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COMPARATIVE INVESTIGATIONS ON THE CARDIOVASCULAR EFFECTS OF ORG NC45 AND PANCURONIUM IN DOGS
Br. J. Anaesth. (1983), 55, 641
COMPARATIVE INVESTIGATIONS ON THE CARDIOVASCULAR EFFECTS OF ORG NC45 AND PANCURONIUM IN DOGS S. FlTZAL, H . GlLLY AND W . ILIAS
Cardiovascular effects of non-depolarizing neuromuscular blocking drugs are important, especially in the anaesthetic management of patients with cardiac disease. It has been shown that Org NC45 (3a, 17 0-diacetoxy-2 0,16 0-dipiperidino-5a androstane 16 fi-N monometho-bromide) has minimal effects on the cardiovascular system in the experimental animal (Booij et al., 1980) and in clinical practice (Lienhart et al., 1981; Morris etal., 1981; Barnes et al., 1982). A clinical dose of Org NC45 produced neither vagolytic activity (Lee Son and Waud, 1980) nor an inhibition of the neuronal and extraneuronal uptake of noradrenaline (Salt, Barnes and Conway, 1980). However, the direct effects of Org NC45 on myocardial contractility have not been studied extensively. The present study was undertaken to examine the direct effects of Org NC 45 on the inotropic state of the myocardium, using an animal model which enabled us to differentiate between systemic and "pure" cardiac effects. The results obtained following administration of Org NC 45 were compared with those following pancuronium, a neuromuscular blocker with a similar chemical structure but which is known to increase cardiac activity (Kelman and Kennedy, 1971; Coleman et al., 1972). MATERIALS AND METHODS Seven mongrel dogs (weight 16-32 kg) were anaesthetized with a-chloralose 100 mg kg" 1 . Anaesthesia S. FrrzAL, M.D.; H. Gnxv, PH.D.; W. ILJAS, M.D.; Klinik fur Anaesthesie und Allgemeine Intensivmedizin der Universitat Wien, Spitalgasse 23, A-1090 Wien, Osterreich.
was maintained with a-chloralose 25-40 mg kg"' h" 1 . Endotracheal intubation was performed without the use of any neuromuscular blocking drug and ventilation, with nitrous oxide and oxygen (2:1), was controlled to maintain normocapnia (PCO2 4.7-5.3kPa). Arterial Po2, PCO2 and pH were measured throughout each experiment (Corning 168 automatic blood-gas analyser) and corrected for body temperature. Acidosis present before the beginning of the experiment was corrected with sodium bicarbonate. Po2 was maintained at about 20.0 kPa. During the experiment, lactated Ringer's solution was administered at a rate of 5 ml kg" 1 h" 1 . After the insertion of appropriate catheters and calibration of the transducers (before and after the experiment) with a mercury manometer, the following haemodynamic variables were recorded continuously: ECG, heart rate (HR), arterial pressure in the aortic arch (AP), pulmonary artery pressure (PAP), central venous pressure (CVP), left ventricular pressure (LVP), left ventricular end-diastolic pressure (LVEDP) and left ventricular dP/dt max. Correct positioning of all implanted catheters, including one inserted from the internal carotid artery into the left coronary artery, was confirmed by angiography. The zero reference point was taken at the level of the right atrium and adjusted before every measurement. Cardiac output (CO) was determined in triplicate by a respiration-triggered thermodilution technique (Cardiotherm 500; KMA, injection temperature 10 ± 2 °C). Total peripheral resistance (TPR), stroke volume (SV), end-systolic volume/100 g left ventricle (ESV) © The Macmillan Press Ltd 1983
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Cardiovascular effects of Org NC 45 and pancuronium were examined in seven anaesthetized dogs. Systemic circulatory effects were measured 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 neuromuscular blocking agent, which produced 90% neuromuscular blockade. Org NC 45 i.v. did not cause any significant cardiovascular changes, whereas pancuronium i.v. produced significant and dose-related increases in heart rate, left ventricular (LV) dP/dtmax and cardiac output (CO). After i.e. injection of equipment doses, neither drug induced any significant change in haemodynamic measurements. This implies that neither drug exerted a direct influence on cardiac contractility, the increases in LV dP/dr max and CO following pancuronium being dependent on heart rate.
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(Bretschneider et al., 1972), end-diastolic TABLE I. Maximal neuromuscular blockade (NB) following ORG volume/100 g left ventricle (EDV) and ejection frac- NC 45 0.025, 0.05 and 0.1 mgkg'' and pancuronium 0.015, 0.03 and 0.06mgkg (meant SEM) tion (EF) were calculated. The weight of the left ventricle was established by applying the formula of Pancuronium OrgNC45 Benirschke, Garner and Jones (1978). For control NB (»=7) NB (» = 7) purposes, the heart and left ventricle were also (mgkg ') (mgkg ) weighed postmortem. 89±1.4 0.015 19.8±5.2 0.025 The exposed peroneal nerve was stimulated with 100 0.03 91.3±2.0 0.05 rectangular pulses of supramaximal voltage for 0.06 100 100 0.1 0.2 ms and 0.1 Hz using a bipolar electrode to quantify the extent and duration of neuromuscular blockade. The resulting twitches of the right tibial muscle were monitored by attaching its tendon to a strainHaemodynamic effects of equipotent doses ofOrgNC gauge transducer; resting tension was adjusted to 45 (0.025mgkg~') and pancuronium (0.03mgkg~') 30-40 g. The paw was fixed to a special splint at two i.v. HR increased significantly from 104.5±9.9 sites by inserting a Kirschner wire through the tibial to 121.1 ±8.6beatmin~ 1 after pancuronium tuberosity and placing an adjustable sling around CP<0.05), whereas Org NC 45 had no effect. CO the forefoot. increased from 116.4± 12.8 to 137.1 ± 19.7mlkg"1 After control values had been determined, each (P<0.05) and LV dP/dt max increased slightly animal received Org NC 45 and pancuronium, first (P<0.05) after pancuronium; both these variables into the left coronary artery (i.e.) and later i.v. At remained unchanged with Org NC 45. Neither drug the beginning of the experiment, both drugs were had any effect on systolic, diastolic or mean arterial, given i.e. to each animal, alternately, in doses re- or left ventricular, pressures. Following the adlated to the weight of the left ventricle (equivalent to ministration of pancuronium, SV decreased slightly Org NC45 0.025 mg k g 1 or pancuronium 0.03 and TPR significantly (P< 0.05), whereas with Org mgkg" 1 i.v. There was a 30-min interval between NC 45, SV and TPR remained unchanged. Neither injections to ensure that there were no residual cardiac volumes (ESV and EDV) nor EF were influeffects of either substance on the heart. The particu- enced by the two drugs. Changes in the pulmonary lar drug administered first to each animal was cho- circulatory system were not statistically different sen randomly. After another 30-min interval both following either agent. LVEDP was decreased by drugs were injected i.v. in random sequence, start- both drugs (n.s.), the trend being more pronounced ing first with Org NC45 0.025, 0.05 and 0.1 with pancuronium. mg kg"1 and then pancuronium 0.015,0.03 and 0.06 Haemodynamic changes after Org NC 45 and panmgkg-' or vice versa. Each increasing dose was curonium i.v. at three doses (figs 1,2). Org NC 45 i.v. withheld until the twitch had returned to its base- did not cause any significant cardiovascular line value, and cardiovascular measurements had changes, whereas even the smallest dose of panstabilized at their baseline values for at least 15 min. curonium i.v. (inducing about 20% twitch depresMeasurements were carried out at 2, 5, 10 and 20 sion) (table I) caused a significant increase in HR min after i.v. administration of the respective ( P < 0.05) and a minor, but significant, increase in neuromuscular blocking agent (after i.e. administ- LV dP/dt max (P< 0.05). Following the two larger ration the intervals were 2, 5 and 10 min). All data doses of pancuronium, changes in HR and LV dP/dt were compared for statistical significance using Stu- max became more pronounced and CO increased dent's t test for paired samples. significantly (P< 0.05). Cardiac volumes, EDV and ESV decreased from 56 ±2.2 ml/100 g to RESULTS 50.2 +1.8 ml/100 g (P< 0.001) and from Table I summarizes the extent of maximum 33.5±1.8ml/100gto31.5±1.6ml/100g(P<0.05) 1 neuromuscular blockade effected by the three dif- respectively after pancuronium 0.06mgkg" . Simiferent i.v. doses of Org NC 45 and pancuronium. lar changes were not found with Org NC 45. From these data, it may be concluded that Org NC Haemodynamic effects of i.e. injection of equipotent 45 0.025mgkg"' and pancuronium O.OSmgkg"1 doses of Org NC 45 and pancuronium (table II). are equipotent and induce about 90% neuromusc- Neither drug altered any of the measured or calcuular blockade. lated variables.
CARDIOVASCULAR EFFECTS OF ORG NC45 AND PANCURONIUM Org NC45(n.7)
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FIG. 1. Changes in heart rate (HR), and mean arterial pressure (MAP^ after pancuronium 0.015mgkg , 0.03 mgkg" 1 and 0.06mgkg" i.v. and after Org NC 45 0.025mgkg" ,0.05mgkg" 1 and 0.1 mgkg" i.v. Values are Mean ± SD. Pancuronium
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FIG. 2. The effect of pancuronium and Org NC 45 after three different i.v. doses on cardiac output (CO) and left ventricular (LV) dP/dtmax.
Downloaded from http://bja.oxfordjournals.org/ at University of Birmingham on June 8, 2015
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DISCUSSION
Under the controlled conditions used during the experiments, it can be assumed that the changes
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recorded were caused by the drugs tested. The neuromuscular blockers were administered i.e. in doses strictly comparable to concentrations reached
CARDIOVASCULAR EFFECTS OF ORG NC45 AND PANCURONIUM
However, Org NC 45, irrespective of dose and type of application, did not induce any changes in HR or systemic pressures nor were there any variations in LV dP/drmax. We may conclude, therefore, that Org NC 45 administered in normal clinical doses does not induce any vagolytic activity and this has been confirmed in other clinical and experimental studies (Durant, Marshall and Savage, 1979; Marshall et al., 1980; Lee Son, Waud and Waud, 1981). Moreover, there was no evidence of a direct inotropic action on the myocardium. Equipotent doses of Org NC 45 and pancuronium were determined and a potency ratio of 1.2 (0.03/0.025) calculated, which is less than the figures arrived at by Fahey and colleagues (1981) and Booij and co-workers (1980).
REFERENCES
Barnes, P. K., Brindle-Smith, G., White, W. D., and Tennant, R. (1982). Comparison of the effects of Org NC 45 and pancuronium bromide on heart rate and arterial pressure in anaesthetized man. Br. J. Anaath., 54,435. Benirschke, K., Garner, F. M., and Jones, F. C. (1978). Pathology of Laboratory Animals, Vol. I, p. 6. Berlin, Heidelberg, New York: Springer.
Booij, L. H. D. J., Edwards, R. P., Sohn, Y. J., and Miller, R. D. (1980). Cardiovascular and neuromuscular effects of Org NC 45, pancuronium, metocurine and d-rubocurarine in dogs. Anath. Analg., 1,26. Bretschneider, H. J., Martel, J., Hellige, G., Hensel, I., and Kettler, D. (1972). Korrclation des endsystolischen Ventrikelvolumens pro Gewichtseinheit (ESV/lOOg) zu Potenzfunktionen des arteriellen Druckes (P) und der ventrikularen Druckanstiegsgeschwindigkeit (dp/dfmax). Verh. Dach. Ga. Kreislauffonch., 38, 233. Coleman, A. J., Downing, J. W., Leary, W. P., Moyes, D. G., and Styles, M. (1972). The immediate cardiovascular effects of pancuronium, alcuronium, and tubocurarine in man. Anaathtsia, 4,415. Domenech, J. S., Garcia, R. C , Sasiain, J. M. R., Loyola, A. Q., and Oroz, J. S. (1976). Pancuronium bromide: an indirect sympathomimetic agent. Br. J. Anaath.,48,1143. Durant, N. N., Marshall, I. G., and Savage, D. S. (1979). The neuromuscular and autonomic blocking activities of pancuronium, Org NC 45, and other pancuronium analogues in the cat. / . Pharm. Pharmacol., 31, 831. Fahey, M. R., Morris, R. B., Miller, R. D., Sohn, Y. J., Cronelly, R., and Gencarelli, P. (1981). Clinical pharmacology of Org NC 45 (Norcuron): A new non-depolarizing muscle relaxant. Anttthaiology, 55, 6. Foldes, F. F., Klonymus,D.H.,Maisel, W., Sciammas, F.,and Pan, T. (1971). Studies of pancuronium in conscious and anesthetized man. Anathaiology, 35,496. Kelman, G. R., and Kennedy, B. R. (1971). Cardiovascular effects of pancuronium in man. Br. J. Anaath., 43, 335. Lee Son, S., Waud, B. E., and Waud, D. R. (1981). Comparison of the neuromuscular blocking and vagolytic effects of Org NC 45 and pancuronium. Anathaiology, 55, 12. Waud, D. R. (1980). Effects of non-depolarizing neuromuscular blocking agents on the cardiac vagus nerve in the guinea pig. Br. J. Anaath., 52, 981. Lienhart, A., Guggiari, M., Tauvent, A., and Viars, P. (1981). Cardiovascular effects of Org NC 45 in man. Acta Anaathaiol. ScW.,25,(Suppl.)72. Loh, L. (1970). The cardiovascular effects of pancuronium bromide. Anaathaia, 25, 356. Marshall, R. J., McGrath, J. C , Miller, R. D., Docherty, J. R., and Lamar, J. C. (1980). Comparison of the cardiovascular actions of Org NC 45 with those produced by other nondepolarizing neuromuscular blocking agents in experimental animals. Br. J. Anaath., 52,21. Miller, R. D., Eger, E. I., Stevens, W. C , and Gibbons, R. (1975). Pancuronium-induced tachycardia in relation to alveolar halothane, dose of pancuronium, and prior atropine. Anathaiology, 3, 352. Morris, R. B., Wilkinson, P. L., Miller, R. D., Cahalan, M., Quasha, A., and Robinson, S. (1981). Cardiovascular effects of Org NC 45 (Norcuron) in patients undergoing coronary artery bypass grafting. Anathaiology, 55, A2O5. Parmentier, P., and Dagnelie, P. (1979). Dose-related tachycardia induced by pancuronium during balanced anaesthesia with and without droperidol. Br. J. Anaath., 51,157. Salt, P. J., Barnes, P. K., and Conway, C. M. (1980). Inhibition of neuronal uptake of noradrenaline is the isolated perfused rat heart by pancuronium and its homologues, Org 6368, Org 726S and NC 45. Br. J. Anaath., 52, 313. Stoelting, R. K. (1972). The hemodynamic effects of pancuronium and d-rubocurarine in anesthetized patients. Anathaiology, 36, 612.
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during routine clinical application to detect possible specific actions on cardiac contractility. Under these circumstances, all indirect influences on dP/drmax, such as pre- and afterload as well as heart rate, were excluded and any inotfopic changes have to be ascribed to a direct influence of the drug itself. The fact that LV dP/df max remained unaltered after i.e. injection but increased after i.v. administration of pancuronium without change in arterial pressure, as observed also by Domenech and colleagues (1976) and Foldes and co-workers (1971), might be taken as proof of heart rate dependency, as was reported previously by Stoelting (1972). A direct enhancement of the inotropic state of the myocardium by pancuronium, as described by Loh (1970), may be discounted. Tachycardia observed in our study after i.v. administration of pancuronium was doserelated, and the same was true for the correlated increase in LV dP/df max. No dose-related increase in heart rate was observed following pancuronium by Miller and colleagues (1975) nor was it reported in the experimental study of Domenech and colleagues (1976). It was, however, described in a clinical investigation by Parmentier and Dagnelie (1979).
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RECHERCHES COMPARATIVES SUR LES EFFETS CARDIOVASCULAIRES DE L'ORG NC45 ET DU PANCURONIUM CHEZ LE CHIEN RESUME
VERQLEICHENDE ERFORSCHUNG DER KARDIOVASKULAREN EFFEKTE VON ORG NC45 U N D PANCURONIUM BEI HUNDEN ZUSAMMENFASSUNG
Bei sieben narkotisierten Hunden wurden die kardiovaskularen Effekte von Org NC45 und Pancuronium untersucht. Die systemischen Kreislaufeffekte wurden nach der Verabreichung ansteigender Dosen als einzelner i.v. Bolus gemessen. Die kardialen Effekte wurden nach der intrakoronaren Injektion aquivalenter Dosen der beiden Muskelrelaxantien zur Herbeifiihrung
INVESTIGACION COMPARATIVA DE LOS EFECTOS CARDIOVASCULARES DEL ORG NC45 Y DEL PANCURONIO EN PERROS SUMAR1O
Se examinaron los efectos cardiovascularcs del Org NC45 y del pancurohio en siete perros anestesiados. Se midieron los efectos circulatorio sistemicos despues de aumentar las dosis administradas como un solo bolo intravenoso. Se midieron los efectos cardiacos despues de la inyeccion intracoronaria (i.e.) de la dosis equivalente del respectivo agente de bloqueo neuromuscular, la cual produjo un bloqueo neuromuscular del 90%. La dosis de Org NC45 intravenosa no produjo cambio cardiovascular significativo, mientras que la de pancuronio produjo aumentos del ritmo cardiaco, max. dP/dr del ventriculo izquierdo (VI) y de la produccion cardiaca, que fueron significativos y en funcion de la dosis. Despues de la inyeccion i.e. de fuertes dosis, ninguna de las drogas Indujo cambio significativo alguno en las mediciones hemodinamicas. De esto se dexprende que ninguna de las drogas ejerci6 una influencia directa sobre la contractabilidad cardiaca, y que los incrementos dP/dt en el VI y de la capacidad cardiaca despues del pancuronio estuvieron en funcion del ritmo cardiaco.
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Les effets cardiovasculaires de l'Org NC45 et du pancuronium ont etc examines chez sept chiens anesthesies. Les effets circulatoires systemiques ont €ti mesures aprcs que l'on ait augmente les doses administrees en injection i.v. unique directe. Les effets cardiaques ont etc iflesures apres injection intracoronaire (i.cor.) de la dose de P,un on l'autre agent curarisant, equivalente a celle qui aurait produit uii bloc neiiromusculaire de 90%. L'Org NC45 i.v. ne produisit aucune modification cardiovasculaire significative alors que lc pancuronium i.v. produisit des augmentations significatives et dose-dipendantcs de la frequence cardiaque, de la dP/dr mar du vtntricule gauche (VG) et du debit cardiaque (Qc). Apres injection i.cor. de doses equipotentei, aucun des deux ageUts be provoqua de modifications signif icatives des parametres hemodynamiques. Ceci implique qu'aucun des deux agents n'exerce d'influence directe sur la contractilite du myocafde, raugWntation de la dP/drmax du VG et du Qc apres injection du pancuronium etant dependante de la frequence cardiaque.
90%iger neuromuskulirer Blockade gemessen. Org NC 45 f iihrte zu keinerlei signifikanten kardiovaskularen Veranderungen, wahrend Pancuronium einen signifikanten und dosisabhangigen Ansticg von Herzfrequenz, linksventnkularem maximalen Druckanstieg pro Zeit und Herzminutenvolumen verursachte. Nach intrakoronarer Injektion aquipotenter Dosen fuhrte keins der beiden Praparate zu signifikanten Veranderungen der hlmodynamischen Parameter. Dies impliziert, dafi kein Praparat direkten Einflufi auf die Herzkontraktilitat hat, sondern dafi der Anstieg des linksventrikularen dP/dt max und des Herzminutenvolumens bei Pancuronium Herzfrequenz-abhangig ist.
COMPARATIVE INVESTIGATIONS ON THE CARDIOVASCULAR EFFECTS OF ORG NC45 AND PANCURONIUM IN DOGS S. FlTZAL, H . GlLLY AND W . ILIAS
Cardiovascular effects of non-depolarizing neuromuscular blocking drugs are important, especially in the anaesthetic management of patients with cardiac disease. It has been shown that Org NC45 (3a, 17 0-diacetoxy-2 0,16 0-dipiperidino-5a androstane 16 fi-N monometho-bromide) has minimal effects on the cardiovascular system in the experimental animal (Booij et al., 1980) and in clinical practice (Lienhart et al., 1981; Morris etal., 1981; Barnes et al., 1982). A clinical dose of Org NC45 produced neither vagolytic activity (Lee Son and Waud, 1980) nor an inhibition of the neuronal and extraneuronal uptake of noradrenaline (Salt, Barnes and Conway, 1980). However, the direct effects of Org NC45 on myocardial contractility have not been studied extensively. The present study was undertaken to examine the direct effects of Org NC 45 on the inotropic state of the myocardium, using an animal model which enabled us to differentiate between systemic and "pure" cardiac effects. The results obtained following administration of Org NC 45 were compared with those following pancuronium, a neuromuscular blocker with a similar chemical structure but which is known to increase cardiac activity (Kelman and Kennedy, 1971; Coleman et al., 1972). MATERIALS AND METHODS Seven mongrel dogs (weight 16-32 kg) were anaesthetized with a-chloralose 100 mg kg" 1 . Anaesthesia S. FrrzAL, M.D.; H. Gnxv, PH.D.; W. ILJAS, M.D.; Klinik fur Anaesthesie und Allgemeine Intensivmedizin der Universitat Wien, Spitalgasse 23, A-1090 Wien, Osterreich.
was maintained with a-chloralose 25-40 mg kg"' h" 1 . Endotracheal intubation was performed without the use of any neuromuscular blocking drug and ventilation, with nitrous oxide and oxygen (2:1), was controlled to maintain normocapnia (PCO2 4.7-5.3kPa). Arterial Po2, PCO2 and pH were measured throughout each experiment (Corning 168 automatic blood-gas analyser) and corrected for body temperature. Acidosis present before the beginning of the experiment was corrected with sodium bicarbonate. Po2 was maintained at about 20.0 kPa. During the experiment, lactated Ringer's solution was administered at a rate of 5 ml kg" 1 h" 1 . After the insertion of appropriate catheters and calibration of the transducers (before and after the experiment) with a mercury manometer, the following haemodynamic variables were recorded continuously: ECG, heart rate (HR), arterial pressure in the aortic arch (AP), pulmonary artery pressure (PAP), central venous pressure (CVP), left ventricular pressure (LVP), left ventricular end-diastolic pressure (LVEDP) and left ventricular dP/dt max. Correct positioning of all implanted catheters, including one inserted from the internal carotid artery into the left coronary artery, was confirmed by angiography. The zero reference point was taken at the level of the right atrium and adjusted before every measurement. Cardiac output (CO) was determined in triplicate by a respiration-triggered thermodilution technique (Cardiotherm 500; KMA, injection temperature 10 ± 2 °C). Total peripheral resistance (TPR), stroke volume (SV), end-systolic volume/100 g left ventricle (ESV) © The Macmillan Press Ltd 1983
Downloaded from http://bja.oxfordjournals.org/ at University of Birmingham on June 8, 2015
Cardiovascular effects of Org NC 45 and pancuronium were examined in seven anaesthetized dogs. Systemic circulatory effects were measured 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 neuromuscular blocking agent, which produced 90% neuromuscular blockade. Org NC 45 i.v. did not cause any significant cardiovascular changes, whereas pancuronium i.v. produced significant and dose-related increases in heart rate, left ventricular (LV) dP/dtmax and cardiac output (CO). After i.e. injection of equipment doses, neither drug induced any significant change in haemodynamic measurements. This implies that neither drug exerted a direct influence on cardiac contractility, the increases in LV dP/dr max and CO following pancuronium being dependent on heart rate.
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(Bretschneider et al., 1972), end-diastolic TABLE I. Maximal neuromuscular blockade (NB) following ORG volume/100 g left ventricle (EDV) and ejection frac- NC 45 0.025, 0.05 and 0.1 mgkg'' and pancuronium 0.015, 0.03 and 0.06mgkg (meant SEM) tion (EF) were calculated. The weight of the left ventricle was established by applying the formula of Pancuronium OrgNC45 Benirschke, Garner and Jones (1978). For control NB (»=7) NB (» = 7) purposes, the heart and left ventricle were also (mgkg ') (mgkg ) weighed postmortem. 89±1.4 0.015 19.8±5.2 0.025 The exposed peroneal nerve was stimulated with 100 0.03 91.3±2.0 0.05 rectangular pulses of supramaximal voltage for 0.06 100 100 0.1 0.2 ms and 0.1 Hz using a bipolar electrode to quantify the extent and duration of neuromuscular blockade. The resulting twitches of the right tibial muscle were monitored by attaching its tendon to a strainHaemodynamic effects of equipotent doses ofOrgNC gauge transducer; resting tension was adjusted to 45 (0.025mgkg~') and pancuronium (0.03mgkg~') 30-40 g. The paw was fixed to a special splint at two i.v. HR increased significantly from 104.5±9.9 sites by inserting a Kirschner wire through the tibial to 121.1 ±8.6beatmin~ 1 after pancuronium tuberosity and placing an adjustable sling around CP<0.05), whereas Org NC 45 had no effect. CO the forefoot. increased from 116.4± 12.8 to 137.1 ± 19.7mlkg"1 After control values had been determined, each (P<0.05) and LV dP/dt max increased slightly animal received Org NC 45 and pancuronium, first (P<0.05) after pancuronium; both these variables into the left coronary artery (i.e.) and later i.v. At remained unchanged with Org NC 45. Neither drug the beginning of the experiment, both drugs were had any effect on systolic, diastolic or mean arterial, given i.e. to each animal, alternately, in doses re- or left ventricular, pressures. Following the adlated to the weight of the left ventricle (equivalent to ministration of pancuronium, SV decreased slightly Org NC45 0.025 mg k g 1 or pancuronium 0.03 and TPR significantly (P< 0.05), whereas with Org mgkg" 1 i.v. There was a 30-min interval between NC 45, SV and TPR remained unchanged. Neither injections to ensure that there were no residual cardiac volumes (ESV and EDV) nor EF were influeffects of either substance on the heart. The particu- enced by the two drugs. Changes in the pulmonary lar drug administered first to each animal was cho- circulatory system were not statistically different sen randomly. After another 30-min interval both following either agent. LVEDP was decreased by drugs were injected i.v. in random sequence, start- both drugs (n.s.), the trend being more pronounced ing first with Org NC45 0.025, 0.05 and 0.1 with pancuronium. mg kg"1 and then pancuronium 0.015,0.03 and 0.06 Haemodynamic changes after Org NC 45 and panmgkg-' or vice versa. Each increasing dose was curonium i.v. at three doses (figs 1,2). Org NC 45 i.v. withheld until the twitch had returned to its base- did not cause any significant cardiovascular line value, and cardiovascular measurements had changes, whereas even the smallest dose of panstabilized at their baseline values for at least 15 min. curonium i.v. (inducing about 20% twitch depresMeasurements were carried out at 2, 5, 10 and 20 sion) (table I) caused a significant increase in HR min after i.v. administration of the respective ( P < 0.05) and a minor, but significant, increase in neuromuscular blocking agent (after i.e. administ- LV dP/dt max (P< 0.05). Following the two larger ration the intervals were 2, 5 and 10 min). All data doses of pancuronium, changes in HR and LV dP/dt were compared for statistical significance using Stu- max became more pronounced and CO increased dent's t test for paired samples. significantly (P< 0.05). Cardiac volumes, EDV and ESV decreased from 56 ±2.2 ml/100 g to RESULTS 50.2 +1.8 ml/100 g (P< 0.001) and from Table I summarizes the extent of maximum 33.5±1.8ml/100gto31.5±1.6ml/100g(P<0.05) 1 neuromuscular blockade effected by the three dif- respectively after pancuronium 0.06mgkg" . Simiferent i.v. doses of Org NC 45 and pancuronium. lar changes were not found with Org NC 45. From these data, it may be concluded that Org NC Haemodynamic effects of i.e. injection of equipotent 45 0.025mgkg"' and pancuronium O.OSmgkg"1 doses of Org NC 45 and pancuronium (table II). are equipotent and induce about 90% neuromusc- Neither drug altered any of the measured or calcuular blockade. lated variables.
CARDIOVASCULAR EFFECTS OF ORG NC45 AND PANCURONIUM Org NC45(n.7)
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FIG. 2. The effect of pancuronium and Org NC 45 after three different i.v. doses on cardiac output (CO) and left ventricular (LV) dP/dtmax.
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DISCUSSION
Under the controlled conditions used during the experiments, it can be assumed that the changes
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recorded were caused by the drugs tested. The neuromuscular blockers were administered i.e. in doses strictly comparable to concentrations reached
CARDIOVASCULAR EFFECTS OF ORG NC45 AND PANCURONIUM
However, Org NC 45, irrespective of dose and type of application, did not induce any changes in HR or systemic pressures nor were there any variations in LV dP/drmax. We may conclude, therefore, that Org NC 45 administered in normal clinical doses does not induce any vagolytic activity and this has been confirmed in other clinical and experimental studies (Durant, Marshall and Savage, 1979; Marshall et al., 1980; Lee Son, Waud and Waud, 1981). Moreover, there was no evidence of a direct inotropic action on the myocardium. Equipotent doses of Org NC 45 and pancuronium were determined and a potency ratio of 1.2 (0.03/0.025) calculated, which is less than the figures arrived at by Fahey and colleagues (1981) and Booij and co-workers (1980).
REFERENCES
Barnes, P. K., Brindle-Smith, G., White, W. D., and Tennant, R. (1982). Comparison of the effects of Org NC 45 and pancuronium bromide on heart rate and arterial pressure in anaesthetized man. Br. J. Anaath., 54,435. Benirschke, K., Garner, F. M., and Jones, F. C. (1978). Pathology of Laboratory Animals, Vol. I, p. 6. Berlin, Heidelberg, New York: Springer.
Booij, L. H. D. J., Edwards, R. P., Sohn, Y. J., and Miller, R. D. (1980). Cardiovascular and neuromuscular effects of Org NC 45, pancuronium, metocurine and d-rubocurarine in dogs. Anath. Analg., 1,26. Bretschneider, H. J., Martel, J., Hellige, G., Hensel, I., and Kettler, D. (1972). Korrclation des endsystolischen Ventrikelvolumens pro Gewichtseinheit (ESV/lOOg) zu Potenzfunktionen des arteriellen Druckes (P) und der ventrikularen Druckanstiegsgeschwindigkeit (dp/dfmax). Verh. Dach. Ga. Kreislauffonch., 38, 233. Coleman, A. J., Downing, J. W., Leary, W. P., Moyes, D. G., and Styles, M. (1972). The immediate cardiovascular effects of pancuronium, alcuronium, and tubocurarine in man. Anaathtsia, 4,415. Domenech, J. S., Garcia, R. C , Sasiain, J. M. R., Loyola, A. Q., and Oroz, J. S. (1976). Pancuronium bromide: an indirect sympathomimetic agent. Br. J. Anaath.,48,1143. Durant, N. N., Marshall, I. G., and Savage, D. S. (1979). The neuromuscular and autonomic blocking activities of pancuronium, Org NC 45, and other pancuronium analogues in the cat. / . Pharm. Pharmacol., 31, 831. Fahey, M. R., Morris, R. B., Miller, R. D., Sohn, Y. J., Cronelly, R., and Gencarelli, P. (1981). Clinical pharmacology of Org NC 45 (Norcuron): A new non-depolarizing muscle relaxant. Anttthaiology, 55, 6. Foldes, F. F., Klonymus,D.H.,Maisel, W., Sciammas, F.,and Pan, T. (1971). Studies of pancuronium in conscious and anesthetized man. Anathaiology, 35,496. Kelman, G. R., and Kennedy, B. R. (1971). Cardiovascular effects of pancuronium in man. Br. J. Anaath., 43, 335. Lee Son, S., Waud, B. E., and Waud, D. R. (1981). Comparison of the neuromuscular blocking and vagolytic effects of Org NC 45 and pancuronium. Anathaiology, 55, 12. Waud, D. R. (1980). Effects of non-depolarizing neuromuscular blocking agents on the cardiac vagus nerve in the guinea pig. Br. J. Anaath., 52, 981. Lienhart, A., Guggiari, M., Tauvent, A., and Viars, P. (1981). Cardiovascular effects of Org NC 45 in man. Acta Anaathaiol. ScW.,25,(Suppl.)72. Loh, L. (1970). The cardiovascular effects of pancuronium bromide. Anaathaia, 25, 356. Marshall, R. J., McGrath, J. C , Miller, R. D., Docherty, J. R., and Lamar, J. C. (1980). Comparison of the cardiovascular actions of Org NC 45 with those produced by other nondepolarizing neuromuscular blocking agents in experimental animals. Br. J. Anaath., 52,21. Miller, R. D., Eger, E. I., Stevens, W. C , and Gibbons, R. (1975). Pancuronium-induced tachycardia in relation to alveolar halothane, dose of pancuronium, and prior atropine. Anathaiology, 3, 352. Morris, R. B., Wilkinson, P. L., Miller, R. D., Cahalan, M., Quasha, A., and Robinson, S. (1981). Cardiovascular effects of Org NC 45 (Norcuron) in patients undergoing coronary artery bypass grafting. Anathaiology, 55, A2O5. Parmentier, P., and Dagnelie, P. (1979). Dose-related tachycardia induced by pancuronium during balanced anaesthesia with and without droperidol. Br. J. Anaath., 51,157. Salt, P. J., Barnes, P. K., and Conway, C. M. (1980). Inhibition of neuronal uptake of noradrenaline is the isolated perfused rat heart by pancuronium and its homologues, Org 6368, Org 726S and NC 45. Br. J. Anaath., 52, 313. Stoelting, R. K. (1972). The hemodynamic effects of pancuronium and d-rubocurarine in anesthetized patients. Anathaiology, 36, 612.
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during routine clinical application to detect possible specific actions on cardiac contractility. Under these circumstances, all indirect influences on dP/drmax, such as pre- and afterload as well as heart rate, were excluded and any inotfopic changes have to be ascribed to a direct influence of the drug itself. The fact that LV dP/df max remained unaltered after i.e. injection but increased after i.v. administration of pancuronium without change in arterial pressure, as observed also by Domenech and colleagues (1976) and Foldes and co-workers (1971), might be taken as proof of heart rate dependency, as was reported previously by Stoelting (1972). A direct enhancement of the inotropic state of the myocardium by pancuronium, as described by Loh (1970), may be discounted. Tachycardia observed in our study after i.v. administration of pancuronium was doserelated, and the same was true for the correlated increase in LV dP/df max. No dose-related increase in heart rate was observed following pancuronium by Miller and colleagues (1975) nor was it reported in the experimental study of Domenech and colleagues (1976). It was, however, described in a clinical investigation by Parmentier and Dagnelie (1979).
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RECHERCHES COMPARATIVES SUR LES EFFETS CARDIOVASCULAIRES DE L'ORG NC45 ET DU PANCURONIUM CHEZ LE CHIEN RESUME
VERQLEICHENDE ERFORSCHUNG DER KARDIOVASKULAREN EFFEKTE VON ORG NC45 U N D PANCURONIUM BEI HUNDEN ZUSAMMENFASSUNG
Bei sieben narkotisierten Hunden wurden die kardiovaskularen Effekte von Org NC45 und Pancuronium untersucht. Die systemischen Kreislaufeffekte wurden nach der Verabreichung ansteigender Dosen als einzelner i.v. Bolus gemessen. Die kardialen Effekte wurden nach der intrakoronaren Injektion aquivalenter Dosen der beiden Muskelrelaxantien zur Herbeifiihrung
INVESTIGACION COMPARATIVA DE LOS EFECTOS CARDIOVASCULARES DEL ORG NC45 Y DEL PANCURONIO EN PERROS SUMAR1O
Se examinaron los efectos cardiovascularcs del Org NC45 y del pancurohio en siete perros anestesiados. Se midieron los efectos circulatorio sistemicos despues de aumentar las dosis administradas como un solo bolo intravenoso. Se midieron los efectos cardiacos despues de la inyeccion intracoronaria (i.e.) de la dosis equivalente del respectivo agente de bloqueo neuromuscular, la cual produjo un bloqueo neuromuscular del 90%. La dosis de Org NC45 intravenosa no produjo cambio cardiovascular significativo, mientras que la de pancuronio produjo aumentos del ritmo cardiaco, max. dP/dr del ventriculo izquierdo (VI) y de la produccion cardiaca, que fueron significativos y en funcion de la dosis. Despues de la inyeccion i.e. de fuertes dosis, ninguna de las drogas Indujo cambio significativo alguno en las mediciones hemodinamicas. De esto se dexprende que ninguna de las drogas ejerci6 una influencia directa sobre la contractabilidad cardiaca, y que los incrementos dP/dt en el VI y de la capacidad cardiaca despues del pancuronio estuvieron en funcion del ritmo cardiaco.
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Les effets cardiovasculaires de l'Org NC45 et du pancuronium ont etc examines chez sept chiens anesthesies. Les effets circulatoires systemiques ont €ti mesures aprcs que l'on ait augmente les doses administrees en injection i.v. unique directe. Les effets cardiaques ont etc iflesures apres injection intracoronaire (i.cor.) de la dose de P,un on l'autre agent curarisant, equivalente a celle qui aurait produit uii bloc neiiromusculaire de 90%. L'Org NC45 i.v. ne produisit aucune modification cardiovasculaire significative alors que lc pancuronium i.v. produisit des augmentations significatives et dose-dipendantcs de la frequence cardiaque, de la dP/dr mar du vtntricule gauche (VG) et du debit cardiaque (Qc). Apres injection i.cor. de doses equipotentei, aucun des deux ageUts be provoqua de modifications signif icatives des parametres hemodynamiques. Ceci implique qu'aucun des deux agents n'exerce d'influence directe sur la contractilite du myocafde, raugWntation de la dP/drmax du VG et du Qc apres injection du pancuronium etant dependante de la frequence cardiaque.
90%iger neuromuskulirer Blockade gemessen. Org NC 45 f iihrte zu keinerlei signifikanten kardiovaskularen Veranderungen, wahrend Pancuronium einen signifikanten und dosisabhangigen Ansticg von Herzfrequenz, linksventnkularem maximalen Druckanstieg pro Zeit und Herzminutenvolumen verursachte. Nach intrakoronarer Injektion aquipotenter Dosen fuhrte keins der beiden Praparate zu signifikanten Veranderungen der hlmodynamischen Parameter. Dies impliziert, dafi kein Praparat direkten Einflufi auf die Herzkontraktilitat hat, sondern dafi der Anstieg des linksventrikularen dP/dt max und des Herzminutenvolumens bei Pancuronium Herzfrequenz-abhangig ist.