COMPARATIVE POTENCY OF PIPECURONIUM BROMIDE AND PANCURONIUM BROMIDE

Cumulative dose-response curves were constructed to determinethe comparative potency of pipecuronium and pancuronium. Fromthese, the ED₅₀ and ED₉₅ values were calculated. These were24.96 g kg^–1 and 44.96 µg kg^–1, respectively,for pipecuronium and 30.42 µg kg^–1 and 61.12 µgkg^–1, respectively, for pancuronium.     

EFFECTS OF AGEING ON THE PHARMACOKINETICS OF PANCURONIUM

The effects of age on the pharmacokinetics of pancuronium wereinvestigated. The distribution volume of pancuronium did notappear to be age-dependent, but elimination of the drug decreasedwith increasing age. The clinical implications of these findingsare discussed. ^*Present address: Toowoomba General Hospital, Toowoomba, Queensland,Australia     

COMPARISON OF THE EFFECTS OF ORG NC45 AND PANCURONIUM BROMIDE ON HEART RATE AND ARTERIAL PRESSURE IN ANAESTHETIZED MAN

The effects of Org NC 45 and pancuronium bromide on heart rateand arterial pressure were studied in anaesthetized man A bolusof either Org NC450.12mg kg^–1 or pancuronium 0.1 mg kg^–1was administered to lightly anaesthetized unstunulated subjects.Following Org NC 45 heart rate decreased in the majority ofsubjects (mean and SEM 3.78 ± 1.36), whereas after pancuroniumheart rate was increased (mean and SEM 11.91 ± 1 9).The changes in mean arterial pressure observed were minimalThe effect of endotracheal intubation on mean arterial pressurewas then studied. Increase of mean arterial pressure was observedin all subjects. The increase was more marked in those patientswho had received pancuronium and was significantly higher thanm those patients who had received Org NC45 (P<0.01) We concludethat Org NC 45 is devoid of vagal blocking acoon, and that thedifference m response to the stimulus of endotracheal intubationis a result of the different effects exerted on the sympatheticnervous system by Org NC 45 and pancuronium. ^*Present addresses: Department of Anaesthetics, Kingston Hospital,Kingston upon Thames, Surrey. Present addresses: Department of Anaesthetics, Royal HampshireCounty Hospital, Winchester, Hants.     

EFFECTS OF ENFLURANE AND HALOTHANE ON CARNOHYDRATE METABOLISM IN ISOLATED PERFUSED RABBIT LUNGS

Isoloated, perfused rabbit lungs were used to investigate theeffects of enflurance and halothane on pulmonary carbohydratemetabolism. The developement of oedema in the preparation wasassessed by continuous measurement of pulmonary artery pressure,airway pressure and lung weight. Ventilation of the lungs with2% enflurane for 3 h had no effect on the rates of glucose utilizationand lactate production and there were only small changes inthe indices of oedema. Likewise, ventilation with 1% halothanefor 1 h had no effect on the rates of glucose utilization andlactate production, and did not change significantly the concentrationsof glycogen, glucose, glycolytic intermediates and high-energyphosphate compounds in lung tissue. Enflurane and halothane,at clinically relevant concentrations, probably do not influencecarbohydrate metabolism in the lung.     

COMPARISON OF THE EFFECTS OF PANCURONIUM AND TUBOCURARINE ON DIFFERENT MUSCLES OF YOUNG AND OLD MICE

In order to evaluate the sensitivity of different muscle typesto neuromuscular blocking drugs, a system using mouse musclesin vitro was developed and applied to detect changes in drugsensitivity in relation to age. The effect of pancuronium andtubocurarine on initial twitch and on the ratio of fourth twitchto first twitch (T4/T1) of a train-of-four at 2 Hz were comparedin fast-twitch, slow-twitch and respiratory muscles in the mouse.The muscles used were: extensor digitorum longus (EDL), soleus(SOL) and diaphragm (DIA). For both drugs the order of decreasingsensitivity was EDL > SOL > DIA. This result was the samewhether first twitch or T4/T1 was used, although the latterwas a more sensitive indicator. The sensitivity of neuromuscularblock was less in muscles from old (30–33 month) animalsthan in the equivalent muscles from young (8–12 month)animals.     

THE EFFECT OF HALOTHANE ON THE ISOLATED CAT HEART

The effect of The effect of halothane on the electrocardiogramrecorded from the isolated perfused cat heart is described.A halothane tension of between 7 and 14 mm Hg produced bradycardia,atrioventricular dissociation, nodal rhythm and finally asystole.Conditions of low oxygen tension and high carbon dioxide tensionproduced ventricular extrasystoles in isolated hearts exposedto halothane. It is suggested that this provides corroborativeevidence for the contention that the ventricular extrasystolesproduced by halothane in cats can occur independently of sympatho-adrenalactivity. Present address: National Nutrition Research Institute, SouthAfrican Council for Scientific and Industrial Research, P.O.Box 395, Pretorin, South Africa     

THE EFFECTS OF ATROPINE AND NEOSTIGMINE ON HEART RATE AND RHYTHM

Fifty patients anaesthetized with nitrous oxide-oxygen, supplementedby thiopentone and pethidine, thiopentone and halothane, ordroperidol and fentanyl, who received tubocurarine for the maintenanceof muscular relaxation were divided into five groups each often. At the end of anaesthesia, the patients of groups A andB received intravenously atropine 6 /ig/kg and neostigmine 20yug/kg, those in groups C and D atropine 12 /fg/kg and neostigmine40 /ig/kg, and those in group E atropine 8 /ig/kg and neostigmine20 /ig/kg. In groups A and C atropine was injected in 60 secondsand was followed 1 minute later by neostigmine also administeredin 60 seconds. In groups B, D, and E atropine and neostigminewere injected together in 60 seconds. Reversal of residual neuromuscularblock was achieved in all five groups without the developmentof any serious arrhythmias. Statistically significant tachycardiadeveloped only in those groups (A and C) in which atropine wasinjected 2 minutes before the administration of neostigmine.Of the different dosages and sequences of administration investigated,the combined injection of atropine 6 /tg/kg and neostigmine20 /tg/kg over 60 seconds appears to be most suitable for thereversal of residual neuromuscular block.     

DIFFERENTIAL EFFECTS OF SEX HORMONES AND PHYTOESTROGENS ON PEAK AND STEADY STATE CONTRACTIONS IN ISOLATED RABBIT DETRUSOR

PURPOSE: Recent evidence suggests that sex steroids may produce rapid inhibition of voltage operated Ca2+ channels (VOCCs). Detrusor smooth muscle is highly dependent upon Ca2+ influx for receptor-activated contractions. Thus, we examined the relative effectiveness of a select group of sex steroids and dietary phytoestrogens to relax detrusor contracted with the muscarinic receptor agonist, bethanechol (BE) and the purinergic P2X receptor agonist, alpha,beta-methylene ATP (alpha,beta-MeATP). MATERIALS AND METHODS: Isolated strips of rabbit detrusor were secured to isometric force transducers in a tissue bath and length-adjusted until maximum contractions were achieved. Peak (P) contractile responses were recorded for alpha,beta-MeATP (P(ATP)) and BE (P(BE)) and steady-state (SS) responses were recorded for BE (SS(BE)) in the presence and absence of selected sex steroids and phytoestrogens (10 microM, unless indicated). RESULTS: The L-type VOCC inhibitor, nifedipine (1 to 10 microM), completely inhibited P(ATP) but reduced SS(BE) by approximately 50%, whereas the VOCC and non-VOCC inhibitor, SKF 96365, inhibited SS(BE) by approximately 95%, suggesting that P(ATP) was entirely dependent on L-type VOCCs, but (BE)-induced contractions depended also on activation of non-VOCCs. 17Beta-estradiol (estradiol) and progesterone inhibited P(ATP) by approximately 60% and 20%, respectively, and 32 microM estradiol and ethinyl estradiol inhibited SS(BE) by approximately 80 and 95%, respectively. Inhibition by estradiol was potentiated, rather than blocked, by the nuclear estrogen receptor antagonist, tamoxifen. Moreover, tamoxifen alone nearly completely relaxed SS(BE). The inactive metabolite of estradiol, 17alpha-estradiol, inhibited both P(ATP) and P(BE) by approximately 40%. Testosterone had no effect on P(ATP) and P(BE). The phytoestrogen and tyrosine kinase inhibitor, genistein, inhibited SS(BE) by 44%, whereas daidzein, a phytoestrogen without tyrosine kinase inhibitory activity, produced only a 7% inhibition. None of the phytoestrogens examined inhibited P(BE), whereas all inhibited P(ATP) by approximately 20 to 35%. A comparison of inhibition of (BE) and alpha,beta-MeATP-induced contractions by selected estrogen isomers showed some distinct differences. For example, estrone did not inhibit P(BE) or SS(BE), but inhibited P(ATP) by approximately 20%, whereas DES inhibited SS(BE) by nearly 90%, but P(ATP) by a lesser degree (approximately 70%). CONCLUSIONS: Our data support the hypothesis that 17beta-estradiol, ethinyl estradiol, DES, tamoxifen and genistein may relax detrusor contractions by inhibition of both VOCCs and non-VOCCs. Moreover, our data show that genistein, a dietary phytoestrogen with tyrosine kinase inhibitory activity, selectively reduced alpha,beta-MeATP-induced peak and BE-induced steady-state contractions, sparing the maximum response to BE. Lastly, the inactive isomer, 17alpha-estradiol, inhibited both BE- and alpha,beta-MeATP-induced contractions. These data suggest that certain dietary phytoestrogens (for example, genistein) or sex steroids, especially those with weak activity at the nuclear steroid site (for example, 17alpha-estradiol), or tamoxifen may prove therapeutically useful in treating overactive bladder caused by elevated muscarinic and purinergic receptor activation.     

COMPARATIVE INVESTIGATIONS ON THE CARDIOVASCULAR EFFECTS OF ORG NC45 AND PANCURONIUM IN DOGS

Cardiovascular effects of Org NC 45 and pancuronium were examinedin seven anaesthetized dogs. Systemic circulatory effects weremeasured after increasing doses administered as a single i.v.bolus. Cardiac effects were measured after intracoronary (i.e.)injection of the equivalent dose of the respective neuromuscularblocking agent, which produced 90% neuromuscular blockade. OrgNC 45 i.v. did not cause any significant cardiovascular changes,whereas pancuronium i.v. produced significant and dose-relatedincreases in heart rate, left ventricular (LV) dP/dt max andcardiac output (CO). After i.e. injection of equipment doses,neither drug induced any significant change in haemodynamicmeasurements. This implies that neither drug exerted a directinfluence on cardiac contractility, the increases in LV dP/drmax and CO following pancuronium being dependent on heart rate.     

COMPARATIVE EFFECTS OF PIPECURONIUM AND TUBOCURARINE ON PLASMA CONCENTRATIONS OF HISTAMINE IN HUMANS

We have examined the effects of a rapid bolus dose of pipecuronium0.1 mg kg^–1 or tubo-curarine 0.5mg kg^–1 on plasmahistamine concentration, heart rate and arterial pressure in20 patients (n = 10 in each group). Anaesthesia was inducedwith thiopentone 6 mg kg^–1 i.v. and maintained with 70%nitrous oxide and halo-thane in oxygen. Neuromuscular blockingdrugs were administered 4 min after administration of thiopentone.Venous blood samples were obtained before induction, 1 min afterthiopentone and 1, 3 and 5 min after the administration of theneuromuscular blocking drugs. Tubocurarine caused 240% and 210%increases in plasma concentration of histamine at 1 and 3 min,respectively. These changes were significant (P < 0.05) at1 min and associated with a decrease in mean arterial pressureand an increase in heart rate. None of the 10 patients receivingpipecuronium had a significant change in plasma concentrationof histamine or in haemo-dynami variables. ^*Present addresses: Department of Anaesthesia, Al-Kasr El-AniHospital, Cairo University, Cairo, Egypt. Present addresses: Department of Pharmacology, Lund University,Lund, Sweden.     

THE EFFECTS OF DIFFERENT LEVELS OF VENTILATION ON THE ACTION OF PANCURONIUM IN MAN

The effect of changes of Pco₂, on the duration of action ofpancuronium was studied. No significant difference was foundbetween the recovery tunes of a group of 16 patients with amean Pco₂ of 38.1 mm Hg, and another group of 16 with a meanPco₂ of 23.8 mm Hg.     

HEART-VOLUME STUDIES II EFFECT OF VARIOUS ANAESTHETICS AND DRUGS ON THE HEART VOLUME IN THE RABBIT

Experimental heart-volume studies were made in the rabbit, using pneumopericardium as a plethysmograph for cardiometry during spontaneous respiration. A model was prepared with recording of respiration, systemic arterial pressure, heart volume, aortic flow and central venous pressure. The effect of various anaesthetics and drugs used in anaesthesia was studied. Ether, Fluothane, intravenous barbiturates, intravenous local anaesthetics and anoxia were found to have a negatively inotropic effect on the heart volume, with dilatation of the heart. Spinal anaesthesia, ganglion-blocking agents and muscular relaxants appeared to have only a minor or no demonstrable effect on the heart volume.

ZUSAMMENFASSUNG

Beim Kaninchen wurden experimentelle Herzvolumen-Untersuchungen durchgeführt, bei denen das Pneumopericard als Plethysmograph für die Cardiometrie während der Spontanatmung benützt wurde. Dabei wurden die nachfolgenden Grössen aufgezeichnet: Atmung, systemischer arterieller Blutdruck, Herzvolumen, Blutstrom in der Aorta und zentraler Venendruck. Es wurden die Wirkungen verschiedener Anaesthetika und von Medikamenten, die während der Narkose verwendet werden, untersucht. Dabei zeigte sich, dass Äther, Halothan, intravenöse Barbiturate, intravenös verabreichte Lokal-anaesthetika und Anoxie einen negativ inotropen Effekt auf das Herzvolumen mit Dilatation des Herzens hatten. Die Spinalanaesthesie, ganglienblockierende Mittel und Muskelrelaxantien schienen nur einen geringen oder keinen nachweisbaren Effekt auf das Herzvolumen zu haben.     

THE ACTION MECHANISM OF RELAXATION EFFECT OF ATROPINE ON THE ISOLATED RABBIT CORPUS CAVERNOSUM

PURPOSE: Atropine has been used to block cholinergic neurotransmission in basic research and has received recent interest clinically in the intracavernosal pharmacotherapy of erectile dysfunction. It has been suggested that at a low dose (10(-8) M), atropine blocks muscarinic receptors, and that at a large dose (10(-3) M), it induces the release of EDRF. However, no report has supported this idea experimentally. We tried to confirm the action of atropine in cavernosal tissue and define its mechanism. MATERIALS AND METHODS: Strips of rabbit corpus cavernosum were mounted in organ chambers. On the precontracted muscle strips with phenylephrine (PHE; 5 x 10(-6) M), atropine was treated with increasing concentration from 10(-11) M. The relaxing activity of atropine was observed in deendothelialized tissue and preparation with treatment with methylene blue (10(-4) M), pyrogallol (10(-4) M), NW-nitro-L-arginine (L-NNA; 3 x 10(-4) M) and indomethacin (10(-4) M). To evaluate the relationship of atropine to Ca++, the muscle strip was incubated in Ca++ free solution, and Ca++ induced contraction by addition of CaCl2 (10(-3) M) was recorded with atropine. Depolarization by KCl was observed with atropine to investigate the relationship of atropine relaxation to K+. RESULTS: On the precontracted muscle strip with PHE, atropine induced a dose-related contraction up to 10(-8) M and began to exert a relaxing effect at the concentration of 10(-7) M and reached the 93.6% relaxation effect at the concentration of 10(-4) M, causing dose-dependent relaxation. The relaxing effect of atropine was partially inhibited by endothelial disruption, and by pretreatment with methylene blue, pyrogallol, L-NNA, and indomethacin, although they were not statistically significant. At the basal state of muscle strips in Ca++ free solution, atropine decreased basal tension as well as inhibited the contraction induced by CaCl2 dose-dependently. However, atropine did not influence depolarization by KCl. CONCLUSIONS: Atropine has both a contraction effect at lower concentrations and a relaxation effect at higher concentrations on cavernosal smooth muscle. It is presumed that the relaxation at higher concentrations is mediated via increasing intracellular calcium sequestration, not by hyperpolarization or secretion of EDRF.     

EFFECTS OF DROPERIDOL ON THE VASOCONSTRICTION PRODUCED BY NORADRENALINE, HISTAMINE, SYMPATHETIC NERVE STIMULATION AND POTASSIUM IONS IN THE ISOLATED RABBIT AURICULAR ARTERY

Droperidol consistently blocked the vasoconstriction inducedby noradrenaline, histamine and sympathetic nerve stimulationin concentrations between 0.01 and 10 µg/ml in the isolatedrabbit auricular artery preparation. Vasoconstriction inducedby potassium ions was blocked in all concentrations of droperidolbut less at the highest concentration. It is postulated, thereforethat droperidol is a non-specific inhibitor of vasoconstrictionrather than a competitive alpha-adrenergic receptor blockingagent.     

EFFECTS OF PANCURONIUM AND ALCURONIUM ON THE CHANGES IN ARTERIAL PRESSURE AND PLASMA CATECHOLAMINE CONCENTRATIONS DURING TRACHEAL INTUBATION

The changes in the plasma concentrations of noradrenaline, adrenalineand dopamine, during tracheal intubation, were studied in 17patients. Nine patients received pancuronium and eight alcuroniumto produce neuromuscular blockade. In the patients receivingpancuronium, intubation of the trachea was accompanied by anincrease in mean arterial pressure, and in the plasma concentrationsof noradrenaline and adrenaline. In the alcuronium group, therewere no significant changes in the plasma concentrations ofany catecholamine, nor any change in mean arterial pressurein response to intubation of the trachea.     

PREJUNCTIONAL AND POSTJUNCTIONAL EFFECTS OF TUBOCURATINE AND PANCURONIUM IN MAN

The effects of small doses of tubocurarine and pancuronium onpeak tetanic tension and tetanie maintenance were compared.Forty patients undergoing elective orthopaedic procedured undergeneral anaesthesisa were studied. Changes in neuromusculartransmission were measured by recording the isometric contractionof the adductor pollicis muscle evoked by supramaximal stimulationof the ulnar nerve at the wrist. Small doses of pancuroniumaffected predominantly the peak tetanic tension, while smalldoses of tubocurarine affected mainly tetanic maintenance. Thus,different degrees of depression of peak tetanic tension andtetanic maintenance were observed with tubocurarine and pancuronium.This clinical study supports Bowman's hypothesis, based uponlaboratory findings in the cat, that prejunctional and postjunctionaleffects of neuromuscular blocking agents depend on their affinityfor cholinoceptors at different sites.     

CARDIAC EFFECTS OF VECURONIUM AND PANCURONIUM DURING HALOTHANE ANAESTHESIA

The cardiac effects of equipotent doses of pancuronium and vecuronium(Org NC 45) were compared in 20 patients, anaesthetized withhalothane. Heart rate and arterial pressure were recorded andthe systolic time intervals were evaluated from simultaneoustracings of ECG, phonocardiogram and carotid pulse curve. Pancuronium0.08 mg kg^–1 caused a significant increase in heart rate(20), insignificant changes in arterial pressure and significantchanges in systolic time intervals compatible with a minor positiveinotropic action. The equipotent dose of vecuronium (0.057 mgkg^–1) caused no significant changes in heart rate, arterialpressure or systolic time intervals.     

INHIBITION OF NEURONAL UPTAKE OF NORADRENALINE IN THE ISOLATED PERFUSED RAT HEART BY PANCURONIUM AND ITS HOMOLOGUES, ORG. 6368, ORG. 7268 AND NC 45

The cardiovascular effects of pancuronium may be caused partlyby an interaction of this drug with the sympathetic nervoussystem. We examined one possible mechanism of interaction, theeffect on the re-uptake processes for noradrenaline. Pancuroniumand its closely related steroidal homologues, Org. 6368, Org.7268 and NC 45, were studied at a high concentration (500 [imollitre^–1) for inhibition of the uptake of tritiated noradrenalineinto neuronal sites (Uptake₂) and extraneuronal sites (Uptake₁)in the isolated perfused rat heart. All drugs tested causedalmost total inhibition of Uptake₁ The bis-quaternary steroidspancuronium and Org. 6368 were selective for Uptaket inhibition,the mono-quaternary steroids Org. 7268 and NC45 also producedsignificant inhibition of Uptake. Uptake₁ inhibition was investigatedin detail using lesser concentrations of the compounds. Allfour steroids were found to cause a concentration-dependentinhibition of Uptake₁. It seems likely, therefore, that inhibitionof neuronal uptake of noradrenaline plays a significant rolein the aetiology of the chronotropic actions of pancuroniumin the rat. ^* Present address: Department of Anaesthetics, Bristol RoyalInfirmary, Bristol BS2 8HW