo a la dosis de pipecuronio: Grupo I (0,04 mg.kg-1) y Grupo II (0,05 mg.kg-1). La medicación preanestésica consistió en midazolam (0,1 mg.kg-1) por vía muscular, 30 minutos antes de la operación. La inducción anestésica se obtuvo con propofol (2,5 mg.kg-1) precedido del fentanil (5 µg.kg-1) y del pipecuronio en las dosis de 0,04 y 0,05 mg.kg-1 para los Grupos I y II, respectivamente. Los pacientes se ventilaron con O2 a 100 por ciento bajo máscara hasta la reducción de un 75 por ciento de la amplitud de la respuesta al estímulo aislado (1 Hz), cuando fueron realizadas la laringoscopía y la intubación traqueal. El isoflurano (0,5 a 1 por ciento) en mezcla de O2 y N(2)0 a un 50 por ciento para el mantenimiento de la anestesia, fue introducido a continuación de la intubación traqueal. Los pacientes fueron ventilados mecánicamente para mantener el P ET CO2 entre 32 y 36 mmHg. La farmacodinámica del pipecuronio se evaluó por aceleromiografía. RESULTADOS: Los tiempos promedios y desviaciones estándar para el inicio de acción, duración clínica (T1(25 por ciento)) e índice de recuperación (T1(25-75 por ciento)) fueron los siguientes: Grupo I (122,10 ± 4,18 seg, 49,63 ± 9,54 min y 48,21 ± 6,72 min) y Grupo II (95,78 ± 8,91 seg, 64,84 ± 13,13 min y 48,52 ± 4,95 min). El inicio de acción, la duración clínica y las condiciones de intubación traqueal fueron significativamente diferentes entre los grupos. CONCLUSIONES: El pipecuronio, en la dosis 0,05 mg.kg-1 puede ser usado en procedimientos de larga duración donde se desee evitar alteraciones ca...

Effect of magnesium sulphate on urinary catecholamine excretion in severe tetanus.

Severe tetanus is characterised by muscle spasms and autonomic dysfunction. We recently reported the results of a randomised placebo controlled trial of magnesium sulphate infusions for the treatment of severe tetanus which showed magnesium was associated with improved muscle spasm and cardiovascular control. We hypothesised that magnesium controlled autonomic dysfunction by reducing catecholamine release and thus urinary excretion. Urinary adrenaline and noradrenaline concentrations were measured during the first 24 h of therapy in 180 adults with severe tetanus randomised to treatment with magnesium (n = 92) or placebo (n = 88). Magnesium therapy was associated with lower urinary adrenaline excretion and higher urinary noradrenaline excretion. High urinary adrenaline concentrations were associated with documented autonomic dysfunction. Patients given magnesium had significantly less autonomic dysfunction, required less cardiovascular stabilising drugs, and had lower urinary concentrations of adrenaline. These findings suggest adrenaline is important in the pathophysiology of severe tetanus and magnesium controls autonomic dysfunction by reducing adrenaline release.

Development of bronchoconstriction after administration of muscle relaxants in rabbits with normal or hyperreactive airways.

Neuromuscular blocking drugs can induce intraoperative bronchospasm. We characterized the magnitude and the temporal profile of the constriction in normal or in hyperresponsive airways after injections of neuromuscular blocking drugs. Respiratory system impedance (Zrs) was measured continuously over a 90-s apneic period in naïve and rabbits sensitized to allergens by ovalbumin. Fifteen s after the start of Zrs recordings, succinylcholine, mivacurium, or pipecuronium was administered in random order. Zrs was then also recorded during the administration of increasing doses of exogenous histamine. To monitor the changes in the airway mechanics during these maneuvers, Zrs was averaged for 2-s time windows, and the airway resistance (Raw) was determined by model fitting. The increases in Raw were significantly larger in the sensitized rabbits than in the naïve animals. The largest increases in Raw and the maximum rate of change in Raw were obtained for succinylcholine (146% +/- 29% and 0.80 +/- 0.12 cm H2O/L, respectively) and mivacurium (80% +/- 25% and 0.71 +/- 0.13 cm H2O/L) and the smallest were obtained for pipecuronium (40% +/- 12% and 0.41 +/- 0.04 cm H2O/L). Allergic sensitization leads to severe and rapidly developing bronchospasm after administrations of mivacurium or succinylcholine. These deleterious side effects should be considered when succinylcholine or mivacurium is administered in the presence of bronchial hyperreactivity.

[Investigation of neuromuscular blocking agents at Richter Ltd]. / Szteroid izomrelaxánsok kutatása a Richterben.

Investigation of new neuromuscular blocking agents was started 30 years ago in Richter Ltd. This paper presents the results obtained by Richter's scientists. 2 compounds out of 100 bisquaternary ammonio steroid having androstane skeleton were selected for further pharmacological study. One of these agents, pipecuronium bromide (Arduan) elicited long-lasting block of neuromuscular transmission without cardiovascular side effects in both animal experiments and clinical studies. Arduan is a powerful competitive antagonist of acetylcholine, since it can bind pre- and postsynaptic (N1) receptors of the transmitters. It has no remarkable cumulative effect. Neostigmine rapidly and completely antagonized the neuromuscular blockade caused by pipecuronium. Arduan was introduced into clinical practice. The second compound, RGH-4201 (Duador) evoked a neuromuscular block of short duration. It showed slight atropin-like cardio-vagolytic effect in animal experiments. In the clinical studies, however, the cardiovascular side effects were found to be too strong. Therefore, it was not introduced in clinical practice.

[Carboxyperitoneum and clinical efficacy of nondepolarizing relaxants with different types of metabolism]. / Karboxyperitoneum i klinicheskaia éffektivnost' nedepoliarizuiushchikh relaksantov s razlichnymi tipami metabolisma.

A total of 108 patients operated on the abdominal cavity were examined with laparoscopic equipment or via laparotomic assess. The recovery time of neuromuscular conduction was defined for a myorelaxant with organ-depended metabolism (pipecuronium) and, predominantly, nonorgan-depended metabolism (athracurium and cisathracurium) in relation to the type of surgical technique (laparoscopy and laparotomy). It is concluded that carboxyperitoneum prolongs the recovery of neuromuscular conduction for pipecuronium without affecting this parameter in athracurium and cisathracurium. It is more expedient to use these myorelaxants during laparoscopic operations than pipecuronium, a myorelaxant having organ-dependent metabolism.

[Correction of cardiorespiratory disorders in laparoscopic cholecystectomy]. / Korrektsiia kardiorespiratornykh narushenii pri laparoskopicheskoi kholetsistéktomii.

Carboxyperitoneum and traditional forced ventilation of the lungs have a negative impact on external respiration function during laparoscopic operations, leading to impairment of the ventilation device, pressure rise in airways, and decrease in oxygen diffusion and carbon dioxide release. This leads to accumulation of carbon dioxide in the blood and tissue with a trend to development of acidosis of mixed origin. Cardiovascular changes during laparoscopic cholecystectomy manifest by hypertension and tachicardia in the presence of increased central venous pressure and total peripheral vascular resistance, decreased stroke and cardiac indexes, decreased right-ventricular diastolic function, increased pressure in the pulmonary artery, and deceleration of venous bloodflow in the inferior and superior venae cavae. The most rational variant of forced ventilation of the lungs in laparoscopic cholecystectomy is high-frequency injection ventilation, which appreciably attenuates the negative effect of carboxyperitoneum on central hemodynamics, gas exchange, and external respiration function. The optimal variant of total anesthesia in laparoscopic cholecystectmy is endotracheal combined narcosis with diprivane and fentanide. The key factor in the choice of forced ventilation protocols is the maintenance of adequate gas exchange in the lungs in the presence of the lowest possible mean pressure in the airways.

Systemic anti-inflammatory effect of somatostatin released from capsaicin-sensitive vagal and sciatic sensory fibres of the rat and guinea-pig.

The systemic anti-inflammatory effect induced by antidromic sensory nerve stimulation was investigated in rats and guinea-pigs. In atropine-pretreated rats, bilateral antidromic stimulation of vagal afferent fibres (8 Hz, 20 min, at C-fibre strength) inhibited plasma extravasation induced by 1% mustard oil on the acutely denervated hindlegs by 36.45+/-3.95%. Both the prevention of this inhibitory effect by cysteamine pretreatment and the stimulation-evoked rise of plasma somatostatin-like immunoreactivity in the two species suggest a mediator role of neural somatostatin. Since this response was blocked by systemic capsaicin pretreatment and slightly reduced after subdiaphragmal vagotomy, participation of thoracic capsaicin-sensitive afferents is indicated. In guinea-pigs pretreated with guanethidine and pipecuronium, antidromic sciatic nerve stimulation induced 45.46+/-5.08% inhibition on the contralateral leg and increased plasma somatostatin-like immunoreactivity. It is concluded that somatostatin released from the activated vagal capsaicin-sensitive sensory nerve terminals of the rat and somatic nerves of the guinea-pigs exerts a systemic humoral function.

Adenosine potentiation of neuromuscular blocking agents in guinea-pigs.

We have investigated the effects of adenosine i.v. on neuromuscular block induced by rocuronium, vecuronium and pipecuronium in an in vivo guinea-pig sciatic nerve-tibialis anterior preparation. The ED50 of each neuromuscular blocker was determined from cumulative log dose-response regression lines (n = 14). In separate experiments, adenosine 0.1 mg kg-1 min-1 or the same volume of 0.9% NaCl was given i.v. via a constant infusion and the ED50 of each neuromuscular blocking agent was then administered (n = 24). Adenosine 0.1 mg kg-1 min-1 increased significantly maximal block induced by the ED50 of these neuromuscular blockers (55-72%, 49-73% and 60-96%, respectively, for rocuronium, vecuronium and pipecuronium; P < 0.05). Time to maximal block after rocuronium was significantly prolonged by adenosine (1.4-2.1 min; P < 0.05) and time to maximal block after vecuronium and pipecuronium was unchanged by adenosine. Time to maximal recovery of twitch tension after administration of the ED50 of all neuromuscular blocking agents was prolonged significantly by adenosine (4.5-10.7 min, 8.2-15.8 min and 47.0-128.7 min, respectively, for rocuronium, vecuronium and pipecuronium; P < 0.05). We conclude that continuous infusion of adenosine 0.1 mg kg-1 min-1 potentiated the effects of neuromuscular blocking agents in this in vivo guinea-pig preparation.

[Evaluation of myorelaxant drug action in surgery for pediatric oncopathologies]. / Otsenka deistviia miorelaksantov pri polostnykh operatsiiakh u detei s onkopatologiei.

Neuro-muscular transmission was studied in 100 children operated on for retroperitoneal and mediastinal tumors using the TOF-Guard accelograph. The device was instrumental in cutting down intubation time, monitoring neuro-muscular transmission system (NMTS), predicting the point of transmission recovery and making extubation possible. NMTS monitoring established such advantages of continuous myorelaxant infusion as lower rate of drug administration and lower total dose; the latter is important to avoid drug cumulation. Due to TOF-Guard application 25-30 and 20% of such myorelaxant drugs as arduan and mivacron was saved, respectively; infusion technique required no decurarization medication. There is quite a potential of variation of myorelaxant administration at different stages of surgery and anesthesia.

[Clinical experience with low- and minimal-flow isoflurane in extensive resections of the liver and liver transplantation]. / Klinicheskii opyt ispol'zovaniia izofliurana v rezhimakh low- i minimal-flow pri obshirnykh rezektsiiakh i transplantatsii pecheni.

A comparative study was performed of general balanced anesthesia on the basis of neuroleptic analgesia (NLA) and inhalation low- and minimal-flow anesthesia with isoflurane in anesthesiological management of extensive operations on the liver. A total of 75 anesthesias were conducted. Because of low hepatotoxicity, absence of its metabolites' pharmacological activity, fast elimination from the body unchanged, isoflurane is effective in long and traumatic operations on the liver. Low-flow isoflurane significantly lowers pharmacological load with opiates, myorelaxants which is essential in patients with hepatic diseases. This leads to more rapid recovery of adequate spontaneous respiration and activation of the patient in low risk of postoperative iatrogenic complications.

[Use of laryngeal masks: variants of hemodynamic response to various methods of anesthesia]. / Ustanovka laringeal'noi maski: varianty gemodinamicheskogo otveta pri razlichnykh metodikakh anestezii.

Choice of induction agent is the decisive factor in utilization of a laryngeal mask (LM) under spontaneous respiration, as insufficient relaxation and unwanted laryngopharyngeal reflexes deteriorate the efficiency of LM functioning during operation and anesthesia. 132 anesthesias with LM were performed, 86 of these for laparoscopic cholecystectomies (LCE) (group 1) and 42 for saphenectomies (group 2). Control group consisted of 60 patients anesthetized for LCE by means of an endotracheal tube (ETT). Combined induction intravenous anesthesia with ketamine, barbiturates, and diprivan was used in group 1 and controls. In group 2 induction anesthesia was based on ketamine and diprivan. Group 1 and control group were matched for demographic characteristics and concomitant diseases. All groups were divided into subgroups, depending on anesthesia. In all groups pipecuronium bromide (0.06 mg/kg) was administered before insertion of EET or LM after injection of induction agents. In total myoplegia, installation of LM was simple, involving no untoward laryngo-pharyngeal reflexes. LM was correctly installed from the first attempt in 98.7% cases. In combined intravenous ketamine-based anesthesia, pressor reaction to LM installation consisted in an increase of heart rate by 5.6% (1K group--control), by 10.2% in 2K group (fractionated ketamine (1.5-2 mg/kg) + diazepam (0.1 mg/kg) and fentanyl (2.6 micrograms/kg); after barbiturates heart rate increased by 6.7% in 1B group (control), after diprivan it did not increase in 1D group (control), while the mean arterial pressure in 2D group (fractionated diprivan (1 mg/kg) + ketamine (25-50 mg), diazepam (0.08 mg/kg) and fentanyl (2.6 micrograms/kg) increased by 10% and heart rate by 6.6%. Reaction to tracheal intubation was pronounced in all types of induction anesthesia. No regurgitation or aspiration was observed in any case. Hence, use of total myoplegia in installation of LM allows the use of various modern anesthetics in optimal doses and notably simplifies the utilization of LM.

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.

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.

[Thermoregulatory reaction in the rabbit fetuses developing under the reduced utero-placental blood flow]. / Osobennosti termoreguliatornykh reaktsii plodov krolika, razvivavshikhsia v usloviiakh umen'shennogo matochno-placentarnogo krovotoka.

Rectal temperature, temperature of the brown adipose tissue, and the heart rate were studied in the rabbit foetus under intact and reduced utero-placenta blood flow in the end of the intrauterine development. With the reduced utero-placenta blood flow, bradycardia and a drop in the brown fat metabolism due, probably, to an insufficient development and functional immaturity of this tissue, were revealed.

Forearm blood flow responses to handgripping after local neuromuscular blockade.

To test the hypothesis that acetylcholine "spillover" from motor nerves contributes significantly to skeletal muscle vasodilation during exercise, we measured the forearm blood flow responses during attempted handgripping after local paralysis of the forearm with the neuromuscular-blocking drug pipecuronium. This compound blocks postsynaptic nicotinic receptors but has no impact on acetylcholine release from motor nerves. The drug was administered selectively to one forearm by using regional intravenous drug administration techniques in five subjects. Pipecuronium reduced maximum forearm grip strength from 40.0 +/- 3.2 kg before treatment to 0.0 kg after treatment. By contrast, drug administration had no effect on maximum voluntary contraction in the untreated forearm (41.3 +/- 3.3 vs. 41.4 +/- 2.7 kg). During 2 min of attempted maximal contraction of the paralyzed forearm, the forearm blood flow increased from only 3.4 +/- 0.8 to 4.8 +/- 1.2 ml.100 ml-1.min-1 (P < 0.05). Heart rate increased from 63 +/- 3 to 73 +/- 8 beats/min (P > 0.05) during attempted contraction, and only three of five subjects showed obvious increases in heart rate. Mean arterial pressure increased significantly (P < 0.05) from 102 +/- 6 to 109 +/- 9 mmHg during attempted contractions. When these increases in flow are considered in the context of the marked (10-fold or greater) increases in flow seen in contracting forearm skeletal muscle, it appears that acetylcholine spillover from motor nerves has, at most, a minimal impact on the hyperemic responses to contraction in humans.

The effect of non-depolarizing neuromuscular blocking agents on the release of acetylcholine from the right atrium of the guinea pig.

The effect of various non-depolarizing neuromuscular blocking agents (gallamine, pancuronium, vecuronium, d-tubocurarine, metocurine, atracurium and pipecuronium) on [3H]acetylcholine release in the response to field electrical stimulation was investigated in vitro in preparations of the guinea pig right atrium. In this preparation, atropine enhanced and oxotremorine, a muscarinic agonist, reduced the release of [3H] acetylcholine. Atropine reversed the inhibitory effect of oxotremorine in a concentration dependent manner, indicating that there is negative feedback modulation of acetylcholine release from the vagal nerve. While pancuronium, gallamine and atracurium enhanced the release of [3H]acetylcholine, d-tubocurarine, metocurine, vecuronium and pipecuronium did not affect it. Pancuronium and gallamine also reduced the inhibitory effect of oxotremorine and the Kd value of pancuronium for muscarinic receptors located on cholinergic nerve terminals was 2.31 microM. These findings indicate that pancuronium and gallamine enhanced the release of acetylcholine from the atrial parasympathetic nerve, probably by inhibiting presynaptic muscarinic receptors.