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CHRONOTROPIC AND DROMOTROPIC EFFECTS OF ATROPINE AND HYOSCINE METHOBROMIDE IN UNANAESTHETIZED DOGS
Br.J. Anaesth. (1985), 57, 214-219
CHRONOTROPIC AND DROMOTROPIC EFFECTS OF ATROPINE AND HYOSCINE METHOBROMIDE IN UNANAESTHETIZED DOGS J. P. KANTELIP, M. ALATIENNE, G. GUEORGUIEV AND P. DUCHENE-MARULLAZ Downloaded from http://bja.oxfordjournals.org/ at Université Laval on June 30, 2015
Small doses of atropine decrease heart rate while larger doses increase it (Harris, 1921; McGuigan, SUMMARY 1921; Danielopolu, 1924). Accordingly, in man very Atrial pacing at progressively increasing frequenslow injections i.v., or injections i.m. or s.c. induce cies was performed in 12 awake dogs through a bimodal effect: a period of bradycardia followed by electrodes implanted aseptically in the right atrium characteristic tachycardia as the dose is increased. and led out through the skin of the neck. Heart rate Atropine-induced tachycardia is known to be and the Wenckebach point (the minimum pacing accompanied by a facilitation of atrioventricular (A- frequency for which a second degree A-V block V) conduction (Bisett, de Soyza et al., 1975). Facili- first appeared) were measured by electrocardiotation of A-V conduction has also been reported graphy. The responses of the sinc—atrial and during the initial phase of bradycardia (Dauchot and auriculo-ventricular nodes to atropine and hyoGravenstein, 1970; Das, Talmer and Weissler, scine methobromide were characteristically 1975). The occurrence of A-V dissociation was bimodal. Slowing of the heart rate and atriovenreported in man by Wilson as early as 1915, and tricular conduction appeared with the lower doses described subsequently in man (Averill and Lamb, of atropine (6.25 fig kg~1 i.v) and hyoscine 1959; Jones, Deutsch and Turndorf, 1961), and in methobromide (0.4 fig kg~1 i.v.); at doses of the unanaesthetized dog (Muir, 1978). atropine 12.5 fig kg-j i.v. and hyoscine metho1 The present investigation compared, in the bromide 1.56figkg~ i.v., onlyatrioventricularconunanaesthetized dog, the effects of atropine on heart duction was slowed; an acceleration of heart rate rate (HR) and A-V conduction as assessed in terms and atrioventricular conduction occurred in of the Wenckebach point (WP) for 2 h following response to the higher doses of both drugs. These results show, in the awake dog, that the effects of administration. In view of the fact that atropine-induced atropine and hyoscine methobromide on heart bradycardia has been attributed at least partly to rate and atrioventricular conduction are entirely stimulation of vagal centres (Heinkaup, 1922; comparable when appropriate doses are used, Katona, Lipson and Dauchot, 1977), the effects of and reveal a difference in the responsiveness of atropine were compared additionally with those of the sino-atrial and auriculo-ventricular nodes to the anticholinergic agent hyoscine methobromide these drugs. (MS) which has limited ability to cross the bloodbrain barrier (Domino and Corssen, 1967). under anaesthesia with pentobarbitone 25 mg kg~' i.v., two-wired stainless steel surgical electrodes MATERIALS AND METHODS (Laboratoires Bruneau, France) were implanted in Twelve mongrel dogs weighing on average the wall of the right atrium. The two electrodes were 15 ± 2 kg were studied. Following thoracotomy placed on either side of the sino-atrial node 2 cm apart. The free ends of the electrodes were tunnelled out through the nape of the animal's neck. The dogs J. P. KANTELIP, M.D.;M. ALATIENNE; P. DLCHENE-MARULLAZ, were given penicillin for 3 days. M.D.; Laboratoire de Pharmacologie Medicale, Inserm U195, After recovery, the dogs were trained to remain Faculte de Medecine, 63001 Clermont-Ferrand Cedex, France. G. GUEORGUIEV, M.D.. Faculty of Medicine, Plovdiv, Bulgaria. calm on an examination table in the presence of one
CARDIAC EFFECTS OF ATROPINE AND HYOSCINE METHOBROMIDE RESULTS
Control values (table I) Injection of 5 ml of sterile saline modified neither HR nor WP which remained stable throughout the 2-h period of observation. Propranolol 1 mg kg" ] affected HR only slightly and inconsistently; no significant effect on WP was observed. Following propranolol, atropine increased the HR from 81 ± 7 to 187 ± 12 beat min" 1 (5th min) and WP from 116 ± 7 to 340 ± 13 beat min" 1 (5th min) (P < 0.001), the increases remaining significant throughout the study. Effects of atropine (fig. 1) Atropine 100 ug kg-1 increased HR and WP significantly throughout the period of observation. HR increased from 113 ± 12 to 217 ± 15 beat min-1 after 5 min and to 153 ± 10 beat min-1 by the 120th min. WP increased from 142 ± 11 to 341 ± 11 beat min-1 after 5 min and reached 312 ± 29 beat min-1 by the 120th min. Atropine 25 ug k g " ' increased HR from 108 ± 6 to 155 ± 8 beat min" 1 after 5 min and to 116 ± 6 beat min" 1 by the 120th min. WP increased from 139 ± 6 to 310 ± 6 beat min" 1 after 5 min and reached 164 ± 6 beat min" 1 after 120 min. All increases were significant. With doses of atropine 12.5 ug kg" 1 , except for a slight cardioacceleration at the 5th min, HR remained close to control values throughout. However, three dogs had second degree A-V block for 4 min after injection (f\g. 2), and at the 5th min WP
TABLE I. Effects of physiological saline, propranolol and autonomic blockade on heart rale (HR) and Wenckebach point (WP) in unanaesthetized dogs. Data expressed as mean ± SEM obtained from six dogs. Significant difference from corresponding means of the basal values: *P < 0.05; ** P < 0.01; ***P < 0.001 Time (min) Basal
5
20
40
60
80
100
120
Saline 5 ml (control group) HR WP
88 ±11 137 ±14
89 ±10 136 ±9
89 ±10 135 ±9
89 ±8 137 ±13
89 ±8 137 ±8
90 ±9 136 ±8
92 ±10 134 ±10
87 ±9 142 ±14
Propranolol lmgkg" 1 HR WP
92 ±10 124 ±13
91 ±9 119 ±13
83 ±8* 119 ±13
85 ±9 121 ±13
86 ±11 129 ±15
83 ±9* 133 ±20
83 ±10* 131 ±18
86 ±10 135 ±15
Atropine lOOngkg"1 after propranolol 81 ±7 HR WP 116 ±7
187 ±12*** 188 ±12*** 182 ±12*** 178 ±14*** 172 ±12*** 162 ±12*** 148 ±12*** 340 ±13*** 342 ±13*** 319 ±15*** 291 ±12*** 279 ±21*** 271 ±8*** 278 ±24***
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investigator. Pharmacological testing began 10-15 days after surgery. An electrocardiogram was recorded (three standard leads: Cardiopan T3). The right atrium was paced at progressively increasing frequencies using a Jansen stimulator (Sid Serial no. F 00058). The Wenckebach point (WP) was determined by increasing the driven atrial frequency by 10 beat min" 1 every min until second degree type I A-V block first appeared. All stimuli were obtained with a 2-ms duration rectangular pulse and twice the initial diastolic threshold voltage. Before testing, a catheter was placed in a cephalic vein. Three control values of the WP were determined before injection, at 5 and 20 min after injection and finally every 20 min for 2 h. Atropine as sulphate and hyoscine methobromide as sulphate were diluted in 0.9% sterile saline. Doses are in terms of the salt. Atropine was given in doses of 100, 25, 12.5 and 6.25 ug kg" 1 i.v. and hyoscine methobromide in doses of 25, 6.25, 1.56, 0.8 and 0.4 ug kg" 1 i.v. in random order to groups of six dogs. This range of doses covered direct stimulating and blocking actions on the muscarinic receptors. Propranolol hydrochloride 1 mg k g " ' in distilled water was given alone, and in combination with atropine lOOugkg" 1 i.v. to block cardiac | 3 r adrenergic or muscarinic receptors, or both, and to evaluate the role of sympathetic tone in the unanaesthetized dog. Values of HR and WP are in beat min" 1 ± SEM. Statistical significances of the effects of the drugs, as a function of time, upon HR and WP were calculated by two-factor analysis of variance followed by a Student Fisher t test.
215
BRITISH JOURNAL OF ANAESTHESIA
216 was substantially lower than control, and remained significantly reduced (initial value 134 ± 10 beat min- 1 , decreasing to between 117 ± 9 and 115 ± 6 beat min" 1 ). With atropine 6.25 |.ig kg" 1 both HR and WP decreased significantly: HR from 91 ± 6 to 84 ± 7 400
25 mm s~'
Atropine 100/jg kg"1
• | 200'
beat min" 1 after 5 min and to 80 ± 6 beat min" 1 after 120 min; WP from 133 ± 10 to 114 ± 3 beat min" 1 after 5 min and to 112 ± 7 beat min" 1 after 120 min.
- 100J ^
Atropine 25/jgkg"
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Atropine 12.5 /jg kg"
r
Atropine 6.25/jg kg"1 150i x . . „ ^ ***
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80
100 120
FIG. 1. The effects of atropine 100, 25, 12.5 and 6.25 ug k g " ' on o) and heart rate ( • • ) in Wenckebach point (o unanaesthetized dogs (n = 6). Changes significantly different from control: *P < 0.05; **P < 0.01; ***P < 0.001. The vertical bars represent SEM. The significant increases appeared in the Wenckebach point and heart rate at 100 and 25 ug kg ' i.v. With atropine 12.5 ug kg ' i.v., decrease in Wenckebach point was significant, whereas there was no significant change in heart rate. Significant decreases appeared in the Wenckebach point and heart rate at 6.25 tig kg ' i.v.
Effects of hyoscine methobromide (fig. 3) Hyoscine methobromide 25 ug k g " ' gave effects comparable to those of atropine 100 ug kg" 1 . HR and WP increased significantly throughout the period of observation: HR from 105 ± 8 to 215 ± 9 beat min"' by the 5th min, and WP from 137 ± 9 to 313 ± 16 beat min" 1 by the 5th min. With 6.25 ^g kg" 1 , HR increased from 100 ± 14 to 183 ± 10 beat min" 1 after 5 min and remained significantly higher than control for 100 min. WP increased from 131 ± 17 to 310 ± 9 beat min"'and remained close to that value throughout. Hyoscine methobromide 1.56 ug k g " ' increased HR from 92 ± 5 to 98 ± 8 beat min" 1 by the 5th min; HR remained significantly higher than the control values for 40 min. Second-degree A-V block appeared in all dogs during the first 4 min after injection (fig. 4). At the 5th min, WP was only slightly greater than HR. Subsequently, the time course of the WP values was parallel to that of HR. At the 20th' and 40th min, WP was significantly higher than control, increasing from 129 ± 8 to 152 ± 8 and 146 ± 6 beat min" 1 , and then decreasing gradually. HR did not change through the administration of hyoscine methobromide 0.8 ug kg" 1 . However, second degree A-V block developed in two dogs for 4 min after injection. WP was decreased but the changes were not significant. Hyoscine methobromide 0.4 ug k g " ' induced a progressive reduction in HR which became significant only at the 40th min (from 94 ± 3 to 83 ± 4
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FIG. 2. Electrocardiogram (lead I, lead II and lead III) modification obtained 4 min after the i.v. administration of atropine 12.5 ug kg"' i.v. in unanaesthetized dogs. Second degree atrioventricular block is shown by the absence of a QRS complex following the P waves (arrows).
300-
CARDIAC EFFECTS OF ATROPINE AND HYOSCINE METHOBROMIDE
25 mm s"
Hyoscine methobromide 25/jg kg"1
FIG. 4. Electrocardiogram (lead I, lead II and lead III) modification obtained 4 min after the i.v. administration of hyoscine methobromide 1.56 ug kg" 1 i.v. in unanaesthetized dogs. Second degree atrio-ventricular block is shown by the absence of a QRS complex following the P waves (arrows).
1
J
Hyoscine methobromide 6.25/jg kg" ***
di
***
f—t' i
DISCUSSION
200 ***
*
*
Hyoscine methobromide 1.56/jg kg"1 **
-150' !
*"--fi
2
5
5
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*3*
| 100-
I 50' Hyoscine methobromide 0.4/jg kg'1
-W r 150
-•.•5!
***
***
100-
*** •
^
—
*
*
^
50 t 5 Control
20
40 60 _. , . . Time (mm)
80
100
120
FIG. 3. The effects of hyoscine methobromide 25, 6.25, 1.56 and 0.4 ug kg" 1 i.v. on Wenckebach point (o o) and heart rate (• • ) in unanaesthetized dogs (n = 6). Changes significantly different from control: *P < 0.05; **P < 0.01; ***P < 0.001. The vertical bars represent SEM. Significant increases appeared in the Wenckebach point and heart rate with 25, 6.25 and 1.56 ug kg" 1 i.v. With 1.56 ug kg" 1 i.v., Wenckebach point decreased sharply (5 min), increased significantly at 20-40 min then returned to control value. The significant decreases appeared in the Wenckebach point and heart rate with 0.4 ug kg" 1 i.v.
beat min-1). WP decreased also (from 155 ± 6 to 145 ± 7 beat min-' after 5 min), and reached a minimum of 130 ± 8 beat min-1 by the 60th min.
Atrial pacing with progressively increasing frequency (Arnould et al., 1963; Scherlag et al., 1969) was preferred to the method of extrastimulus (Krayer, Mandoki and Mendez, 1951; Moe, Preston and Burlington, 1956), the reason for this choice in the unanaesthetized dog having been detailed in a previous study (Duchene-Marullaz et al., 1982). Both methods, according to Bisset, Kane and colleagues (1975) give comparable results in functional investigations. Under our experimental conditions, the vagi would appear to exert a strong inhibitory influence on the canine cardiac pacemaker as suggested by the positive cardiac chronotropic effect of atropine or hyoscine methobromide in intact or propranololpretreated animals. Thus, it follows that, in the unstressed dog, the intrinsic (in the absence of autonomic control) firing frequency of the sinus node is greater than the basal rate. In contrast, the sympathetic contribution to baseline heart rate in the presence of vagal tone was minimal, as indicated clearly by the effects of propranolol given alone. The effects of atropine on heart rate in the dog are entirely comparable to those observed in man, provided the dog is not anaesthetized (Muir, 1978). Low blood concentrations following injection of small doses, slow i.v. injections, and s.c. or i.m. injections which release atropine only slowly into the bloodstream, induce bradycardia (Harris, 1921; Morton and Thomas, 1958; Kottmeier and Gravenstein, 1968). Higher blood concentrations induce tachycardia. Anaesthesia with chloralose (Kottmeier and Gravenstein, 1968) prevents this bradycardiac phase from being seen in the dog. The mechanism of this bradycardia is unclear. It has been suggested (Katona, Lipson and Dauchot, 1977) that it might arise, at least in part, from stimu-
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E300T
217
218
12.5 fig kg ' HR increased at the 5th min while WP was decreased significantly. Thereafter, WP remained decreased, whereas HR decreased gradually to values lower than control. Similarly, hyoscine methobromide 1.56 ug kg" 1 increased HR significantly at the 5th, 20th and 40th min, but induced second-degree A-V block immediately after injection and a significant decrease in WP by the 5th min. Under certain circumstances, atropine may shift the site of A-V block. Atropine may change the site of block from the A-V node to the His-Purkinje system. Sinus acceleration and enhanced A-V nodal conduction result in shorter H-H intervals and atropine has no direct enhancing effect on His-Purkinje conduction (Aktar et al., 1974). At relatively low driving rates, the functional refractory period of the Purkinje system can exceed that of the A-V node and premature beats may fail to traverse the Purkinje system for this reason (Spear and Moor, 1971). Atropine and hyoscine methobromide contribute to this by providing the prerequisite balance between nodal conduction velocity and refractoriness within the A-V node. Consequently, A-V block may emerge during atrial acceleration. Thus, we consider that the limit of stimulation and blocking action on the muscarinic receptors of the heart was probably obtained near atropine 12.5 ug kg" 1 and hyoscine methobromide 1.56 |^g kg" 1 . However, at the 20th and 40th min, tachycardia was associated with facilitated A-V conduction. Thus although, in general, the effects of atropine and hyoscine methobromide on S-A and A-V nodes are in the same direction, effects in the opposite direction may occur immediately after injection. A difference in sensitivity of the muscarinic cholinoceptors of the SA and A-V nodes has been reported. Musgrave, Branch and Beckett (1981) showed that, in the unanaesthetized dog, the A-V node was 1.9 times more sensitive to acetylcholine than the S-A node. The cholinesterase concentration is, moreover, greater in the A-V node than in the S-A node (James and Spence, 1966). The fact that hyoscine methobromide-induced tachycardia decreased gradually, whereas the WP remained stable over 2 h after 25 and 6.25 ug kg" l injection does not indicate a differential sensitivity of the S-A and A-V nodes. There is considerable evidence that the tachycardia produced by atropine is much greater than that produced by vagotomy or ganglionic blocking drugs (Brunstingetal., 1979). More importantly, Loeb, Dalton and Moran (1981) have observed that the negative chronotropic effect of acetylcholine at the S-A node is decreased
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lation of vagal centres. However, such a postulate is in contradiction to the fact that bradycardia still occurs after bilateral vagotomy (Duchene-Marullaz, Arnould and Schaff, 1963; Kottmeier and Gravenstein, 1968), and that a comparable effect may be obtained with agents which do not cross the bloodbrain barrier, such as atropine methyl bromide (Kottmeier and Gravenstein, 1968; Fennell et al., 1979) methyl-atropine nitrate (Graham and Lazarus, 1940) or hyoscine methobromide (Fenell et al., 1979). Thus, the bradycardiac effects of atropine that persist for days after vagotomy may still result from inhibition of acetylcholinesterase, since the post-ganglionic vagal nerves that are not affected by the vagotomy may still show spontaneous release of acetylcholine. Our results show that a similar degree of bradycardia is obtained with either atropine - l or hyoscine methobromide 6.25 ug kg 0.4 ug kg '. Atropine has also been shown to inhibit the activity of cholinesterase (Sekiya, 1954; Kato, 1971) and it has been postulated that, with small doses, this anticholinesterase activity may predominate and, thus, lead to enhanced response of the receptor to naturally-existing acetylcholine. However, if this were the case, the bradycardia produced by atropine would disappear a few days after bilateral vagotomy, and this has not been observed (Duchene-Marullaz, Arnould and Schaff, 1963). It is difficult to say whether a direct effect on pacemaker cells is involved or rather an action on the cholinergic receptors themselves. According to Patton (1960), most receptor-blocking agents in small doses produce transient depolarization of the receptors, resulting in stimulation. However, with the smallest doses of atropine and hyoscine methobromide used in our experiments, the bradycardia was far from brief (more than 2 h). It has been shown (Duchene-Marullaz et al., 1982) that, under similar experimental conditions, the injection of 5 ml of sterile saline solution modifies neither HR nor WP over a 2-h period in well-trained dogs. Thus, the bradycardia induced by atropine and hyoscine methobromide is evidently a persistent vagomimetic effect. With the smallest doses used, this vagomimetic effect occurred concurrently at both the S-A and AV nodes. This finding is at variance with the observations of Dauchot and Gravenstein (1970) and Das, Talmer and Weissler (1975), according to whom AV conduction is facilitated even at doses low enough to decrease HR. Our results indicate that such dissociation of HR and A-V conduction occurs only briefly after injection. Thus, with atropine
BRITISH JOURNAL OF ANAESTHESIA
CARDIAC EFFECTS OF ATROPINE AND HYOSCINE METHOBROMIDE
REFERENCES
Aktar, M., Damato, A. N., Caracta, A. R., Batsfort, W. P., Josephson, M. E., and Lau, S. H. (1974). Electrophysiologic effects of atropine on atrioventricular conduction. Am.J. Cardiol, 33, 333. Arnould, P., Duchene-Marullaz, P., Boulange, M., and Schaff, G. (1963). Le tonus dromotrope des nerfs extrinseques du coeur chez le chien. C.R. Soc. Biol., 157, 1069. Averill, K. H., and Lamb, L. E. (1959). Less commonly recognized actions of atropine on cardiac rhythm. Am.J. Med. Sci., 273, 304. Bisett, J. K., Kane, J. J., de Soyza, N. D. B., and Murphy, M. L. (1975). Electrophysiological significance of rapid atrial pacing as a test of atrioventricular conduction. Cardiovasc. Res., 9, 593. de Soyza, N. D. B., Kane, J. J., and Murphy, M. L. (1975). Electrophysiology of atropine. Cardiovasc. Res., 9, 73. Brunsting, J. R., Bennekers, J. H., Schuil, H. A., and Zijlstra, W. G. (1979). Incomplete cardiac vagal blockade with atropine in the anesthetized dog. Pflugers Arch., 391, 293. Chassaing, C., Godeneche, D., Boucher, M., and DucheneMarullaz, P. (1979). A comparison of changes in atropineinduced tachycardia and atropine concentration in conscious dogs. Eur.J. Pharmacol., 58, 433. Danielopolu, A. (1924). Action des doses faibles et des doses fortes d'atropine sur la conductibilite auriculo-ventriculaire. Dissociation de l'action chronotrope et dromotrope de l'atropine. C.R. Soc. Biol., 91, 741. Das, G., Talmer, F. N., and Weissler, A. M. (1975). New observations on the effects of atropine on the sinoatrial and atrioventricular nodes in man. Am.J. Cardiol., 36, 281. Dauchot, P.,andGravenstein, J. S. (1970). Effects of atropine on the electrocardiogram in different age groups. Clin. Pharmacol. Ther., 12, 274. Domino, E. G., and Corssen, G. (1967). Central and peripheral effects of muscarinic cholinergic blocking agents in man. Anesthesiology, 28, 568. Duchene-Marullaz, P., Arnould, P., and Schaff, G. (1963). Influence de l'atropine sur la frequence cardiaque du chien bivagotomise. C.R. Soc. Biol., 157, 2214.
Duchene-Marullaz, P., Fabry-Delaigue, R., Gueorguiev, G., and Kantelip, J. P. (1982). Influence of chloralose and pentobarbital sodium on atrio-ventricular conduction in dogs. Br. J. Pharmacol., 77, 309. Fennell, W. H., Takeda, H., Hsieh, Y. Y., Goldberg, L. J., and Chao, G. C. (1979). Chronotropic effects of atropine sulfate and methscopolamine bromide in normal subjects and patients undergoing cardiac catheterization.J'. Cardiovasc. Pharmacol., 1, 649. Graham, J. D. P., and Lazarus, S. (1940). The action of methylatropine nitrate. J. Pharmacol. Exp. Ther., 70, 165. Harris, I. (1921). The action of digitalis and atropine on the peripheral blood pressure. Lancet, 1, 1072. Heinkaup,W. J. R. (1922). The central influence of atropine and hyoscine on the heart rate. J. Lab. Clin. Med., 8, 104. James, T. N., and Spence, C. A. (1966). Distribution of cholinesterase within the sinus node and AV node of the human heart. Anal. Rec, 155, 151. Jones, R. E., Deutsch, S., and Turndorf, H. (1961). Effects of atropine on cardiac rhythm in conscious and anesthetized man. Anesihesiology, 22, 67. Kato, G. (1971). NMR studies on drug receptor interactions. Int. J. Clin. Pharmacol., 5, 12. Katona, P. G., Lipson, D., and Dauchot, P. J. (1977). Opposing central and peripheral effects of atropine on parasympathetic control. Am.J. Physiol., 232, H146. Kottmeier, C. A., and Gravenstein, J. S. (1968). The parasympathomimetic activity of atropine and atropine methylbromide. Anesihesiology, 29, 1125. Krayer, O., Mandoki, J., and Mendez, C. (1951). Studies on veratrum alkaloids XVI. The action of epinephrin and of veratramine on the functional refractory period of the auriculo-ventricular transmission in the heart-lung preparation of the dog. J. Pharmacol. Exp. Ther., 103, 412. Loeb, J. M., Dalton, D. P., and Moran, J. M. (1981). Sensitivity differences of SA and AV node to vagal stimulation: attenuation of vagal effects at SA node. Am.J. Physiol., 241, H684. McGuigan, H. (1921). The effect of small doses of atropine on the heart rate.7./l.Af.i4., 76, 1338. Moe, G. K., Preston, J. B., and Burlington, H. (1956). Physiologic evidence for a dual AV transmission system. Circ. Res., 4, 357. Morton, H. J., and Thomas, E. T. (1958). Effect of atropine on the heart rate. Lancet, D e c , 1313. Muir, W. W. (1978). Effects of atropine on cardiac rate and rhythm in dogs..?. Am. Vet. Med. Ass., 172, 917. Musgrave, G. E., Branch, C. E., and Beckett, D. S. (1981). Relative sensitivity of the canine sinus node and atrioventricular node to acetylcholine. Can.J. Physiol. Pharmacol., 59, 1058. Patton, W. D. M. (1960). The principles of drug action. Proc. R. Soc. Med., 53, 815. Scherlag, B. J., Lau, S. H., Helfant, R. H., Berkowitz, W. O., Stein, E., and Damato, A. N. (1969). Catheter technique for recording His bundle activity in man. Circulation, 39, 13. Sekiya, A. (1954). Action of atropine on rabbit blood cholinesterase. Jap.J. Pharmacol., 4, 22. Spear, J., and Moore, E. N. (1971). Electrophysiologic studies on Mobitz type II second degree heart block. Circulation, 44, 1087. Wilson, F. N. (1915). The production of atrioventricular rhythm in man after the administration of atropine. Arch. Int. Med., 16, 989.
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during vagal stimulation, whereas the negative dromotropic effect on A-V nodal conduction remains unaltered. It has been observed also, that continuous infusion of atropine fails to maintain HR at the same value; induced cardio-acceleration decreases even though the blood concentration of atropine increases (Chassaing et al., 1979). No analogous investigation of the time course of A-V conduction during the infusion of atropine has been reported. Nonetheless, the results obtained here with hyoscine methobromide 25 and 6.25 |a,g kg" 1 suggest that blockade of A-V nodal cholinoceptors is likely to be more stable. In spite of these few differences, and of the fact that A-V blockade does not preclude tachycardia, S-A and A-V nodes evidently respond in much the same way to atropine and hyoscine methobromide. A negative chronotropic effect is generally accompanied by a negative dromotropic effect.
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CHRONOTROPIC AND DROMOTROPIC EFFECTS OF ATROPINE AND HYOSCINE METHOBROMIDE IN UNANAESTHETIZED DOGS J. P. KANTELIP, M. ALATIENNE, G. GUEORGUIEV AND P. DUCHENE-MARULLAZ Downloaded from http://bja.oxfordjournals.org/ at Université Laval on June 30, 2015
Small doses of atropine decrease heart rate while larger doses increase it (Harris, 1921; McGuigan, SUMMARY 1921; Danielopolu, 1924). Accordingly, in man very Atrial pacing at progressively increasing frequenslow injections i.v., or injections i.m. or s.c. induce cies was performed in 12 awake dogs through a bimodal effect: a period of bradycardia followed by electrodes implanted aseptically in the right atrium characteristic tachycardia as the dose is increased. and led out through the skin of the neck. Heart rate Atropine-induced tachycardia is known to be and the Wenckebach point (the minimum pacing accompanied by a facilitation of atrioventricular (A- frequency for which a second degree A-V block V) conduction (Bisett, de Soyza et al., 1975). Facili- first appeared) were measured by electrocardiotation of A-V conduction has also been reported graphy. The responses of the sinc—atrial and during the initial phase of bradycardia (Dauchot and auriculo-ventricular nodes to atropine and hyoGravenstein, 1970; Das, Talmer and Weissler, scine methobromide were characteristically 1975). The occurrence of A-V dissociation was bimodal. Slowing of the heart rate and atriovenreported in man by Wilson as early as 1915, and tricular conduction appeared with the lower doses described subsequently in man (Averill and Lamb, of atropine (6.25 fig kg~1 i.v) and hyoscine 1959; Jones, Deutsch and Turndorf, 1961), and in methobromide (0.4 fig kg~1 i.v.); at doses of the unanaesthetized dog (Muir, 1978). atropine 12.5 fig kg-j i.v. and hyoscine metho1 The present investigation compared, in the bromide 1.56figkg~ i.v., onlyatrioventricularconunanaesthetized dog, the effects of atropine on heart duction was slowed; an acceleration of heart rate rate (HR) and A-V conduction as assessed in terms and atrioventricular conduction occurred in of the Wenckebach point (WP) for 2 h following response to the higher doses of both drugs. These results show, in the awake dog, that the effects of administration. In view of the fact that atropine-induced atropine and hyoscine methobromide on heart bradycardia has been attributed at least partly to rate and atrioventricular conduction are entirely stimulation of vagal centres (Heinkaup, 1922; comparable when appropriate doses are used, Katona, Lipson and Dauchot, 1977), the effects of and reveal a difference in the responsiveness of atropine were compared additionally with those of the sino-atrial and auriculo-ventricular nodes to the anticholinergic agent hyoscine methobromide these drugs. (MS) which has limited ability to cross the bloodbrain barrier (Domino and Corssen, 1967). under anaesthesia with pentobarbitone 25 mg kg~' i.v., two-wired stainless steel surgical electrodes MATERIALS AND METHODS (Laboratoires Bruneau, France) were implanted in Twelve mongrel dogs weighing on average the wall of the right atrium. The two electrodes were 15 ± 2 kg were studied. Following thoracotomy placed on either side of the sino-atrial node 2 cm apart. The free ends of the electrodes were tunnelled out through the nape of the animal's neck. The dogs J. P. KANTELIP, M.D.;M. ALATIENNE; P. DLCHENE-MARULLAZ, were given penicillin for 3 days. M.D.; Laboratoire de Pharmacologie Medicale, Inserm U195, After recovery, the dogs were trained to remain Faculte de Medecine, 63001 Clermont-Ferrand Cedex, France. G. GUEORGUIEV, M.D.. Faculty of Medicine, Plovdiv, Bulgaria. calm on an examination table in the presence of one
CARDIAC EFFECTS OF ATROPINE AND HYOSCINE METHOBROMIDE RESULTS
Control values (table I) Injection of 5 ml of sterile saline modified neither HR nor WP which remained stable throughout the 2-h period of observation. Propranolol 1 mg kg" ] affected HR only slightly and inconsistently; no significant effect on WP was observed. Following propranolol, atropine increased the HR from 81 ± 7 to 187 ± 12 beat min" 1 (5th min) and WP from 116 ± 7 to 340 ± 13 beat min" 1 (5th min) (P < 0.001), the increases remaining significant throughout the study. Effects of atropine (fig. 1) Atropine 100 ug kg-1 increased HR and WP significantly throughout the period of observation. HR increased from 113 ± 12 to 217 ± 15 beat min-1 after 5 min and to 153 ± 10 beat min-1 by the 120th min. WP increased from 142 ± 11 to 341 ± 11 beat min-1 after 5 min and reached 312 ± 29 beat min-1 by the 120th min. Atropine 25 ug k g " ' increased HR from 108 ± 6 to 155 ± 8 beat min" 1 after 5 min and to 116 ± 6 beat min" 1 by the 120th min. WP increased from 139 ± 6 to 310 ± 6 beat min" 1 after 5 min and reached 164 ± 6 beat min" 1 after 120 min. All increases were significant. With doses of atropine 12.5 ug kg" 1 , except for a slight cardioacceleration at the 5th min, HR remained close to control values throughout. However, three dogs had second degree A-V block for 4 min after injection (f\g. 2), and at the 5th min WP
TABLE I. Effects of physiological saline, propranolol and autonomic blockade on heart rale (HR) and Wenckebach point (WP) in unanaesthetized dogs. Data expressed as mean ± SEM obtained from six dogs. Significant difference from corresponding means of the basal values: *P < 0.05; ** P < 0.01; ***P < 0.001 Time (min) Basal
5
20
40
60
80
100
120
Saline 5 ml (control group) HR WP
88 ±11 137 ±14
89 ±10 136 ±9
89 ±10 135 ±9
89 ±8 137 ±13
89 ±8 137 ±8
90 ±9 136 ±8
92 ±10 134 ±10
87 ±9 142 ±14
Propranolol lmgkg" 1 HR WP
92 ±10 124 ±13
91 ±9 119 ±13
83 ±8* 119 ±13
85 ±9 121 ±13
86 ±11 129 ±15
83 ±9* 133 ±20
83 ±10* 131 ±18
86 ±10 135 ±15
Atropine lOOngkg"1 after propranolol 81 ±7 HR WP 116 ±7
187 ±12*** 188 ±12*** 182 ±12*** 178 ±14*** 172 ±12*** 162 ±12*** 148 ±12*** 340 ±13*** 342 ±13*** 319 ±15*** 291 ±12*** 279 ±21*** 271 ±8*** 278 ±24***
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investigator. Pharmacological testing began 10-15 days after surgery. An electrocardiogram was recorded (three standard leads: Cardiopan T3). The right atrium was paced at progressively increasing frequencies using a Jansen stimulator (Sid Serial no. F 00058). The Wenckebach point (WP) was determined by increasing the driven atrial frequency by 10 beat min" 1 every min until second degree type I A-V block first appeared. All stimuli were obtained with a 2-ms duration rectangular pulse and twice the initial diastolic threshold voltage. Before testing, a catheter was placed in a cephalic vein. Three control values of the WP were determined before injection, at 5 and 20 min after injection and finally every 20 min for 2 h. Atropine as sulphate and hyoscine methobromide as sulphate were diluted in 0.9% sterile saline. Doses are in terms of the salt. Atropine was given in doses of 100, 25, 12.5 and 6.25 ug kg" 1 i.v. and hyoscine methobromide in doses of 25, 6.25, 1.56, 0.8 and 0.4 ug kg" 1 i.v. in random order to groups of six dogs. This range of doses covered direct stimulating and blocking actions on the muscarinic receptors. Propranolol hydrochloride 1 mg k g " ' in distilled water was given alone, and in combination with atropine lOOugkg" 1 i.v. to block cardiac | 3 r adrenergic or muscarinic receptors, or both, and to evaluate the role of sympathetic tone in the unanaesthetized dog. Values of HR and WP are in beat min" 1 ± SEM. Statistical significances of the effects of the drugs, as a function of time, upon HR and WP were calculated by two-factor analysis of variance followed by a Student Fisher t test.
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216 was substantially lower than control, and remained significantly reduced (initial value 134 ± 10 beat min- 1 , decreasing to between 117 ± 9 and 115 ± 6 beat min" 1 ). With atropine 6.25 |.ig kg" 1 both HR and WP decreased significantly: HR from 91 ± 6 to 84 ± 7 400
25 mm s~'
Atropine 100/jg kg"1
• | 200'
beat min" 1 after 5 min and to 80 ± 6 beat min" 1 after 120 min; WP from 133 ± 10 to 114 ± 3 beat min" 1 after 5 min and to 112 ± 7 beat min" 1 after 120 min.
- 100J ^
Atropine 25/jgkg"
200-
100J
Atropine 12.5 /jg kg"
r
Atropine 6.25/jg kg"1 150i x . . „ ^ ***
J*-*-T* t 5 Control
20
***
***
***
-i—i—i—t—I 40 60 Time (min)
80
100 120
FIG. 1. The effects of atropine 100, 25, 12.5 and 6.25 ug k g " ' on o) and heart rate ( • • ) in Wenckebach point (o unanaesthetized dogs (n = 6). Changes significantly different from control: *P < 0.05; **P < 0.01; ***P < 0.001. The vertical bars represent SEM. The significant increases appeared in the Wenckebach point and heart rate at 100 and 25 ug kg ' i.v. With atropine 12.5 ug kg ' i.v., decrease in Wenckebach point was significant, whereas there was no significant change in heart rate. Significant decreases appeared in the Wenckebach point and heart rate at 6.25 tig kg ' i.v.
Effects of hyoscine methobromide (fig. 3) Hyoscine methobromide 25 ug k g " ' gave effects comparable to those of atropine 100 ug kg" 1 . HR and WP increased significantly throughout the period of observation: HR from 105 ± 8 to 215 ± 9 beat min"' by the 5th min, and WP from 137 ± 9 to 313 ± 16 beat min" 1 by the 5th min. With 6.25 ^g kg" 1 , HR increased from 100 ± 14 to 183 ± 10 beat min" 1 after 5 min and remained significantly higher than control for 100 min. WP increased from 131 ± 17 to 310 ± 9 beat min"'and remained close to that value throughout. Hyoscine methobromide 1.56 ug k g " ' increased HR from 92 ± 5 to 98 ± 8 beat min" 1 by the 5th min; HR remained significantly higher than the control values for 40 min. Second-degree A-V block appeared in all dogs during the first 4 min after injection (fig. 4). At the 5th min, WP was only slightly greater than HR. Subsequently, the time course of the WP values was parallel to that of HR. At the 20th' and 40th min, WP was significantly higher than control, increasing from 129 ± 8 to 152 ± 8 and 146 ± 6 beat min" 1 , and then decreasing gradually. HR did not change through the administration of hyoscine methobromide 0.8 ug kg" 1 . However, second degree A-V block developed in two dogs for 4 min after injection. WP was decreased but the changes were not significant. Hyoscine methobromide 0.4 ug k g " ' induced a progressive reduction in HR which became significant only at the 40th min (from 94 ± 3 to 83 ± 4
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FIG. 2. Electrocardiogram (lead I, lead II and lead III) modification obtained 4 min after the i.v. administration of atropine 12.5 ug kg"' i.v. in unanaesthetized dogs. Second degree atrioventricular block is shown by the absence of a QRS complex following the P waves (arrows).
300-
CARDIAC EFFECTS OF ATROPINE AND HYOSCINE METHOBROMIDE
25 mm s"
Hyoscine methobromide 25/jg kg"1
FIG. 4. Electrocardiogram (lead I, lead II and lead III) modification obtained 4 min after the i.v. administration of hyoscine methobromide 1.56 ug kg" 1 i.v. in unanaesthetized dogs. Second degree atrio-ventricular block is shown by the absence of a QRS complex following the P waves (arrows).
1
J
Hyoscine methobromide 6.25/jg kg" ***
di
***
f—t' i
DISCUSSION
200 ***
*
*
Hyoscine methobromide 1.56/jg kg"1 **
-150' !
*"--fi
2
5
5
***
*3*
| 100-
I 50' Hyoscine methobromide 0.4/jg kg'1
-W r 150
-•.•5!
***
***
100-
*** •
^
—
*
*
^
50 t 5 Control
20
40 60 _. , . . Time (mm)
80
100
120
FIG. 3. The effects of hyoscine methobromide 25, 6.25, 1.56 and 0.4 ug kg" 1 i.v. on Wenckebach point (o o) and heart rate (• • ) in unanaesthetized dogs (n = 6). Changes significantly different from control: *P < 0.05; **P < 0.01; ***P < 0.001. The vertical bars represent SEM. Significant increases appeared in the Wenckebach point and heart rate with 25, 6.25 and 1.56 ug kg" 1 i.v. With 1.56 ug kg" 1 i.v., Wenckebach point decreased sharply (5 min), increased significantly at 20-40 min then returned to control value. The significant decreases appeared in the Wenckebach point and heart rate with 0.4 ug kg" 1 i.v.
beat min-1). WP decreased also (from 155 ± 6 to 145 ± 7 beat min-' after 5 min), and reached a minimum of 130 ± 8 beat min-1 by the 60th min.
Atrial pacing with progressively increasing frequency (Arnould et al., 1963; Scherlag et al., 1969) was preferred to the method of extrastimulus (Krayer, Mandoki and Mendez, 1951; Moe, Preston and Burlington, 1956), the reason for this choice in the unanaesthetized dog having been detailed in a previous study (Duchene-Marullaz et al., 1982). Both methods, according to Bisset, Kane and colleagues (1975) give comparable results in functional investigations. Under our experimental conditions, the vagi would appear to exert a strong inhibitory influence on the canine cardiac pacemaker as suggested by the positive cardiac chronotropic effect of atropine or hyoscine methobromide in intact or propranololpretreated animals. Thus, it follows that, in the unstressed dog, the intrinsic (in the absence of autonomic control) firing frequency of the sinus node is greater than the basal rate. In contrast, the sympathetic contribution to baseline heart rate in the presence of vagal tone was minimal, as indicated clearly by the effects of propranolol given alone. The effects of atropine on heart rate in the dog are entirely comparable to those observed in man, provided the dog is not anaesthetized (Muir, 1978). Low blood concentrations following injection of small doses, slow i.v. injections, and s.c. or i.m. injections which release atropine only slowly into the bloodstream, induce bradycardia (Harris, 1921; Morton and Thomas, 1958; Kottmeier and Gravenstein, 1968). Higher blood concentrations induce tachycardia. Anaesthesia with chloralose (Kottmeier and Gravenstein, 1968) prevents this bradycardiac phase from being seen in the dog. The mechanism of this bradycardia is unclear. It has been suggested (Katona, Lipson and Dauchot, 1977) that it might arise, at least in part, from stimu-
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E300T
217
218
12.5 fig kg ' HR increased at the 5th min while WP was decreased significantly. Thereafter, WP remained decreased, whereas HR decreased gradually to values lower than control. Similarly, hyoscine methobromide 1.56 ug kg" 1 increased HR significantly at the 5th, 20th and 40th min, but induced second-degree A-V block immediately after injection and a significant decrease in WP by the 5th min. Under certain circumstances, atropine may shift the site of A-V block. Atropine may change the site of block from the A-V node to the His-Purkinje system. Sinus acceleration and enhanced A-V nodal conduction result in shorter H-H intervals and atropine has no direct enhancing effect on His-Purkinje conduction (Aktar et al., 1974). At relatively low driving rates, the functional refractory period of the Purkinje system can exceed that of the A-V node and premature beats may fail to traverse the Purkinje system for this reason (Spear and Moor, 1971). Atropine and hyoscine methobromide contribute to this by providing the prerequisite balance between nodal conduction velocity and refractoriness within the A-V node. Consequently, A-V block may emerge during atrial acceleration. Thus, we consider that the limit of stimulation and blocking action on the muscarinic receptors of the heart was probably obtained near atropine 12.5 ug kg" 1 and hyoscine methobromide 1.56 |^g kg" 1 . However, at the 20th and 40th min, tachycardia was associated with facilitated A-V conduction. Thus although, in general, the effects of atropine and hyoscine methobromide on S-A and A-V nodes are in the same direction, effects in the opposite direction may occur immediately after injection. A difference in sensitivity of the muscarinic cholinoceptors of the SA and A-V nodes has been reported. Musgrave, Branch and Beckett (1981) showed that, in the unanaesthetized dog, the A-V node was 1.9 times more sensitive to acetylcholine than the S-A node. The cholinesterase concentration is, moreover, greater in the A-V node than in the S-A node (James and Spence, 1966). The fact that hyoscine methobromide-induced tachycardia decreased gradually, whereas the WP remained stable over 2 h after 25 and 6.25 ug kg" l injection does not indicate a differential sensitivity of the S-A and A-V nodes. There is considerable evidence that the tachycardia produced by atropine is much greater than that produced by vagotomy or ganglionic blocking drugs (Brunstingetal., 1979). More importantly, Loeb, Dalton and Moran (1981) have observed that the negative chronotropic effect of acetylcholine at the S-A node is decreased
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lation of vagal centres. However, such a postulate is in contradiction to the fact that bradycardia still occurs after bilateral vagotomy (Duchene-Marullaz, Arnould and Schaff, 1963; Kottmeier and Gravenstein, 1968), and that a comparable effect may be obtained with agents which do not cross the bloodbrain barrier, such as atropine methyl bromide (Kottmeier and Gravenstein, 1968; Fennell et al., 1979) methyl-atropine nitrate (Graham and Lazarus, 1940) or hyoscine methobromide (Fenell et al., 1979). Thus, the bradycardiac effects of atropine that persist for days after vagotomy may still result from inhibition of acetylcholinesterase, since the post-ganglionic vagal nerves that are not affected by the vagotomy may still show spontaneous release of acetylcholine. Our results show that a similar degree of bradycardia is obtained with either atropine - l or hyoscine methobromide 6.25 ug kg 0.4 ug kg '. Atropine has also been shown to inhibit the activity of cholinesterase (Sekiya, 1954; Kato, 1971) and it has been postulated that, with small doses, this anticholinesterase activity may predominate and, thus, lead to enhanced response of the receptor to naturally-existing acetylcholine. However, if this were the case, the bradycardia produced by atropine would disappear a few days after bilateral vagotomy, and this has not been observed (Duchene-Marullaz, Arnould and Schaff, 1963). It is difficult to say whether a direct effect on pacemaker cells is involved or rather an action on the cholinergic receptors themselves. According to Patton (1960), most receptor-blocking agents in small doses produce transient depolarization of the receptors, resulting in stimulation. However, with the smallest doses of atropine and hyoscine methobromide used in our experiments, the bradycardia was far from brief (more than 2 h). It has been shown (Duchene-Marullaz et al., 1982) that, under similar experimental conditions, the injection of 5 ml of sterile saline solution modifies neither HR nor WP over a 2-h period in well-trained dogs. Thus, the bradycardia induced by atropine and hyoscine methobromide is evidently a persistent vagomimetic effect. With the smallest doses used, this vagomimetic effect occurred concurrently at both the S-A and AV nodes. This finding is at variance with the observations of Dauchot and Gravenstein (1970) and Das, Talmer and Weissler (1975), according to whom AV conduction is facilitated even at doses low enough to decrease HR. Our results indicate that such dissociation of HR and A-V conduction occurs only briefly after injection. Thus, with atropine
BRITISH JOURNAL OF ANAESTHESIA
CARDIAC EFFECTS OF ATROPINE AND HYOSCINE METHOBROMIDE
REFERENCES
Aktar, M., Damato, A. N., Caracta, A. R., Batsfort, W. P., Josephson, M. E., and Lau, S. H. (1974). Electrophysiologic effects of atropine on atrioventricular conduction. Am.J. Cardiol, 33, 333. Arnould, P., Duchene-Marullaz, P., Boulange, M., and Schaff, G. (1963). Le tonus dromotrope des nerfs extrinseques du coeur chez le chien. C.R. Soc. Biol., 157, 1069. Averill, K. H., and Lamb, L. E. (1959). Less commonly recognized actions of atropine on cardiac rhythm. Am.J. Med. Sci., 273, 304. Bisett, J. K., Kane, J. J., de Soyza, N. D. B., and Murphy, M. L. (1975). Electrophysiological significance of rapid atrial pacing as a test of atrioventricular conduction. Cardiovasc. Res., 9, 593. de Soyza, N. D. B., Kane, J. J., and Murphy, M. L. (1975). Electrophysiology of atropine. Cardiovasc. Res., 9, 73. Brunsting, J. R., Bennekers, J. H., Schuil, H. A., and Zijlstra, W. G. (1979). Incomplete cardiac vagal blockade with atropine in the anesthetized dog. Pflugers Arch., 391, 293. Chassaing, C., Godeneche, D., Boucher, M., and DucheneMarullaz, P. (1979). A comparison of changes in atropineinduced tachycardia and atropine concentration in conscious dogs. Eur.J. Pharmacol., 58, 433. Danielopolu, A. (1924). Action des doses faibles et des doses fortes d'atropine sur la conductibilite auriculo-ventriculaire. Dissociation de l'action chronotrope et dromotrope de l'atropine. C.R. Soc. Biol., 91, 741. Das, G., Talmer, F. N., and Weissler, A. M. (1975). New observations on the effects of atropine on the sinoatrial and atrioventricular nodes in man. Am.J. Cardiol., 36, 281. Dauchot, P.,andGravenstein, J. S. (1970). Effects of atropine on the electrocardiogram in different age groups. Clin. Pharmacol. Ther., 12, 274. Domino, E. G., and Corssen, G. (1967). Central and peripheral effects of muscarinic cholinergic blocking agents in man. Anesthesiology, 28, 568. Duchene-Marullaz, P., Arnould, P., and Schaff, G. (1963). Influence de l'atropine sur la frequence cardiaque du chien bivagotomise. C.R. Soc. Biol., 157, 2214.
Duchene-Marullaz, P., Fabry-Delaigue, R., Gueorguiev, G., and Kantelip, J. P. (1982). Influence of chloralose and pentobarbital sodium on atrio-ventricular conduction in dogs. Br. J. Pharmacol., 77, 309. Fennell, W. H., Takeda, H., Hsieh, Y. Y., Goldberg, L. J., and Chao, G. C. (1979). Chronotropic effects of atropine sulfate and methscopolamine bromide in normal subjects and patients undergoing cardiac catheterization.J'. Cardiovasc. Pharmacol., 1, 649. Graham, J. D. P., and Lazarus, S. (1940). The action of methylatropine nitrate. J. Pharmacol. Exp. Ther., 70, 165. Harris, I. (1921). The action of digitalis and atropine on the peripheral blood pressure. Lancet, 1, 1072. Heinkaup,W. J. R. (1922). The central influence of atropine and hyoscine on the heart rate. J. Lab. Clin. Med., 8, 104. James, T. N., and Spence, C. A. (1966). Distribution of cholinesterase within the sinus node and AV node of the human heart. Anal. Rec, 155, 151. Jones, R. E., Deutsch, S., and Turndorf, H. (1961). Effects of atropine on cardiac rhythm in conscious and anesthetized man. Anesihesiology, 22, 67. Kato, G. (1971). NMR studies on drug receptor interactions. Int. J. Clin. Pharmacol., 5, 12. Katona, P. G., Lipson, D., and Dauchot, P. J. (1977). Opposing central and peripheral effects of atropine on parasympathetic control. Am.J. Physiol., 232, H146. Kottmeier, C. A., and Gravenstein, J. S. (1968). The parasympathomimetic activity of atropine and atropine methylbromide. Anesihesiology, 29, 1125. Krayer, O., Mandoki, J., and Mendez, C. (1951). Studies on veratrum alkaloids XVI. The action of epinephrin and of veratramine on the functional refractory period of the auriculo-ventricular transmission in the heart-lung preparation of the dog. J. Pharmacol. Exp. Ther., 103, 412. Loeb, J. M., Dalton, D. P., and Moran, J. M. (1981). Sensitivity differences of SA and AV node to vagal stimulation: attenuation of vagal effects at SA node. Am.J. Physiol., 241, H684. McGuigan, H. (1921). The effect of small doses of atropine on the heart rate.7./l.Af.i4., 76, 1338. Moe, G. K., Preston, J. B., and Burlington, H. (1956). Physiologic evidence for a dual AV transmission system. Circ. Res., 4, 357. Morton, H. J., and Thomas, E. T. (1958). Effect of atropine on the heart rate. Lancet, D e c , 1313. Muir, W. W. (1978). Effects of atropine on cardiac rate and rhythm in dogs..?. Am. Vet. Med. Ass., 172, 917. Musgrave, G. E., Branch, C. E., and Beckett, D. S. (1981). Relative sensitivity of the canine sinus node and atrioventricular node to acetylcholine. Can.J. Physiol. Pharmacol., 59, 1058. Patton, W. D. M. (1960). The principles of drug action. Proc. R. Soc. Med., 53, 815. Scherlag, B. J., Lau, S. H., Helfant, R. H., Berkowitz, W. O., Stein, E., and Damato, A. N. (1969). Catheter technique for recording His bundle activity in man. Circulation, 39, 13. Sekiya, A. (1954). Action of atropine on rabbit blood cholinesterase. Jap.J. Pharmacol., 4, 22. Spear, J., and Moore, E. N. (1971). Electrophysiologic studies on Mobitz type II second degree heart block. Circulation, 44, 1087. Wilson, F. N. (1915). The production of atrioventricular rhythm in man after the administration of atropine. Arch. Int. Med., 16, 989.
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during vagal stimulation, whereas the negative dromotropic effect on A-V nodal conduction remains unaltered. It has been observed also, that continuous infusion of atropine fails to maintain HR at the same value; induced cardio-acceleration decreases even though the blood concentration of atropine increases (Chassaing et al., 1979). No analogous investigation of the time course of A-V conduction during the infusion of atropine has been reported. Nonetheless, the results obtained here with hyoscine methobromide 25 and 6.25 |a,g kg" 1 suggest that blockade of A-V nodal cholinoceptors is likely to be more stable. In spite of these few differences, and of the fact that A-V blockade does not preclude tachycardia, S-A and A-V nodes evidently respond in much the same way to atropine and hyoscine methobromide. A negative chronotropic effect is generally accompanied by a negative dromotropic effect.
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