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Br. J. Anaath. (1982), 54,1105 EFFERENT VAGAL DISCHARGE AND HEART RATE IN RESPONSE TO METHOHEXITONE, ALTHESIN, KETAMINE AND ETOMIDATE IN CATS K. INOUE AND J. O. ARNDT SUMMARY The effects of methoheatone, Altfaesin, lr^tamjp^ and etomidate on single fibre discbarge of cardiac vagal efferents and on heart rate were studied in cats. Cardiac vagal efferents were inhibited markedly and regularly for equihypnotic doses of methohexitone (2.0mgkg~')) Althesin (0.1 ml kg"1) and ketamine (S.Omgkg"1), but not of etomidate (0.8mgkg"'). These inhibitory effects were independent of arterial pressure and mirrored the increases of heart rate elicited by the first three agents. Etomidate did not consistently affect cardiac vagal discharge or heart rate. Thus methohexitone, Althesin and ketamine inhibit efferent cardiac vagal drive by their central action independently of baroreflex function. This central vagolysis is probably the cause of their positive chronotropk effects. I.v. anaesthetics such as barbiturates, steroids and phencyclidine derivatives cause tachycardia in man and animals (Arndt and Zindler, 1978). Since all these agents slow the isolated heart (Reynolds, Chiz and Pasquet, 1970; Fischer, 1973; Fischer and Marquort, 1977) and most of them also markedly inhibit efferent sympathetic nerve activity (Millar et al., 1970; Skovsted, Price and Price, 1970; MacKenzie et al., 1976; Skovsted and Sapthavichaikul, 1977) the tachycardia seems to result from an inhibition of cardiac vagal drive. However, the mechanism is not generally agreed. The arterial hypotension usually associated with anaesthesia has tacitly been considered the prime mover which, via baroreflex, would inhibit vagal cardiac tone, but there is no direct proof for this notion and the hypertensive action of ketamine, for example, is certainly not compatible with such a view. This study was undertaken to analyse the effects of i.v. anaesthetics on cardiac vagal drive and it will be shown that they attenuate markedly the activity of cardioinhibitory neurones independently of baroreflex function. METHODS The analysis of the effects of i.v. anaesthetics on efferent vagal activity was performed on 58 cats with a body weight between 2.0 and 4.2kg. In these K. INOUE. M D., J. O. ARNDT, M.D ; Abteilung fur Experiment- elle Anaesthesiologie des Institutes fur Anaesthesiologie der Univeraitat DGsseldorf, Gebaude 23.02.01, Universititsstrasse 1, D-4000 Dusseldorf, Federal Republic of Germany. 0007-0912/82/101105-12 $01.00 experiments, vagal transmission to the heart was blocked by vagal dissection in the course of fibre dissection and the use of the muscle relaxant, pancuronium. We therefore evaluated the heart rate response to these agents in additional experiments on awake cats with intact vagal cardiac innervation and, for comparison, also during nitrous oxide anaesthesia. Anaesthesia. For induction of anaesthesia, the animals were placed in an airtight box into which 3-4% halothane in nitrous oxide in oxygen (3:1) was administered. After intubation of the trachea, the lungs were ventilated with a Starling pump to provide an end-expiratory carbon dioxide concentration of about 4% measured continuously by massspectrometry (Perkin Elmer MGA 1100). Surgery, which required 2 h on average to prepare for nerve activity recording was performed under 0.5-1.5% halothane in nitrous oxide in oxygen (3:1). Halothane was discontinued at least 1 h before starting nerve activity recording and the animals were immobilized with pancuronium, 0.2mgkg"' i.v. initially and 0.1 mg kg"1 i.v. supplements as needed, so that the actual experiments were performed under nitrous oxide in oxygen (3:1). The animals with an intact vagal innervation, in which the heart rate responses to the agents were analysed using nitrous oxide anaesthesia, received suxamethonium lmgkg" 1 i.v. intermittently instead of pancuronium. Body temperature was maintained at 37.5+0.5 °C with a heating lamp. Recording of nerve activity. The right cervical © The Macmillan Press Ltd 1982 BRITISH JOURNAL OF ANAESTHESIA 1106 Identification of cardiac and non-cardiac vagal efvagus was dissected free in the neck, covered with paraffin oil at body temperature to prevent drying ferents. Various vagal efferents (named type A, B and filamented under a microscope until single ac- and C in the present study) were identified accordtive fibres were obtained from central nerve bundles ing to their response to a brief increase in arterial separated from the nerve trunk. Spikes were picked pressure induced by occlusion of the descending up with bipolar platinum -iridium electrodes and aorta with an inflatable balloon (Fogarty biliary amplified with a capacitance-coupled amplifier of probe No. 5; fig. 1): type A activity increased when our own design which had an input impedance of arterial pressure was increased. Such fibres, the discharge of which has been shown to correlate 22 Mil and a bandpass between 30and 35 000Hz. Nerve activity was monitored with a loudspeaker inversely with heart rate (Jewett, 1964; Inoue, and an- oscilloscope (Tektronix type 565). The Samodelov and Arndt, 1980), are considered to be spikes were shaped to standard pulses (5 V, 0.5 ms cardioinhibitory. Type B activity decreased with induration) with a Schmitt trigger to trigger reliably a creasing arterial pressure. Type C activity remained digital counter of our own design which produced a unchanged in spite of increasing arterial pressure. spike count at 2.5- or 5-s intervals. To calculate the Types B and C are non-cardiac, although their average discharge rate (spikess"1)) the 2.5- or 5-s target organs were not identified. values were averaged for periods of 10-30 s. The Evaluation of the drug effects. The drug effects on technical details of the spike processing system have type A fibres were evaluated in two different ways: been described in detail (Arndt, Morgenstern and (l)From the time-course of average discharge rate Samodelov, 1977). following drug injections either independently of Parameters measured. Arterial pressure was meas-arterial pressure or at arterial pressures kept at or ured electromanometricaUy (Statham P 37 B) with a greater than the pre-injection values by inflation of fluid-filled catheter advanced into the thoracic aorta the aortic balloon. (2) By comparing pressurefrom a femoral artery and heart rate with a car- response curves determined before and 2 min after drug injections. These pressure-response diotachometer triggered by the e.c.g. All data were recorded continuously oil a mul- curves were derived by relating average discharge tichannel pen-recorder (Beckmann type RM dyno- rates with various arterial pressures increased or decreased relative to the control pressure by inflatgraph recorder). TIME SCALE (•) ARTERIAL PRESSURE Aortic SPIKES Occlusion l ! i l l i t i l| EFFERENT VAGAL DISCHARGE RATE (Spikes/2.5s) HEART RATE _ (beotmin"1) Typ. B Typ. C FIG. 1. Responses of various vagal efferents to an inHii™-H hypertension. Original recordings from three cats nitrous oxide in oxygen anaesthesia. The transient increase in arterial pressure by aortic occlusion i to an increase (type A), decrease (type B) or no rtungr in fibre discharge (type C). VAGAL DISCHARGE AND HEART RATE IN CATS ing or by rapidly deflating the aortic balloon (fig. 1). Responses of non-cardiac type B and type C efferents to the drugs were evaluated qualitatively and judged as activation, no change or inhibition. The following doses were used: methohexitone 2.0mgkg-', Althesin O.lmlkg- 1 , ketamine S.Omgkg"1 and etomidate 0.8mgkg-'. They were found to be equipotent according to pilot experiments in awake cats. Experimental procedure. The experiments were started at least 1 h after surgery when nerve activity, arterial pressure and heart rate were in a steady state and when several pressure-response curves were identical. Each drug was administered within 3 s through a catheter placed in the right atrium. The drugs were administered in random sequence and sufficient time, usually 45min, was allowed between each injection for complete recovery of the variables studied. XX 200 XX 1107 In the experiments for the evaluation of the chronotropic effects of the agents in anaesthetized cats, each drug was given in the same way as above, but at least Smin after the injection of suxamethonium to avoid interference with cardiovascular effects of the muscle relaxant. Data analysis. To demonstrate the time-course of the drug effects on discharge rate of cardioinhibitory vagal efferents the data are expressed as percentages of the values before injection for each individual fibre. The pressure-response curves were constructed for each individual fibre before and after drug injection. The discharge rates and corresponding arterial pressures were averaged to derive the average pressure-response curves. The data are presented in means + SEM except for the time-course of the drug effects. The differences between values before and after injection were 200 Methohexitone (2 0mg kef1) Althesin (0 1ml kg'1) 150 /7=6 /7=6 LU 100 •J- / / t- cc tr 200 J- _l 10 10 ° L l_l 0 200 r 10 y UJ i 150 100 Ketamine l5 0mg kg"1) 150 Etomidate IO8mg kg"1) n-1 100 10 TIME 0 (mm) FlG. 2. Heart rates after i.v. injections of the four anaesthetics in awake cats (mean ± SEM). Significance test between the controls and postinjection values: x P < 0 . 0 5 ; x x P < 0 . 0 1 . 10 BRITISH JOURNAL OF ANAESTHESIA 1108 tested with Student's ttest for paired samples, since Drug effects on cardiac vagal efferents in anaestheteach cat served as its own control. Differences were ized cats. The discharge rates of cardioinhibitory vagal efferents always decreased with methohexconsidered significant when P<0.05. itone, Althesin and ketamine, but their responses to etomidate were unpredictable. As shown in original RESULTS recordings (fig. 3), the average discharge rates are Hypnotic and chronotropic effects of the drugs in awake much less after than before the injection of cats. The doses used were found to be equipotent in methohexitone, Althesin and ketamine, but there their hypnotic effects by pilot studies on awake cats. was hardly a response to etomidate. Awake cats lay down, closed their eyes, and lost To exclude the initial, transient decrease in arteritheir righting reflexes within 5-25 s after injection al pressure seen in figure 3 as a possible factor for a and woke up 4-6 min later as judged by their ability baroreflex-mediated vagal inhibition, the decrease to raise their heads and open their eyes. in pressure was prevented by balloon occlusion of As is seen in figure 2, this was accompanied by an the descending aorta in some experiments. abrupt increase in heart rate by about 40 beat min-1 In the example shown in figure 4, vagal discharge within 30 s after injection of methohexitone and rate clearly decreased following methohexitone in Althesin. With ketamine, the increase in heart rate spite of constant arterial pressure and with Althesin by about 20 beat min-1 developed gradually and and ketamine even when arterial pressure was inreached its maximum 2 min after injection. Etomi- creased. The last is worth stressing because indate had no consistent effect except for a transient creased arterial pressure by itself in the absence of increase immediately after the injection. anaesthetics activates vagal discharge of type A T I M E SCALE (*) ARTERIAL PRESSURE 200 H kPtO 200 20 100 10 0 0 100 1 SPIKES EFFERENT VAGAL DISCHARGE RATE (Spik*i/S») 20 0 Methohexitone (2.0 mg kg-1| Althesin (01ml kg'1) TIME SCALE (») (mmHo) (kPo) ARTERIAL 200 PRESSURE L20 100 "U SPIKES EFFERENT VAGAL DISCHARGE RATE 20 (Spikts/St) Ketamine l5 0mg kg"1) Etomidate 10 8 mg kg"1! FIG 3. Effects of the four anaesthetics on discharge rates of cardioinhibitory vagal efferents. Original recordings from four cats under nitrous oxide in oxygen anaesthesia. VAGAL DISCHARGE AND HEART RATE IN CATS 1109 ARTERIAL PRESSURE SPIKES EFFERENT VAOAL DISCHARGE RATE (Spikm/Ss) —'-jttm Etomidate (0.8 mg kg"1) FIG 4. Effects of the four anaesthetics on discharge rates of cardioinhibitory vagal efferents with constant or slightly increased arterial pressure. Original recordings from three cats under nitrous oxide in oxygen anaesthesia. The initial decrease in arterial pressure seen in figure 3 was prevented here by controlled balloon occlusion of the descending aorta. fibres (fig. 1). Such an activation, in fact, is seen with etomidate in figure 4. Methohexitone, Althesin and ketamine had similar effects in all experiments, as is seen in figure 5. Irrespective of whether the early decrease in arterial pressure was prevented, discharge rate decreased without exception during the first 5 min after injections of these three agents and returned gradually to the controls during the following 30 min. In contrast to this, etomidate did not produce regular changes in discharge rates, irrespective of the arterial pressure. The differences in the time courses of vagal activity are also of interest. After injections of methohexitone and Althesin, discharge rates attained their minimum rapidly during the 1st min, but more slowly within 2 min following ketamine. We considered it therefore appropriate to compare the inhibitory action of these agents for their values 2 min after injections, particularly since, at this time, arterial pressure had reached the pre-injection values in all experiments. For quantitative analysis of the fibre response, pressure-response curves were determined for each cardioinhibitory fibre before and 2 min after drug injections. The original recording in figure 6 shows how these response curves were derived. In the control, nerve discharge rate increased above the preocclusion value when arterial pressure was increased for about 25 s by inflating the aortic balloon and decreased below the preocclusion value when the balloon was deflated. Clearly, 2 min after the injection of ketamine, average discharge rate was less for each arterial pressure value which was of the same magnitude as during the control. Thus, ketamine inhibits nerve activity independently of arterial pressure. Figure 7 was obtained by relating discharge rates and the corresponding pressure values before and 2 min after injections for each fibre. Except for etomidate, the pressure-response curves are dis- 1110 BRITISH JOURNAL OF ANAESTHESIA 200 EFFERENT VAOAL OISCHAROE RATE MEAN ARTERIAL PRESSURE Methohexitone (2.0mgkg' 1 ) 200 150 150 100 100 50 50 0 0 130 130 100 100 Althesm (0.1 ml kg'1) •J:-.-.-.~.~,.-t (H) 70 EFFERENT VAOAL OISCHAROE RATE 200 70 L W/Ketamine (5.0 mg kg'1) (00 " /\ Etomidate (0.8 mgkg'1) 150 100 50 0 MEAN ARTERIAL PRESSURE 130 100 70 >- » i5 20 Time (min) 25 30 5 10 15 20 25 30 Time (min) FIG S. Time course of the discharge of cardioinhibitory vagal efferents foUowingithe injection of the four ^anaesthetics. Data from 19 cats under nitrous oxide in oxygen anaesthesia. The initial decrease in arterial pressure was either not prevented (continuous lines) or was prevented by aortic occlusion (dotted lines). placed to lower activity and their slopes are reduced. Methohexitone, Althesin and ketamine not only inhibit vagal discharge independently of arterial pressure but, in addition, they also inhibit the pressure-dependent fibre response as indicated by the reduced slopes. Taking the average discharge rate at the control pressures (centre point of the curves) as 100, the activity is reduced by 90, 73 and 55% for Althesin, methohexitone and ketamine, respectively. Thus, for equipotent doses, the extent of the pressureindependent, central inhibition of vagal cardioinhibitory efferents is different for various agents. It is most marked with Althesin, followed by methohexitone and ketamine, whereas etomidate has no effect. Drug effects on non-cardiac vagal efferents in anaes- thetized cats. Non-cardiac fibres responded less uniformly to the anaesthetics than the cardiac. According to table I, inhibition prevailed with methohexitone and Althesin which, however, had no effect on about one-third of type C fibres. This nonuniformity was more pronounced with ketamine. It inhibited only a minority of non-cardiac fibres, had no effect in about half of them and even activated some. The response-pattern of non-cardiac fibres agreed with that of the cardiac only in case of etomidate. Thus, the same anaesthetic may act differently on different neurones (type A, B and C) whereas the particular cardioinhibitory type A VAGAL DISCHARGE AND HEART RATE IN CATS 1111 Control TIME SCALE (») (mmHg) (kPo) ARTERIAL 200 PRESSURE SPIKES EFFERENT VAGAL DISCHARGE RATE (Splk»»/2S«) 0 2min after Kttamin* I5mg kg"1iv) TIME SCALE (*) (mmHgMkPa) gMk ARTERIAL 2 PRESSURE 1oo ,., i.o o-L o-L o SPIKES EFFERENT VAOAL DISCHARGE RATE (Splk*i/2Si) 40 20 0 FIG 6. The discharge of a cardioinhibitory vagal fibre at three different arterial pressures before and 2 min after injection of ketamine. Original recording from a cat under nitrous oxide in oxygen anaesthesia. Arterial pressures were altered by controlled occlusion of the descending aorta by a balloon. neurone is inhibited by various anaesthetics (methohexitone, Althesin and ketamine). etomidate. These effects correspond, by and large, with our observation in awake cats shown in Chronotropic effects of the agents in anaesthetized figure2. cats with intact cardiac vagal innervation. The chronotropic effects could not be analysed in these experiments because of the atropine-like action of pancuronium and the disruption of the vagal nerves in the course of fibre dissection. Therefore, it was necessary to evaluate the heart rate responses to the agents in cats with an intact vagal innervation, but otherwise under similar conditions. According to table II, the heart rate increased 2 min after injections of methohexitone, Althesin and ketamine by 36, 52 and 23 beatmin"1, respectively, and there was on average no change with DISCUSSION Our experiments were primarily designed to study the effects of anaesthetics on cardiac vagal drive and a central question is if the fibres of which responses were tested here, do innervate the heart. In general, it is difficult to identify the organ specificity of vagal efferents. Such differentiation has been attempted according to their response to variations in arterial pressure and lung mechanics. In spontaneously breathing dogs, Jewett (1964) discriminated seven BRITISH JOURNAL OF ANAESTHESIA 1112 15 15 Althesm (01ml kg*1) Methohexitone l2 0mg kg'1 10 10 n=6 1 10 DC 50 100 150 200 5 0 1 0 0 1 5 0 2 0 0 2 5 0 250 < O 15 15 Ketamine 15.0 nig kg'1 Etomidate (08mg kg'1) 10 10 30 (kPo) 100 150 200 250 50 100 MEAN ARTERIAL PRESSURE 150 200 250 (mmHg) FIG. 7. Pressure-response curves of cardioinhibitory vagal efferents in the control (O) and 2 min after the injection ( • ) of the four anaesthetics. Results from cats under mtroui oxide in oxygen anaesthesia (mean±SEM). Significance test between the controls and postinjection values. x P < 0 . 0 5 ; x x P < 0 . 0 1 . different fibre groups. His type I fibres were activated only during expiration, their discharge increased with increasing arterial pressure and correlated inversely with heart rate. In Jewett's view, which was later adopted by several others (Katrona et al., 1970; Hakumaki, 1972; Davidson, Goldner and McCloskey, 1976) these fibres are cardioinhibitory. Since we worked with ventilated and paralysed cats, neither lung mechanics nor the heart rate response which was blocked by the vagolytic action of the muscle relaxant, could be taken into consider- ation. Nevertheless, our type A fibres conform to Jewett's type I in one important point, in that they were not only activated by an increase in arterial pressure, but their discharge followed without delay the induced arterial pressure change and correlated closely with the arterial pressure as shown by the pressure-response curves in figure 7. By these criteria, the type A fibres the discharge rate of which has previously been shown to correlate with heart rate (Inoue, Samodelov and Arndt, 1980), could be distinguished clearly from non-cardiac vagal fibres. VAGAL DISCHARGE AND HEART RATE IN CATS 1113 TABLE I. Effects of the four anaesthetics on acttmties of various vagal efferents Methohexitone 2.0mgkg" 1 Althesin 0.1 ml kg"1 Ketamine O.Smgkg"1 Inhibition Activation No change 8/8 6/6 7/7 3/7 3/7 1/7 TypeB Inhibition Activation No change 5/5 3/3 2/4 1/4 1/4 2/4 2/4 TypeC Inhibition Activation No change 11/16 12/17 5?16 5/17 3/13 3/13 7/13 4/11 2/11 5/11 Fibre Response Type A Etomidate TABLE II. Heart rate (beat mtn~l) after injections of the four anaesthetics (mean 1 SEM). *P < 0.05, **P < 0.01 Tune after injection (min) Drug 0.25 Methohexitone 2.0mgkg" 1 («=6) 158±8 Althesin 0.1 ml kg"1 (» = 6) 0.5 177±9 * * 195±3 * * 155114 180112 197113 Ketamine 159110 188112 ** Etomidate 161112 173111 n.s. 10 194±5 * * 193±5 * * 204113 206113 207113 207113 192117 180112 * 183111 * 182111 * 181111 * 179111 ** 176112 n.s. 173112 n.s. 168113 n.s. 164113 n.s. 162114 n.s. 160114 n.s. 161111 n.s. Our non-cardiac type B and C fibres which were either inhibited or not affected by the induced arterial pressure change, contained a variety of fibres. Since we were only interested to observe how these non-cardiac fibres would respond to anaesthetics in comparison with cardioinhibitory type A fibres, no further attempts were made to identify their target organs. The atropine-like action of pancuronium and vagal dissection in the course of the nerve filamentation blocked the effects on heart rate which were seen after drug injection in conscious and anaesthetized cats with intact vagal innervation. Irrespective of the actual heart rate response, the type A fibres are cardioinhibitory and their activity may be taken as a neurophysiological correlate of cardiac vagal tone. Nitrous oxide, which renders cats analgesic with- * 194±4 * * 191 ± 5 * 184±5 * out impairing evoked potentials in the brain, has been advocated as the most suitable anaesthetic for neurophysiological work (Venes, Collins and Taub, 1971). It was preferred also because there is evidence that nitrous oxide does not alter the heart rate effects of other anaesthetics. In man, the heart rate increased little (2.65%) when nitrous oxide was added to light halothane anaesthesia (0.8-1.2% in oxygen) and by even less (0.82%) when nitrous oxide was added to deep halothane anaesthesia (1.2-2.0% in oxygen) (Smith et al., 1970). Finally, in dogs, addition of nitrous oxide to halothane anaesthesia (0.5-2.5% in oxygen), elicited the same degree of bradycardia found with halothane in oxygen (Smith and Corbascio, 1966). It appears reasonable to interpret the described responses of the type A fibres as the drug action perse rather than as a consequence of their additive action with nitr- 1114 ous oxide. Methohexitone, Althesin and ketamine, but not etomidate, inhibited without exception cardioinhibitory vagal efferents. These fibres originate from the vagal nuclei in the medulla, the nucleus ambiguus and vagalis dorsalis (Spyer, 1980), and their discharge constitutes the neurophysiological correlate of cardiac vagal tone and thus of heart rate (Jewett, 1964). In the dose range used in this study, none of these agents exerts an atropine-like peripheral action (McGrath, MacKenzie and Millar, 1975; MacKenzie et al., 1976). All have a negative chronotropic effect on the isolated heart (Reynolds, Chiz and Pasquet, 1970; Fischer, 1973; Fischer and Marquort, 1977) and, with the exception of ketamine, all inhibit efferent sympathetic drive (Millar etal., 1970; Skovsted, Price and Price, 1970; MacKenzie et al., 1976; Skovsted and Sapthavichaikul, 1977). The positive chronotropic actions of these agents are therefore the consequence of an inhibition of cardiac vagal drive. This applies also to ketamine, which activates efferent sympathetic drive (Niederstrasser, 1981) but the action of which in producing tachycardia is nevertheless blocked by atropine rather than by propranolol (Traber, Wilson and Priano, 1970a, b). In our neurophysiological studies, the drug effects on heart rate could not be identified. When cardiac vagal innervation was intact, the heart rate responded similarly in the conscious state and under nitrous oxide anaesthesia. Under both conditions, the tachycardia, in correspondence with the degree of vagal inhibition, was most pronounced with Althesin followed by methohexitone and ketamine whereas etomidate had no effect. It seems permissible, therefore, to consider the responses of cardiac vagal efferents to these agents as a principal cause of their heart rate effects. The inhibition of vagal efferents was shown to be independent of arterial pressure as it occurred at constant and even at increased pressure, which usually activates these fibres. This conclusion is also supported by the clear-cut displacement of the pressure-response curves to lower activities with all agents except etomidate. Pressure-dependent effects via arterial baroreflexes cannot, therefore, explain the fibre responses. Also probably excluded are drug-induced changes in baroreceptor activity which, in the presence of constant arterial pressure, might have altered afferent baroreceptor drive. Methohexitone, for example, excites baroreceptors (Schumacher BRITISH JOURNAL OF ANAESTHESIA and Arndt, 1978). This, however, should activate cardiac vagal efferents but not inhibit them. Ketamine has no effect on baroreceptors (Slogoff and Allen, 1974; Hagenau, Pietsch and Arndt, 1976), but nevertheless inhibits vagal efferents. A peripheral event via the afferent discharge of arterial baroreflexes is therefore an unlikely causal factor for the inhibitory action of these agents on cardiac vagal tone. Hence one can conclude that, contrary to the widely held view, the vagolytic action of certain i.v. anaesthetics is of central origin and independent of arterial pressure and baroreflex function. This conclusion does not, however, deny the importance of baroreflexes in anaesthesia. In fact, the well-known impairment of baroreflex function (Morrison, Walker and Richardson, 1950; Bristow et al., 1969; MacKenzie et al., 1976) is seen also in our experiments in the reduced slopes of the pressure-response curves of cardioinhibitory vagal efferents, which are particularly pronounced with methohexitone and Althesin. This shows that these agents, in addition to their central vagolytic effects, also attenuate the baroreflex-mediated, pressuredependent control of heart rate. Hence, the action of anaesthetic agents on the cardiac vagus has two different aspects. They exert a central vagolytic action which is independent of arterial pressure and which determines heart rate. They also attenuate the pressure-dependent responsiveness of cardiac vagal tone and thereby the body's capability to stabilize reflexly its arterial pressure against challenges such as blood loss and orthostatic stress by the appropriate heart rate responses. Although the neurophysiological evidence is lacking at present, it is presumably the central vagolytic action of anaesthetics that determines the heart rate response in other species. First, heart rate is dominated physiologically by vagal rather than sympathetic influences (Bishop, Peterson and Horwitz, 1976). Second, in animals, most i.v. anaesthetics inhibit efferent sympathetic drive which was demonstrated for thiopentonc in man also (Wallin and Konig, 1976). Third, the heart rate responses to the agents studied correspond roughly with those found in other species. Whereas etomidate affects heart rate little in dogs as well as in man, the others elicit pronounced tachycardia in both species (Patschke et al., 1977; Arndt and Zindler, 1978). In nonpremedicated man, for example, heart rate increases by 20 beatmin"1 or 30% on average for recommended clinical doses of barbiturates, Althesin and ketamine, and by 45 beat min~' after complete VAGAL DISCHARGE AND HEART RATE IN CATS 1115 carotid sinus reflex. Am. J. Phynol., 218, 1030. Inoue, K., Samodelov, L. F., and Amdt, J. O. (1980). Fentanyi activates a particular population of vagal efferent* which are cardioinhibitory. Naunyn Schmudtbtrg's Arch. Pharmacol., 312, 57. Jewett, D. L. (1964). Activity of single efferent fibres in the cervical vagus nerve of the dog, with special reference to possible cardioinhibitory fibres. / . Physiol. (Land.), 175, 321. McGrath, J. C , Mackenzie, J. 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O., Morgens.tern, J-, and Samodelov, L. (1977). The Patschke, D . , Bruckner, J. B., Gethmann, J. W., Tarnow, J., physiologically relevant information regarding systemic blood and Weymar, A. (1977). A comparison of the acute effects of pressure encoded m the carotid sinus baroreceptor discharge intravenous induction agents (thiopentone, methohexitone, pattern. / . Physiol. (Land.), 268, 775. propanidid, Althesin, ketiunine, piritramide and etomidate) on Zindler.M. (1978). Effects of intravenous anesthetics on the '. modynamics and myocardial oxygen consumption in dogs; circulation and its control; in Hemodynamtc Changes in Anesin Etomidate—An Intravenous Hypnotic Agent (ed. A. tkesia, Academie Europeene D'Anesthesiologie, The 5th EuroDoenkke), Anaesth Wiederbei, vol. 106, p. 49. Berlin, pean Congress of Anaesthesiology, Pans, vol. 3, p. 1069. Heidelberg, New York: Springer-Verlag. Bishop, V. S., Peterson, D. F., and Horwitz, L. D. (1976). Factors influencing cardiac performance. Int. Rev. Phynol., 9, Reynolds, A. K., Chiz, J. F , and Pasquet, A. F. (1970). 239. Halo thane and methoxyflurane—A comparison of their effects on cardiac pacemaker fibers. Anesthestology, 33,602. Bnstow, J. D . , Prys-Roberts, C , Fisher, A., Pickering, T. G., and Sleight, P. (1969). Effects of anesthesia on baroreflex Robinson, B. F., Epstein, S. E., Beiser, G. D . , and Braunwald, control of heart rate in man. Antsthawlogy, 31,422. E. (1966). Control of heart rate by the autonomic nervous system. Cm. Res., 19,400. Davidson, N. S., Goldner, S., and McCloskey, D. I. (1976). Respiratory modulation of baroreceptor and chemoreceptor Schumacher, I. G., and Amdt, J. O. (1978). Der Effekt von reflexes affecting heart rate and cardiac vagal efferent nerve Methobexital, Fentanyi, Dehydrobenzperidol sowie von activity. / . Phynol. (Loud.), 259, 523. Chloralose auf die Aktivitat der Barorezeptoren des Aortenbogens decerebrierter Katzen. Anaesthesist, 27,10. Fischer, K. (1973). Vergleichende tierexperimentelle UnterSkovsted, P., Price, M. L., and Price, H. L. (1970). The effects suchungen zum Finflnft verschiedener Narkotica auf das Herz; of short-acting barbiturates on arterial pressure, preganglionk in Kttamint—Neue Ergtbnisu in Fonchung und Klinik (eds M. sympathetic activity and barostatic reflexes. Anathtsiology, 33, Gemperlem, D. Langrehr and H. Kreuscher), Anattth. 10. Wiederbel., vol. 69, p. 11. Berlin, Heidelberg, New York: Springer-Verlag. Sapthavkhaikul, S. (1977). The effects of etomidate on arterial pressure, pulse rate and preganghonk sympathetic Marquort, H. (1977). Experimental investigations on the activity in cats. Can. Anaesth. Soc. J., 24, 565. direct effect of etomidate on myocardial contractility; in Etomidate—An Intravenous Hypnotic Agtnt(cd. A. Doemcke), Slogoff, S., and Allen, G. W. (1974). The role of baroreceptors in the cardiovascular response to ketamine. Anath. Analg. Anaatk. Wiederbel., vol. 106, p. 95. Berlin, Heidelberg, New (CUv*.), 53, 704. York: Springer-Verlag. Smith, N. T., and Corbascio, A. N. (1966). The cardiovascular Hagenau, W., Pietsch, D., and Amdt, J. O. (1976). Der Effekt effects of nitrous oxide during halothane anesthesia in the dog. von Halothan und Enfhirane sowie von Propanidid und KetaAnesthestology, 27, 560. min auf die Aktivitat der Barorezeptoren des Aortenbogens Eger, E. I., n, Stoelting, R. K., Whayne.T. F.,Cullen, D., decerebrierter Katzen. Anaesthetist, 25,331. and Kadis, L. B. (1970). The cardiovascular and symHakumiki, M. O. K. (1972). Vagal and sympathetic efferent pathomimetic responses to the addition of nitrous oxide to discharge in the Bainbridge reflex of dogs. Ada. Physiol. halothane in man. Anesthestology, 32,410. Scand., 85,414. Spyer, M. (1980). Neural organisation and control of barorecepKatona, P. G., Poitras, J. W., Barnet, G. O , and Terry, B. S. tor reflex. Rev. Physiol. Biochem. Pharmacol., 88,24. (1970). Cardiac vagal efferent activity and heart period in the vagolysis with atropine 0.04mg kg"1 (Robinson et al., 1966). The estimate based on this comparison agrees fully with the neurophysiologically documented vagal inhibition in case of ketamine, but is smaller for Althesin and methohexitone. Yet, considering the dose-dependency of the heart rate effects (Patschke et al., 1977) and the problem of comparing equipotency of doses between species, not much emphasis can be put on these differences. It is presumably, therefore, the central vagolytic action which determines the heart rate response to these agents in man also. The central inhibition of cardiac vagal neurones was- demonstrated here neurophysiologically and found to be independent of baroreflex function and to differ in degree for equihypnotic doses of Althesin, methohexitone and ketamine. Etomidate had no consistent effect on cardiac vagal drive. BRITISH JOURNAL OF ANAESTHESIA 1116 Trabcr, D. L., Wilson, R. D , and Priano, L. L. (1970s). The effect of beta-adrenergic blockade on the cardiopulmonary response to ketamine. Anesth. Analg. (Cleve.), 49,604. (1970b). A Hftail>H study of the cardiopulmonary response to ketamine and its blockade by atropine. South. Med. /.,63,1077. Venes.J. L.,Collins, W.F.,andTaub, A. (1971). Nitrous oxide: an anesthetic for experiments in cats. Am. J. Phyttol., 220, 2028. Wallin, B. G., and Konig, U. (1976) Changes of skin nerve sympathetic activity during induction of general anaesthesia with thiopentone in man Brain Res., 103,157. RESPONSE VAGALE EFFERENTE ET FREQUENCE CARDIAQUE APRES INJECTION DE METHOHEXITONE, D'ALTHESIN, DE KETAMINE ET D'ETOMIDATE CHEZ LE CHAT. EFFERENTE VAGUSENTLADUNG UND HERZFREQUENZ NACH METHOHEXITAL, ALTHESIN, KETAMIN UND ETOMIDATE BEI KATZEN ZUSAMMENFASSUNG Die chronotropen Effekte von Methohexital, Althesin, Ketamin und Etomidate auf die FntlaHnng riner Faser des efferenten Herzvagus und auf die Herzfrequenz wurde an Katzen untersucht. Der efferente Herzvagus wurde ausgepragt und regelmafiig durch aquipotene Dosen von Methohexital (S.Omgkg"1) Althesin (O.lmlkg" 1 ) und Ketamin (5,0mgkg~ l ), aber nkht durch Etomidate (O.Smgkg"1) inhibiert. Diese inhibitorachen Effekte waren nnahhangig vom arteriellen Druck und spiegelten den Anstieg der Herzfrequenz, die durch die ersten drei Substanzen ausgeldst worden war, wkder. Etomidate beeinflufite weder die Entladung des Herzvagus noch die Herzfrequenz. So inhibieren also Metohexital, Althesin und Ketamin den efferenten Herzvagus durch ihre zentrale Wirkung unabhangig von der Funktkra der Baroreflex-Funktion. Diese zentrale Vagolyse ist wahrscheinlich die Ursache ihres positiven chronotropen Effektes. DESCARGA VAGAL EFERENTE Y RTTMO CARDlACO EN RESPUESTA A METOHEXITONA, ALTESINA, QUETAMINA Y ETOMIDATO EN LOS GATOS RESUME SUMAJUO Nous avons etudie les effets chronotropes de la methohexitone, de 1'Althesin, de la ketamine et de l'etomidate sur la decharge d'une fibre unique des efferents cardiaques vagaux et sur la frequence cardiaque chez le chat. Les efferents cardiaques vagaux etaient inhibes de facon marquee et reproductible pour des doses equihypnotiques de methohexitone (2,0mgkg-') d'Althcsin (O.lmlkg"1) et de ketamine (S.Omgkg"1) mais pas d'etomidate (0,8mgkg~')- Ces effets mhibiteurs etaient independants de la pression arterielle et refletaient les augmentations de frequence cardiaque induites par les trois premiers agents. L'etomidate n'avait reguliirement pas d'eifets stir la decharge cardiaque vagale ou la frequence cardiaque. Ainsi la methohexitone, 1'Althesin et la ketamine inhibent la transmission vagale cardiaque efferente par leur action centrale independemment du baroreflexe. Cette vagolyse centrale est probablement la cause de leurs effets chronotropes positifs. Se llevaron a cabo estudios sobre los efectos cronotropicos de la metohexitona, la altesina, la quetamina y el etomidato en la descarga de fibra unica de los eferentes vagales cardiacos y en el ntmo cardiaco. Los eferentes vagales cardiacos fueron inhibidos de manera marrada y regular por dosis equihipnoticas de metohexitona (2,0mgkg~ 1 ), de Altesina (0,1 ml/kg"1) y de quetamina (5,0 mg/kg"), perono fue asi por las de etomidato (0,8 mg/kg" 1 ). Dichos efectos inhibitorios fueron independientes de la presion arterial y reflejaron los aumentos del ritmo cardiaco producidos por los tres pnmeros agentes. El etomidato no afecto la descarga vagal cardiaca ni tampoco el ritmo cardiaco, y eso de manera uniforme y constante. Entonces, la metohexitona, la Altesina y la quetamina inhiben el impulso vagal cardiaco eferente por su accidn central, independientemente de la funcion de baroreflejo. Esta vagblisis central constituye probablemente la causa de sus efectos cronotropicos posirivos.