A new short-acting non-depolarizing muscle relaxant (SZ1677) without cardiovascular side-effects.

BACKGROUND: In order to facilitate rapid tracheal intubation, the development of a rapid onset, short duration, non-depolarizing muscle relaxant without cardiovascular side-effects would be a significant accomplishment in the field of anesthesiology. The aim of the present study was to test the action of a new non-depolarizing muscle relaxant (SZ1677) on neuromuscular transmission, muscarinic (M2, M3) receptors and cardiovascular reactions and to compare it with clinically used muscle relaxants. METHODS: Neuromuscular transmission was studied by recording muscle contractions elicited by indirect electrical stimulation, using (i). in vitro isolated phrenic nerve-hemidiaphragm preparation of mice, rats and guinea pigs and (ii). in vivo sciatic nerve-anterior tibial muscle preparation of anesthetized rats, guinea pigs and cats. Cardiovascular effects of muscle relaxants were evaluated on the grounds of their effects on changes of blood pressure and heart rate induced by electrical stimulation of the right vagal nerve in anesthetized cats. To study postsynaptic antimuscarinic affinity of muscle relaxants on M3 receptors, oxotremorine-induced contractions of longitudinal muscle strip of guinea pig ileum were registered in their presence and absence. RESULTS: One of more than 120 newly synthesized non-depolarizing muscle relaxants compounds, 1-3[alpha-hydroxy-17beta-acetyloxy-2beta-(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)-5alpha-androstane-16beta-il] -1-(2-propenyl)pyrrolidinium bromide (SZ1677), excelled with its advantageous pharmacological properties: relatively short duration of action, no accumulation and lack of unwanted side-effects. Pharmacodynamic studies show that SZ1677 is a non-depolarizing neuromuscular blocking agent with a relatively short duration and rapid onset of action in a variety of laboratory animal species. It is without cumulative effect, does not reduce blood pressure, and fails to produce tachycardia. Significant cardiac vagal blocking effects were not observed even at concentrations or dosages of 8 times the ED90. This compound, unlike many other muscle relaxants, does not have atropine-like effects on human atrial tissue; it does not increase the release of NA from sympathetic innervation in the heart. In all practical ways, at least from the vantage point of the preclinical study, SZ1677 compares favorably with all presently available short-acting muscle relaxants, including rapacuronium. CONCLUSION: In experiments, SZ1677 proved to be a short-acting neuromuscular blocking compound having a large safety margin between the doses required to produce neuromuscular block and those likely to lead to cardiovascular side-effects.

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 neuromuscular and cardiovascular effects of two doses of rapacuronium (ORG 9487) versus mivacurium and succinylcholine.

BACKGROUND: This study compares the neuromuscular blocking and cardiovascular effects of rapacuronium (ORG 9487), a new aminosteroid nondepolarizing muscle relaxant, to recommended intubating doses of succinylcholine and mivacurium. METHODS: Adult patients were randomized in an open-label fashion to receive 1-5 microg/kg fentanyl before 1.5 mg/kg propofol induction followed by 1.5 or 2.5 mg/kg rapacuronium, 1.0 mg/kg succinylcholine, or 0.25 mg/kg mivacurium (i.e., 0.15 mg/kg followed by 0.1 mg/kg 30 s later). RESULTS: Patient neuromuscular blockade status was monitored by measuring the train-of-four response to a supramaximal stimulus at the ulnar nerve every 12 s. Percentage of the first twitch of the train-of-four (T1) at 60 s was similar in patients receiving 1.5 mg/kg rapacuronium, 2.5 mg/kg rapacuronium, and succinylcholine and was significantly less than in patients in the mivacurium group (26, 16, and 18%, respectively, vs. 48%; P < 0.01). Times to 80% T1 depression were also similar among patients in the 1.5 mg/kg rapacuronium, 2.5 mg/kg rapacuronium, and succinylcholine groups and significantly longer in the mivacurium group (62, 54, and 54 s, respectively, vs. 112 s; P < 0.01). Clinical duration was longer in all groups compared with the succinylcholine group; however, clinical duration in the 1.5 mg/kg rapacuronium group was shorter compared with the mivacurium group (15 vs. 21 min, respectively; P < 0.01). Heart rate changes were mild in the 1.5 mg/kg rapacuronium, succinylcholine, and mivacurium groups. The patients in the 2.5 mg/kg rapacuronium group had significantly higher heart rates compared with patients in the mivacurium group. No differences were found in blood pressure changes among patients in the four groups. CONCLUSIONS: Rapacuronium, 1.5 and 2.5 mg/kg, produced neuromuscular blockade as rapidly as succinylcholine and significantly faster than mivacurium. Although succinylcholine continued to show the shortest duration, 1.5 mg/kg rapacuronium used a rapid onset and a relatively short duration and may be considered an alternative to succinylcholine.

Modulation of norepinephrine release by ATP-dependent K(+)-channel activators and inhibitors in guinea-pig and human isolated right atrium.

OBJECTIVE: The aim of this study was to show, whether ATP sensitive K+ channels (KATP channels), are involved in the modulation of norepinephrine (NE) release from the sympathetic nerves innervating the guinea-pig and human right atrium. METHODS: The resting and stimulation-evoked release of [3H]norepinephrine ([3H]NE) was measured from the isolated guinea-pig and human right atrium and the effect of activators and inhibitors of ATP sensitive K+ channels was studied. RESULTS: Cromakalim (30-300 microM), a KATP channel-agonist decreased concentration-dependently the stimulation-evoked release of NE from the guinea-pig atrium, an effect, antagonized by glibenclamide, a KATP channel-antagonist (30 microM). Diazoxide (30-300 microM), another activator of the KATP channels reduced the resting release of NE, and also attenuated the evoked release at a single concentration (100 microM), and this latter action was also counteracted by glibenclamide (30 microM). Pinacidil, increased dose-dependently the resting and stimulation-evoked release of NE in a glibenclamide-sensitive manner and reversed the inhibitory effect of cromakalim (100 microM), suggesting that it acts as an antagonist. Glibenclamide (30-300 microM), by itself enhanced the stimulation-evoked release of [3H]NE, and also increased the resting release of NE. On the other hand, 5-hydroxydecanoate, an ischemia-selective inhibitor of cardiac KATP channels did not change NE release. Adenosine, (30-300 microM), an A1-receptor agonist, clonidine (3 microM), an alpha 2-adrenoceptor agonist and oxotremorine, a muscarinic receptor agonist (30 microM) all reduced the evoked release of [3H]NE, but these effects were not modified by glibenclamide (300 microM), indicating that neuronal adenosine (A1), adrenergic (alpha 2) and muscarinic (M3) receptors do not act on KATP channels. In the human right atrium, cromakalim, and diazoxide did not affect significantly the release of [3H]NE. However, glibenclamide (30-300 microM) and pinacidil (30-300 microM) enhanced dose-dependently the evoked-release of NE, and pinacidil also augmented the resting release. CONCLUSIONS: Our results indicate that sympathetic nerve endings of the human and guinea-pig atrium are endowed with ATP-sensitive K+ channels. These channels responded to agonists and antagonists under the experimental conditions applied and they could modulate the release of NE thereby affecting the autonomic control of cardiac function under various physiological and pathophysiological conditions.

[Neostigmine and edrophonium. Antagonism of profound and shallow mivacurium blockade]. / Neostigmin und Edrophonium. Antagonisierung einer tiefen und oberflächlichen Mivacuriumblockade.

UNLABELLED: Mivacurium has a short duration of action because it is rapidly hydrolysed by plasma cholinesterase. There is ongoing controversy concerning the antagonism of mivacurium-induced neuromuscular block, firstly because of its short spontaneous recovery time, and secondly because the metabolism of mivacurium may be inhibited by anticholinesterases. We therefore compared neostigmine and edrophonium reversal of deep and moderate mivacurium-induced blocks. METHODS: After approval by the local ethics committee, 48 ASA class I and II adult patients were investigated during nitrous oxide-fentanyl-thiopental anaesthesia using train-of-four (TOF) stimulation and monitoring of the isometric force of adduction of a thumb. The patients received 0.2 mg/kg mivacurium i.v. Neuromuscular transmission was allowed to recover spontaneously in 10 patients (group SP). In 2 other groups the neuromuscular block was antagonised by administration of 0.04 mg/kg neostigmine (group N5; n = 9) or 1.0 mg/kg edrophonium (group E5; n = 10) when T1 had recovered spontaneously to 5% of control. In two other groups the neuromuscular block was antagonised with the same doses of neostigmine or edrophonium in 10 patients (group N25) and 9 patients (group E25), respectively, when T1 had recovered spontaneously to 25% of control. RESULTS: Neostigmine or edrophonium administered when T1 had recovered spontaneously to 25% of control shortened the recovery time (time from administration of ant-agonist to a T4/T1-ratio of 0.7) significantly from 10.7 +/- 2.2 min (mean +/- SD) in the SP group to 5.1 +/- 2.0 and 5.3 +/- 1.5 min in the N25 and E25 groups, respectively (P < 0.05). The corresponding recovery times in the SP, N5, and E5 groups were 15.9 +/- 2.9, 10.0 +/- 1.9, and 7.7 +/- 2.2 min, respectively. The difference between the SP and E5 groups was significant (P < 0.05). The recovery indices (time from 25% to 75% recovery of T1) of 3.0 +/- 1.3 and 1.7 +/- 0.9 min for the E5 and E25 groups, respectively, were shorter than those of the SP group at 6.1 +/- 2.0 min (P < 0.05). CONCLUSIONS: Two theoretical reasons, the very rapid onset time and the fact that it does not inhibit plasma cholinesterase, suggest edrophonium to be the preferred antagonist of a mivacurium-induced blockade. These two characteristics are reflected in our results: only edrophonium was able to shorten the recovery index significantly and, administered at a profound level of mivacurium-induced neuromuscular block, only edrophonium was successful in shortening recovery time significantly. Therefore, edrophonium should be the anticholinesterase of choice to antagonise a mivacurium-induced neuromuscular block.

Effects of adenosine on norepinephrine and acetylcholine release from guinea pig right atrium: role of A1-receptors.

The effect of adenosine or its stable analogues (2-chloroadenosine, CADO: 5'-N-ethyl-carboxamidoadenosine, NECA; and N6-cyclopentyladenosine, CPA) and a non-selective A1 and A2-receptor antagonist, 8-phenyltheophylline (8-PT), or an A1-receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), on the stimulation-evoked release of [3H]norepinephrine ([3H]NE) and [3H]acetylcholine ([3H]ACh) from the isolated guinea pig right atrium was investigated. Adenosine and its stable analogues (CADO, NECA and CPA) inhibited the stimulation-evoked release of [3H]NE in a concentration-dependent manner. The order of potencies was CPA > NECA > CADO > adenosine. CGS 21680 (30 nM), an A2a receptor agonist, failed to affect the release. The inhibitory effect of adenosine and CADO on [3H]NE release was competitively antagonized by 8-PT. DPCPX also prevented the effect of adenosine (Kd = 5.2 nM) and CADO (Kd = 3.3 nM). The Kd value of 8-PT was 0.40 microM for the antagonism of CADO and 0.51 microM for the antagonism of adenosine. When the negative feedback modulation of NE release was inhibited by idazoxan, the inhibitory effect of adenosine and CADO on [3H]NE release was more pronounced. Under this condition DPCPX (10 nM) prevented the inhibitory effect of CADO, indicating that A1-purinoceptors are involved in this action. The release of [3H]NE is tonically modulated by ACh release from the vagal nerve endings, as evidenced by the finding that 4-diphenylacetoxy-N-methyl-piperidine methiodide (4-DAMP), a M3-subtype selective muscarinic receptor antagonist, and atropine significantly enhanced the release of NE. Adenosine, its stable analogues (CADO and NECA), and 8-PT inhibition was eliminated by atropine, adenosine and CADO did not have any effect on [3H]ACh release. Quinpirole, a selective D2-receptor agonist, and neuropeptide Y (NPY) failed to affect the release of ACh. However, atropine and 4-DAMP, a selective M3-receptor antagonist, significantly enhanced the stimulation-evoked release of [3H]ACh. These findings indicate that there are no presynaptic heteroceptors (adenosine, D2, and NPY) on the vagal nerve endings of the guinea pig right atrium. It is concluded that the sympathetic nerve endings of the guinea pig right atrium are equipped with A1-, subclass of purinoceptors and alpha 2B-, and muscarinic (M3)-receptors. Cholinergic vagal nerve endings in the heart are only equipped with muscarinic autoreceptors. Therefore, adenosine liberated during hypoxia inhibits NE release from the cardiac sympathetic nerve and thereby protects against tachyarrhythmia caused by myocardial hypoxia. In contrast, adenosine does not inhibit the vagal innervation of the right atrium.

The pharmacodynamics of rocuronium in pediatric patients anesthetized with halothane.

The aim of this study was to determine the neuromuscular blocking potency of rocuronium (ORG 9426) in 4-to 14-year old children anesthetized with halothane. After induction of anesthesia, the ulnar nerve was stimulated with electrical impulses of 0.2 ms duration every 12 s and the force of contraction of the thumb (P) was continuously recorded. Doses of 0.12, 0.16, 0.20, and 0.24 mg·kg(-1) rocuronium were administered, in a randomized fashion, to 4 groups of 12 patients each. The ED50, ED90, and ED95 of rocuronium determined from the log dose-probit regression lines were 0.18, 0.34, and 0.40 mg·kg(-1), respectively. To facilitate tracheal intubation, after the development of the maximal effect of the first dose, a variable second dose of rocuronium was administered to increase the total dose to 0.3 mg·kg(-1). If after the second dose P was greater than 10% of control, additional 0.025-0.1 mg·kg(-1) increments of rocuronium were administered until P became less than 10% of control. At this time the trachea was intubated. Muscular relaxation was maintained with 0.075, 0.1, or 0.125 mg·kg(-1) rocuronium, administered whenever P recovered to 25% of control. The clinical duration of these doses was 6.9±2.8, 6.1±0.4, and 8.1±0.6 min, respectively. On repeated administration of three 0.1 or 0.125 mg·kg(-1) doses, rocuronium showed little cumulative tendency. Time for spontaneous recovery of P from 25% to 75%, 8.4±0.39 min and from 10% to 90%, 16.19±0.15 min, of control, were relatively short. When at termination of anesthesia T4/T1 ratios were lower than 0.75, the residual neuromuscular block could be antagonized with 0.5 mg·kg(-1) edrophonium in 2 min. Rocuronium, 0.3 mg·kg(-1) caused a 13.5% increase of heart rate but had no effect on blood pressure. In conclusion, in 4 to 14-year-old children, rocuronium appears to have a more rapid onset and shorter duration of action than other steroid-type muscle relaxants.

[Anesthesia before and after curare]. / Anästhesie vor und nach Curare.

Before the advent of curare, muscular relaxation essential for upper abdominal and intrathoracic surgery adequate operating conditions, could only be provided by deep ether or cyclopropane anaesthesia. The required depth of anaesthesia frequently caused severe cardiovascular depression, metabolic and respiratory acidosis and alteration of kidney and liver function. Ether, and especially cyclopropane sensitized the heart to the development of arrhythmias and the danger of explosion was never far away. For fear of anaesthetic mortality essential, life saving operations were often abandoned in poor risk patients. The administration of anaesthesia was more an art, mastered by relatively few, than a science that could be taught to many. It is a tribute to the early masters of anaesthesiology that they were able to carry their patients through the dangers associated with the provision of anaesthesia for major surgical procedures, with relatively low morbidity and mortality. The introduction of curare into anaesthetic practice, by Griffith and Johnson, in 1942, caused profound changes in the efficacy and safety of anaesthesiology. It made possible the development of true balanced anaesthesia, and the elimination of the explosive inhalation anaesthetics and the profound metabolic disturbances associated with their use. The concept of "inoperability," due to severe pathology or extremes of age became obsolete. It would be hard to envisage how open heart, organ transplant and radical brain and cranio-facial surgery could have developed without muscle relaxants.(ABSTRACT TRUNCATED AT 250 WORDS)

Presynaptic A1-purinoceptor-mediated inhibitory effects of adenosine and its stable analogues on the mouse hemidiaphragm preparation.

1. The effect of adenosine or its stable analogues (2-chloroadenosine, CADO; 5'-N-ethylcarboxamidoadenosine, NECA; and N6-cyclopentyladenosine, CPA) on the release of [3H]-acetylcholine ([3H]-ACh), and on the development of force of contraction evoked by electrical stimulation of the nerve, were studied in the mouse phrenic nerve-hemidiaphragm preparation. Evidence was obtained that the release of ACh is subject to presynaptic modulation through presynaptic A1(P1)-purinoceptors. 2. Adenosine or its stable analogues (CADO, NECA, CPA) inhibited, in a concentration-dependent manner, both the release of ACh and the force of the indirectly elicited contraction of hemidiaphragm preparation, provided in the latter case that the margin of safety was reduced by (+)-tubocurarine or magnesium. The order of potency in reducing ACh release was CPA greater than NECA greater than CADO greater than adenosine with IC50 values of 0.08 +/- 0.01, 0.74 +/- 0.05, 9.05 +/- 0.20, and 410.2 +/- 42.5 mumol/l, respectively. The order of potency in reducing twitch tension was CPA greater than NECA greater than CADO greater than adenosine with IC50 values of 0.11 +/- 0.02, 0.48 +/- 0.03, 2.07 +/- 0.49, and 240.4 +/- 20.0 mumol/l, respectively. 3. 8-Phenyltheophylline (8-PT) antagonized the inhibitory effects of the adenosine receptor agonists on ACh release and twitch tension.(ABSTRACT TRUNCATED AT 250 WORDS)

Facilitation of rapid-sequence intubation with large-dose vecuronium with or without priming.

STUDY OBJECTIVES: To determine the effect of priming on the intubation and onset times of vecuronium 0.3 mg/kg. DESIGN: Randomized, unblinded study. SETTING: Operating rooms and postanesthetic recovery unit of a university-affiliated general hospital. PATIENTS: Thirty female ASA physical status I and II patients scheduled for intraperitoneal surgery divided into two groups of 15 each. INTERVENTIONS: Anesthesia was induced and maintained with sufentanil, droperidol, thiopental sodium, and nitrous oxide in oxygen. Patients in Group 1 were given vecuronium 0.015 mg/kg 4 minutes before induction and vecuronium 0.285 mg/kg 1 minute after induction. Patients in Group 2 received a single 0.3 mg/kg dose of vecuronium 1 minute after thiopental sodium. The ulnar nerve was stimulated every 10 seconds with train-of-four supramaximal impulses of 0.2 millisecond duration at 2 Hz. The compound electromyogram (EMG) of the adductor pollicis was continuously recorded. The trachea was intubated when the amplitude of the EMG decreased to 15% to 25% of control. At the end of surgery, residual neuromuscular block was reversed with edrophonium 0.75 mg/kg. MEASUREMENTS AND MAIN RESULTS: All patients in Group 1 could be intubated in 80 seconds or less, and the longest onset time was 120 seconds. In Group 2, the longest intubation time was 140 seconds, and the longest onset time was 200 seconds. Clinical durations in both groups were unpredictable, ranging from 47 to 185 minutes in Group 1 and from 63 to 160 minutes in Group 2. Ten of the 30 patients required an additional 0.5 mg/kg of edrophonium for antagonism of the residual neuromuscular block. There were no significant changes in heart rate or blood pressure attributable to vecuronium. CONCLUSIONS: Seventy-five percent to 85% neuromuscular block of the adductor pollicis, required for atraumatic tracheal intubation, developed in 80 seconds or less when vecuronium 0.3 mg/kg was administered in divided doses and in 140 seconds or less when it was injected as a single bolus dose. Clinical duration of vecuronium 0.3 mg/kg is long and unpredictable, and reversal of residual neuromuscular block may require larger doses of anticholinesterases. It is recommended that an intubating dose of vecuronium 0.3 mg/kg be used only in patients undergoing long surgical procedures that require prolonged postanesthetic mechanical ventilation.

The neuromuscular effects of ORG9426 in patients receiving balanced anesthesia.

In searching for a nondepolarizing muscle relaxant with intermediate duration but more rapid onset of action than the presently available compounds, the neuromuscular and circulatory effects of ORG9426 were investigated in two studies in humans receiving fentanyl, droperidol, thiopental, and nitrous oxide-oxygen anesthesia. Eighty patients, randomly assigned to one of four groups of 20 each, received 0.12, 0.16, 0.20, or 0.24 mg/kg ORG9426. In the first study, the doses (in milligrams per kilogram) of ORG9426 that caused 50% (ED50), 90% (ED90), or 95% (ED95) neuromuscular block were determined by the individual dose-response method; they were 0.170, 0.268, and 0.305 mg/kg, respectively. In the second study, after induction of anesthesia, patients received 0.6 mg/kg (about 2 x ED95) of ORG9426, either in a single bolus (group 1) or in two unequal (0.1 and 0.5 mg/kg) increments 4 min apart (group 2). After the administration of 0.6 mg/kg ORG9426, maximal neuromuscular block developed in 1.5 +/- 0.12 min in group 1 and in 1.2 +/- 0.14 min in group 2. Patients tracheas were intubated after development of the maximal neuromuscular effect of the intubating dose and after the recording of heart rate and systolic and diastolic blood pressure. There was no difference in the clinical duration of the intubating doses, which were 40.0 +/- 3.2 (15-73) min in group 1 and 39.3 +/- 2.4 (19-57) min in group 2.(ABSTRACT TRUNCATED AT 250 WORDS)

Presynaptic interaction between vagal and sympathetic innervation in the heart: modulation of acetylcholine and noradrenaline release.

It is generally accepted that there is a functional antagonism between the sympathetic and parasympathetic (vagal) effects on the heart. In this study guinea-pig right atria loaded either with [3H]noradrenaline or [3H]choline were used and the release of [3H]noradrenaline or [3H]acetylcholine in response to field stimulation was measured under conditions when the negative feedback modulation was excluded. Strong evidence was obtained for a one-sided interaction between the sympathetic and vagal nerves at the level of the prejunctional axon terminals that send the final chemical message to the heart muscle affecting heart rate and force. Acetylcholine released from the vagal nerve inhibited its own release and also decreased the release of noradrenaline from the sympathetic axon terminals through muscarinic receptor stimulation. But muscarinic receptors located on cholinergic axon terminals are different from those present on the noradrenergic axon terminals. There is a significant difference in the dissociation constants (Kd) of different antimuscarinic drugs: The Kd values of pancuronium on vagal and sympathetic axon terminals were 5.68 +/- 0.41 and 7.20 +/- 0.25, respectively. By contrast, noradrenaline released from the sympathetic nerves or exogenous noradrenaline were not able to modulate the release of acetylcholine from the cholinergic axon terminals even under condition when the negative feedback modulation of acetylcholine release was excluded. These findings indicate that vagal axon terminals are not equipped with alpha 2- or alpha 1-adrenoceptors. However, noradrenaline released from the sympathetic axon terminals was able to inhibit its own release via alpha 2-adrenoceptor stimulation.

Pain control with intrathecally and peridurally administered opioids and other drugs.

Sharp pain is conducted rapidly by myelinated delta A fibers and diffused pain slowly by nonmyelinated C fibers to pseudobipolar neurons in the posterior ganglion and from there to neurons located in the posterolateral horn of the spinal cord. From here on nociferous impulses are transmitted by excitatory peptides (e.g. substance P) or amino acids (e.g. glutamate, aspartate) through interconnecting neurons of the pain pathways, primarily on the contralateral side, to the brain stem and from there to the sensory cortex, where they are appreciated and acted upon. There are specific inhibitory receptors located on axon terminals, near to the release sites of the excitatory amino acids and peptides. Stimulation of these receptors by their appropriate ligands such as endogenous (e.g. enkephalis, endorphins) or exogenous opioids, clonidine, serotonin, somatostatin inhibits the release of excitatory neurotransmitters and relieves pain. There are at least 3 different opioid receptors, called mu-, kappa- and delta-receptors in the spinal cord. These can be differentiated from one another by their specific affinity toward different endogenous or exogenous opioids and the pure narcotic antagonist, naloxone. It appears that the nociferous impulses transmitted by parallel pathways equipped with different inhibitory receptors have to be integrated to produce pain sensation and partial inhibition of transmission in different pathways or complete inhibition in one of the pathways may relieve pain. In recent years the concept of "selective spinal analgesia" has been applied clinically for the relief of postoperative, obstetrical and chronic pain. At first it was expected that the intrathecal or peridural administration of morphine will produce analgesia without the side effects of systemically administered morphine. It soon became evident, however, that intrathecally and peridurally administered morphine after several hours of delay reaches the fourth ventricle and by stimulating mu-receptors may cause respiratory depression and other undesired effects (e.g. nausea, vomiting, pruritus). Several different approaches are being investigated for the production of selective spinal analgesia without side effects. They include: a. the use of more lipophilic, long-lasting opioids (e.g. lofentanil) which would be almost completely absorbed by the spinal cord and therefore would not reach the medullary centers; b. the development of opioids with specific affinity to kappa- and for delta- and little or no affinity to mu-receptors, primarily responsible for side effects; and c. combining lower doses of opioid agonists with alpha 2-adrenergic agonists (e.g. clonidine) or with somatostatin. It is conceivable that in the not-too-distant future, it will be possible to achieve through these measures, selective spinal analgesia without side effects.

The pre- and postjunctional components of the neuromuscular effect of antibiotics.

The relative contributions of the pre- and postsynaptic components of the myoneural blocking effect of different antibiotics were studied using: (a) a radio-active method that measures selectively the Ca(2+)-dependent, stimulation evoked, quantally released, (3)H-acetylcholine ((3)H-ACh) from the mouse in vitro phrenic nerve-hemidiaphragm preparation without cholinesterase inhibition; (b) measurement of the force of contraction of the indirectly or directly stimulated muscle. The antibiotics studied (neomycin, polymyxin B and lincomycin), reduced the release of (3)H-ACh evoked by stimulation (18 trains of 40 shocks at 50 Hz) in a concentration dependent manner. While the inhibitory effect of neomycin was inversely related to [Ca(2+)](o), that of lincomycin was moderately and that of polymyxin B was not affected by increasing [Ca(2+)](o) from 0.75 to 5.0 mM. Similarly, the d-tubocurarine (d-Tc)-induced inhibition of the release of (3)H-ACh was independent of [Ca(2+)](o). The K-channel blocking agent, 4-aminopyridine (4-AP), enhanced the release of ACh in a concentration dependent manner and prevented the neuromuscular effect of neomycin. However, the neuromuscular effect of polymyxin B and of lincomycin was not affected by 4-AP. Atropine, enhanced the release of (3)H-ACh. Antibiotics, however, were still able to reduce the release of ACh when the negative muscarinic feedback mechanism of ACh release was eliminated by atropine. Our findings indicate that the antibiotics studied possess both pre- and postsynaptic effects. Presynaptically they reduce the evoked release of ACh; postsynaptically they inhibit muscle contractility. The rank order of presynaptic action is neomycin >polymyxin B >lincomycin.

Neuromuscular and cardiovascular effects of pipecuronium.

Pipecuronium bromide (Arduan) is a bisquaternary, steroid-type neuromuscular blocking agent in clinical use in Eastern Europe. Before its introduction into clinical practice in the USA, in the first phase of this study the neuromuscular potency of pipecuronium was determined under "balanced" and enflurance anaesthesia by the cumulative log dose-response method in 30 patients each. In the second phase the intubation and onset times, clinical duration of the first and repeated doses, spontaneous recovery index, reversibility of its residual neuromuscular effect by an anticholinesterase and its effect on heart rate and blood pressure was compared with the same variables observed in patients, anaesthetized with identical techniques but who had received vecuronium or pancuronium. The neuromuscular potency of pipecuronium was greater under enflurane (ED95 = 23.6 +/- 1.1 micrograms.kg-1 (mean +/- SEM)] than under balanced (ED95 = 35.1 +/- 17 micrograms.kg-1) anaesthesia. Pipecuronium was more potent than vecuronium under both balanced (ED95 = 45.8 micrograms.kg-1) and enflurane anaesthesia (ED95 = 27.4 micrograms.kg-1). Following the administration of 2 x ED95 doses there were no clinically significant differences in the intubation or onset times of pipecuronium, vecuronium and pancuronium. Under balanced anaesthesia the clinical duration of 2 x ED95 dose of pipecuronium (110.5 +/- 0.3 min) or pancuronium (115.8 +/- 8.1 min) were similar and about three times longer than that of vecuronium (36.3 +/- 2.1 min). The recovery indices of pipecuronium (44.5 +/- 8.2 min) and pancuronium (41.3 +/- 4.2 min) were also similar and about three times longer than that of vecuronium (14.3 +/- 1.4 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of mobilization of acetylcholine: the weak link in neuromuscular transmission during partial neuromuscular block with d-tubocurarine.

The authors have demonstrated earlier, by direct measurement of acetylcholine (ACh), that d-tubocurarine (d-Tc) and other nondepolarizing muscle relaxants decrease the release of ACh from the indirectly stimulated mouse hemidiaphragm preparation. It was the purpose of the present study to determine whether the decrease of the stimulated release of ACh and the increase in the intensity of the partial neuromuscular block observed at higher stimulation rates is caused by the inhibition of mobilization of ACh from reserve depots to release sites or by inhibition of the release process itself. To attain our objective, the authors have investigated the influence of the progressive increase of the rate of stimulation from 0.1 to 1, 2, 3, and 5 Hz on the force of contraction on the in vitro phrenic nerve-hemidiaphragm and in vivo sciatic nerve-tibialis anterior preparation in the absence of drugs and after about 20% neuromuscular block produced by d-Tc or by Mg2+. The latter is known to inhibit the Ca2+ dependent release of ACh. In the absence of drugs increasing the stimulation rate increased the force of contraction, in vivo and in vitro, during both indirect and direct stimulation. In the phrenic nerve-hemidiaphragm preparation the increase was significant at 1, 2, 3, and 5 Hz (P less than 0.001) with both types of stimulation. In the sciatic nerve-tibialis anterior preparation the force of contraction was only higher at 3 and 5 Hz (P less than 0.01). The similar magnitude of the increase of the force of contraction during direct and indirect stimulation indicates that it is caused by facilitation of the contraction of the muscle fibers.(ABSTRACT TRUNCATED AT 250 WORDS)

Species variation in the site and mechanism of the neuromuscular effects of diadonium in rodents.

The unusually wide, 80-fold species variation observed by others (1,2) in the neuromuscular (NM) potency of diadonium, a nondepolarizing muscle relaxant (MR), between cat and man suggested that the site and mechanism of its NM effect may vary in different species. To obtain information on this question, the NM potency of diadonium and the reversibility of its NM effect by neostigmine and/or 4-aminopyridine (4AP) was investigated on the in vitro phrenic nerve--hemidiaphragm preparations of rats, mice and guinea pigs. The concentration of diadonium that caused 90% NM block (IC90) was much greater in guinea pigs, 1.74 +/- 0.02 and 1.28 +/- 0.01 mu, when the preparations were stimulated with single stimuli at 0.1 Hz or with 0.1 s trains of 50 Hz tetani every 10 s, respectively, than in rats (IC90 = 62.4 +/- 0.89 and 52.1 +/- 1.00 microM) or mice (IC90 = 51.9 +/- 0.98 and 44.4 +/- 0.22 microM). In guinea pigs, the NM blocking effect of diadonium could be antagonized by neostigmine. This indicates that in this species the NM blocking effect of diadonium is primarily caused by inhibition of the interaction of acetylcholine (ACh), released by the nerve impulse, with the cholinergic receptors (cholinoceptors) of the postjunctional membrane (p.j.m.). By contrast, in rats and mice diadonium was not antagonized by neostigmine but was reversed by 4-aminopyridine. This suggests that in these species, in contrast to other nondepolarizing MR, diadonium does not inhibit NM transmission postsynaptically, but by inhibiting the positive nicotinic feedback mechanism of mobilization of ACh from reserve depots to release sites, causes a presynaptic NM block.(ABSTRACT TRUNCATED AT 250 WORDS)

In vitro comparison of the neuromuscular antinicotinic and intestinal antimuscarinic effects of different nondepolarizing muscle relaxants.

The postsynaptic antimuscarinic properties of different nondepolarizing muscle relaxants were compared with their postsynaptic antinicotinic effect. d-Tubocurarine, pipecuronium and vecuronium were the most selective antagonists on postsynaptic nicotinic receptors. Gallamine, diadonium and Duador (RGH-4201) had relatively greater effect on postsynaptic muscarinic receptors. Therefore, much less side effect is expected to occur when pipecuronium, d-tubocurarine or vecuronium are used.

The influence of temperature and calcium concentration on the myoneural effect of antibiotics.

To obtain information on the sites and mechanisms of the myoneural effect of aminoglycoside and polypeptide type antibiotics, the influence of neomycin, streptomycin, gentamicin and polymyxin B on the depression of the force of contraction (P) of the rat phrenic nerve-hemidiaphragm preparation was investigated at 37 degrees C, 27 degrees C or 17 degrees C and also at 37 degrees C in electrolyte solutions containing 2.5, 1.25 or 0.625 mM CaCl2. Decreasing the temperature or the CaCl2 concentration ((CaCl2)o) of the bath significantly (p less than 0.001) decreased P. The depressant effect of aminoglycosides on P (about 50% of control at 17 degrees C) was increased more with lower temperatures than that of polymyxin B (about 20%). The effect of lowering the (CaCl2)o on the depression of P (about 90% of control at the lowest (CaCl2)o) was about the same with the 4 antibiotics. The development of the maximal effect and the recovery of P after washout was slower with polymyxin B than with the 3 aminoglycosides. 4-Aminopyridine antagonized the depression of P caused by polymyxin B less than that caused by aminoglycosides. The findings suggest that aminoglycosides depress myoneural activity primarily by inhibiting stimulated release of ACh. Polymyxin B also inhibits ACh release, but inhibition of the contraction of myofibrils contributes more significantly to its myoneural effects than with aminoglycosides. It is conceivable that blocking of the ionophores of the postjunctional membrane also contributes to the myoneural effects of polymyxin B.

Heterogeneity of presynaptic muscarinic receptors involved in modulation of transmitter release.

In order to extend the characterization of muscarinic receptors at presynaptic sites their inhibitory effect on the stimulation-evoked release of [3H]noradrenaline and [3H]acetylcholine from different axon terminals was studied and the dissociation constants and potencies of different antagonists were estimated, in guinea-pig and rat. While oxotremorine reduced the release of [3H]acetylcholine and [3H]-noradrenaline in a concentration-dependent manner from different release sites (Auerbach plexus, noradrenergic neurons in the right atrium, cerebral cortex), McN-A 343, an M1 receptor agonist, enhanced their release evoked by field stimulation. When the inhibitory effect of oxotremorine on transmitter release was studied, pancuronium, pirenzepine and atropine were competitive antagonists of presynaptic muscarinic receptors located on the noradrenergic axon terminals of the atrium. While atropine and pirenzepine inhibited the muscarinic receptors of cholinergic axon terminals in the Auerbach plexus, pancuronium and gallamine had a very low affinity. Significant differences were found in the affinity constants of antagonists for muscarinic receptors located in the cholinergic axon terminals of Auerbach plexus and cerebral cortex, and noradrenergic axon terminals of the atrium. While atropine and pirenzepine exerted similar effects on these presynaptic sites, pancuronium, gallamine and (11-(2-[diethylamino)-methyl)-1-piperidinyl)acetyl)-5, 11-dihydro-6(1-pyrido(2,3-b)(1,4)-benzodiazepin-6-on) were much more effective on muscarinic receptors controlling acetylcholine release from the cerebral cortex and noradrenaline release from the heart. There was more than 100-fold (2.0 pA2 units) difference in affinities of these antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)