Abstract
Purpose
The bradycardia produced by neostigmine and edrophonium was examined according to its relation to cholinesterase inhibition and to its sensitivity to block by muscarinic receptor antagonists. For comparison, the ability of muscdrinic antagonists to block the bradycardia produced by electrical stimulation of the vagus nerve was determined.
Methods
Cats were anaesthetized, vagotomized and propranolol-treated. Heart rate was continuously recorded. Erythrocyte cholinesterase activity of arterial blood was measured using a radiometric technique. The right vagus nerve was isolated for electrical stimulation. The muscarinic antagonists used were atropine, glycopyrrolate, pancuronium, gallamine, and AFDX-116.
Results
Neostigmine produced a dose-dependent decrease in cholinesterase activity which, reached a plateau at a cumulative dose of 0.16 mg · kg−1 (ED50 0.009 ± 0.003 mg · kg−1). Neostigmine produced a dose-dependent decrease in heart rate with the. dose-response relationship (ED50 0.1 ± 0.01 mg · kg−1; P = 0.0006) shifted to the right of that for the inhibition of cholinesterase activity. In contrast to the anticholinesterase effect, the bradycardic effect did not reach a plateau and continued to increase even at doses at which the cholinesterase inhibition was maximal. The maximal decrease in heart rate when the heart was still in sinus rhythm was by 81 ± 13 bpm (49 ± 7% of baseline), which was produced by a dose of 0.32 mg · kg−1. Edrophonium produced dose-dependent decreases in cholinesterase activity and heart rate, which were highly correlated (correlation coefficient r = 0.99, P < 0.0001).The ED50 of the reduction in heart rate (0.9 ± 0.75 mg · kg−1) and cholinesterase activity (0.89 ± 0.12 mg · kg−1) produced by edrophonium were similar. Moreover, the reduction in heart rate and cholinesterase activity produced by edrophonium reached a plateau at the same dose (6.4 mg · kg−1). At this dose, heart rate decreased by 22 ± 2 bpm (14.6 ± 0.9% of baseline). Compared to the bradycardia produced by stimulation of the vagus nerve, that produced by neostigmine was blocked by muscarinic antagonists at significantly lower doses while that produced by edrophonium was blocked at similar doses.
Conclusions
The neostigmine-induced bradycardia is poorly correlated with cholinesterase inhibition compared to that produced by edrophonium, and has a higher sensitivity to muscarinic receptor antagonists compared to that produced by edrophonium or vagus nerve stimulation. These results are consistent with the hypothesis that the neostigmine-induced bradycardia is, in pari, the result of neostigmine directly activating cholinergic receptors within the cardiac parasympathetic pathway. The bradycardia produced by edrophonium may be accounted for solely by an anticholinesterase action.
Résumé
Objectif
La bradycardie produite par la néostigmine et l’édrophonium fait l’objet de cette communication qui s’intéresse spécifiquement à sa correlation avec l’inhibition cholinestérasique et l’effet des antagonistes des récepteurs muscariniques. Pour fin de comparaison, l’influence des antagonistes muscariniques sur le blocage de la bradycardie induite par la stimulation électrique du nerf vague a été déterminée.
Méthodes
Des chats étaient anesthésiés, vagotomisés et traités au propanolol. La fréquence cardiaque était enregistrée en continu. L’activité cholinestérasique érythrocytaire du sang artériel était mesurée par radiométrie. Le nerf vague droit était isolé pour la stimulation électrique. Les antagonistes muscariniqu.es suivants étaient utilisés: l’atropine, le glycopyrrolate, le pancuronium, la gallamine et l’AFDX-116.
Résultats
La néostigmine a produit une baisse proportionnelle à la dose de l’activité cholinestérasique qui a atteint un plateau à la dose cumulative de 0,16 mg · kg−1 (ED50 0,009 ±0,003 mg · kg−1). La néostigmine a provoqué une baisse proportionnelle à la dose de la fréquence cardiaque avec une relation dose-effet (ED50 0,1 ± 0,01 mg · kg−1; P = 0,0006) déviée à droite de celle de l’inhibition de l’activité cholinestérasique. Contrairement à l’effet anticholinestérasique, l’effet bradycardique n’a pas atteint de plateau et a continué d’augmenter même aux doses d’inhibition cholinestérasique maximale. La baisse maximale delà fréquence cardiaque en rythme sinusal a été de 81 ± 13 bpm (49 ± 7% de la ligne de base) et a été induite par une dose de 0,32 mg · kg−1. L’édrophonium a provoqué des baisses proportionnelles à la dose nettement corrélées de l’activité cholinestérasique et de la fréquence cardiaque, (coefficient de corrélation r = 0,99, P < 0,0001). L’ED50 de la baisse de fréquence cardiaque (0,9 ± 0,18 mg · kg−1) et celle de l’activité cholinestérasique (0,89 ± 0,12 mg · kg−1) produites par l’édrophonium étaient identiques. En outre, la baisse de la fréquence cardiaque et de l’activité cholinestérasique produite par l’édrophonium a atteint un plateau à une dose identique (6,4 mg · kg−1). A cette dose, la fréquence cardiaque a diminué de 22 ± 2 bpm (14,6 ± 0,9% de la ligne de base). Comparativement à la bradycardie produite par la stimulation vagale, la bradycardie produite par la néostigmine était bloquée par les antagonistes muscariniques à des doses plus faibles alors que celle produite par l’édrophonium était bloquée à des doses identiques.
Conclusions
La bradycardie induite par la néostigmine est en faible corrélation avec l’inhibition cholinestérasique comparativement à celle qui est produite par l’édrophonium, et est plus sensible aux antagonistes des récepteurs muscariniques comparativement à celle qui est produite par l’édrophonium ou la stimulation vagale. Ces résultats concordent avec l’hypothèse selon laquelle la bradycardie induite par la néostigmine est partiellement causée par l’activation directe de récepteurs cholinergiques empruntant la voie de conduction cardiaque parasympathique. La bradycardie produite par l’édrophonium peut s’expliquer uniquement par un effet anticholinestérasique.
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References
Hill M. Death after neostigmine injection (Letter). BMJ 1949; 2: 601.
Macintosh RR. Death following injection of neostigmine. BMJ 1949; 1: 852.
Backman SB, Bachoo M, Polosa C. Mechanism of the bradycardia produced in the cat by the anticholinesterase neostigmine. J Pharm Exp Ther 1993; 265: 194–200.
Brehm G, Lindmar R, Löffelholz K. Inhibitory and excitatory muscarinic receptors modulating the release of acetylcholine from the postganglionic parasympathetic neuron of the chicken heart. Naunyn Schmiedebergs Arch Pharmacol 1992; 346: 375–82.
Brown JH, Taylor P. Muscarinic receptor agonists and antagonists. In: Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Gilman AG (Eds.). Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 9th ed New York: McGraw-Hill, 1996: 141–60.
Mitchelson F. Muscarinic receptor differentiation. Pharmacol Ther 1988; 37: 357–423.
Morris RB, Cronnelly R, Miller RD, Stanski DR, Fahey MR. Pharmacokinetics of edrophonium and neostigmine when antagonizing d-tubocurarine neuromuscular blockade in man. Anesthesiology 1981; 54: 399–402.
Riker WF Jr, Wescoe WC. The direct action of prostigmine on skeletal muscle; its relationship to the choline esters. J Pharmacol Exp Ther 1946; 88: 58–66.
Pascoe JE. The effects of acetylcholine and other drugs on the isolated superior cervical ganglion. J Physiol 1956; 132: 242–35.
Long JP, Eckstein JW. Ganglionic actions of neostigmine methylsulfate. J Pharmacol Exp Ther 1961; 133: 216–22.
Mason DFJ. A ganglion stimulating action of neostigmine. Br J Pharmacol 1962; 18: 76–86.
Mason DFJ. Depolarizing action of neostigmine at an autonomic ganglion. Br J Pharmacol 1962; 18: 572–87.
Carlyle RF. The mode of action of neostigmine and physostigmine on the guinea-pig trachealis muscle. Br J Pharmacol 1963; 21: 137–49.
Takeshige C, Volle RL Asynchronous postganglionic firing from the cat superior cervical sympathetic ganglion treated with neostigmine. Br J Pharmacol 1963; 20: 214–20.
Kostowski W, Gumutka W. Actions of neostigmine and physostigmine on sympathetic ganglia in the cat. International Journal of Neuropharmacology 1966; 5: 193–8.
Mihara S, Ikeda K, Nishi S. Muscarinic M2 receptors on cardiac ganglion neurons of the guinea-pig heart. Kurume Med J 1988;35: 183–92.
Hoover DB, Baisden RH, Xi-Moy SX. Localization of muscarinic receptor mRNAs in rat heart and intrinsic cardiac ganglia by in situ hybridization. Circ Res 1994; 75: 813–20.
Allen TGJ, Burnstock G. M1 and M2 muscarinic receptors mediate excitation and inhibition of guinea-pig intracardiac neurons in culture. J Physiol 1990; 422: 463–80.
Dunlap J, Brown JH. Heterogeneity of binding sites on cardiac muscarinic receptors induced by the neuromuscular blocking agents gallamine and pancuronium. Mol Pharmacol 1983; 24: 15–22.
Brown JH, Wetzel GT, Dunlap J. Activation and blockade of cardiac muscarinic receptors by endogenous acetylcholine and cholinesterase inhibitors. J Pharm Exp Ther 1982; 223: 20–4.
Campbell GD, Edwards FR, Hirst GDS, O’Shea JE. Effects of vagal stimulation and applied acetylcholine on pacemaker potentials in the guinea-pig heart. J Physiol 1989; 415: 57–68.
De Wildt DJ, Oud PHJH, Porsius AJ. The inotropic and chronotropic effects of physostigmine and neostigmine on guinea-pig isolated atria. J Auton Pharmacol 1982; 2: 111–7.
Cronnelly R, Morris RB, Miller RD. Edrophonium: duration of action and atropine requirement in humans during halothane anesthesia. Anesthesiology 1982; 57: 261–6.
Fogdall RP, Miller RD. Antagonism of d-tubocurarineand pancuronium-induced neuromuscular blockades by pyridostigmine in man. Anesthesiology 1973; 39: 504–9.
Backman, SB, Fox, GS, Stein, RD, Ralley, FE. Neostigmine decreases heart rate in heart transplant patients. Can J Anaesth 1996; 43: 373–8.
Backman SB, Ralley FE, Fox GS. Neostigmine produces bradycardia in a heart transplant patient. Anaesthesiology 1993; 78: 777–9.
Backman SB, Stein RD, Fox GS, Polosa C. Effect of edrophonium on heart rate in cardiac transplant patients and in the denervated cat heart. Can. J Anaesth 1996; 43: (in press).
Ramamurthy S, Ylagan LB, Winnie AP. Glycopyrrolate as a substitute for atropine: a preliminary report. Anesth Analg 1971; 50: 732–6.
Mirakhur RK, Dundee JW, Clarke RSJ. Glycopyrrolateneostigmine mixture for antagonism of neuromuscular block: comparison with atropine-neostigmine mixture. Br J Anaesth 1977; 49: 825–9.
Salem MG, Richardson JC, Meadows GA, Lamplugh G, Lai KM. Comparison between glycopyrrolate and atropine in a mixture with neostigmine for reversal of neuromuscular blockade. Br J Anaesth 1985; 57: 184–7.
Orduro KA. Glycopyrrolate methobromide. 2. Comparison with atropine sulphate in anaesthesia. Can Anaesth Soc J 1975; 22: 466–73.
Ostheimer GW. A comparison of glycopyrrolate and atropine during reversal of nondepolarizing neuromuscular block with neostigmine. Anesth Analg 1977; 56: 182–6.
Meyers EF, Tomeldan SA. Glycopyrrolate compared with atropine in prevention of the oculocardiac reflex during eye-muscle surgery. Anesthesiology 1979; 51: 350–2.
Mirakhur RK, Dundee JW, Jones CJ, Goppel DL, Clarke RSJ. Reversal of neuromuscular blockade: dose determination studies with atropine and glycopyrrolate given before or in a mixture with neostigmine. Anesth Analg 1981; 60: 557–62.
Abboud T, Raya J, Sadri S, Grobler N, Stine L, Miller F. Fetal and maternal cardiovascular effects of atropine and glycopyrrolate. Anesth Analg 1983; 62: 426–30.
Preiss D, Berguson P. Dose-response studies on glycopyrrolate and atropine in conscious cardiac patients. Br J Clin Pharmacol 1983; 16: 523–7.
Berger J, Gravenstein J, van der Aa J, Paulus L, Sabah-Maren E, Mclaughlin G. Comparative potency of atropine sulphate and glycopyrrolate on heart rate in man. Eur J Anaesthesiol 1988; 5: 23–30.
Green DW, Bristow ASE, Fisher M. Comparison of i.v. glycopyrrolate and atropine in the prevention of bradycardia and arrhythmias following repeated doses of suxamethonium in children. Br J Anaesth 1984; 56: 981–4.
Ali-Melkkila T, Kaila T, Antila K, Halkola L, Iisalo E. Effects of glycopyrrolate and atropine on heart rate variability. Acta Anaesthesiol Scand 1991; 35: 436–41.
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This work was supported by grants from the Canadian Anaesthetists’ Society and the Royal Victoria Hospital Research Institute to S.B.B. and from the Medical Research Council to B.C.
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Backman, S.B., Stein, R.D., Blank, D.W. et al. Different properties of the bradycardia produced by neostigmine and edrophonium in the cat. Can J Anesth 43, 731–740 (1996). https://doi.org/10.1007/BF03017959
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DOI: https://doi.org/10.1007/BF03017959