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Br.J. Anaesth. (1976), 48, 935 CARDIOVASCULAR EFFECTS OF KETAMINE IN THE PITHED RAT, RABBIT AND CAT A. S. CLANACHAN, J. C. MCGRATH AND J. E. MACKENZIE SUMMARY The effects of i.v. ketamine on arterial pressure and heart rate were examined in pithed rats, rabbits and cats. In all three species ketamine caused a brief decrease in arterial pressure and heart rate. In the rat, but not in the other two species, this initial decrease in arterial pressure was followed by a pressor response which was resistant to oc-adrenoceptor blockade, depletion of tissue noradrenaline stores and adrenalectomy. It is concluded that the peripherally mediated pressor response found in the pithed rat is specific to this species, is not a result of liberation of peripheral catecholamines and does not explain the pressor effect of ketamine found in mnn and several animal species. Ketamine increases arterial pressure and heart rate in man and in several animal species (Domino, Chodoff and Corssen, 1965; McCarthy et al., 1965) by effects exerted via the autonomic nervous system (Traber and Wilson, 1969; Schwartz and Horwitz, 1975). However, it has also a direct negative inotropic action on the myocardium (Dowdy and Kaya, 1968; Fischer, 1973; Treese, Niemezyk and Reuther, 1973; Schwartz and Horwitz, 1975), so that its effect on arterial pressure may consist of an increase, a decrease, or a biphasic effect according to the experimental conditions and dose employed (McCarthy et al., 1965; Dowdy and Kaya, 1968; Traber and Wilson, 1969; McGrath, MacKenzie and Millar, 1975). In a study designed to eliminate the influence of the central nervous system, Chang, Chan and Ganendran (1969) found that ketamine 2 mg/kg i.v. caused an increase in arterial pressure in the pithed rat which was decreased by the a-blocker phentolamine, reserpine pretreatment or adrenalectomy, and which they attributed to a release by ketamine of catecholamines from the peripheral sympathetic nervous system. In a more recent study of the effects of ketamine on peripheral autonomic neurotransmission in the pithed rat (Clanachan and McGrath, 1975), ketamine caused a biphasic change in arterial pressure. The present work was designed to investigate this response further and extend the study to two further species, the rabbit and cat. METHODS The animals used were Sprague-Dawley rats (200-250 g), New Zealand White rabbits (3.03.5 kg) and cats (3—4 kg). The animals were pithed under halothane anaesthesia—rats and cats by the method of Gillespie, MacLaren and Pollock (1970), rabbits by the method of McGrath and MacKenzie (1976). Rats were given pancuronium bromide 2 mg/kg, rabbits and cats gallamine 1 mg/kg, and respiration with 100% oxygen (Harvard ventilator) was adjusted to give an end-tidal carbon dioxide concentration of 4% (Beckman LB2 medical gas analyser). A. S. CLANACHAN,* B.SC., PH.D.; I. C. MCGRATH, t B.sc., PH.D.; J. E. MACKENZIE, B.SC., PH.D., M.P.S.J University The left carotid artery was cannulated for measurement of arterial pressure (Bell and Howell transducer). Heart rate was derived from the arterial pressure pulse with a Devices ratemeter and displayed, together with arterial pressure, on a Devices MX4 or M19 recorder. Therightjugular vein was cannulated for the administration of drugs. Stimulation of the sympathetic outflow, where appropriate, was accomplished using the tip of the pithing rod, placed in the appropriate region of the spinal canal, and an indifferent electrode placed under the skin (Devices gated pulse generator and isolated stimulator, 1-ms pulses, supramaximal voltage (nominal 70-100 V) at the frequencies indicated in the text). The rectal temperature of the rats was maintained at 37 + 1 °C using a tungsten lamp, and of the rabbits and cats at 38 + 0.5 °C by means of a Palmer homoeothermic blanket. Department of Anaesthesia, Royal Infirmary, Glasgow G4 0SF. Present addresses: * Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada. •f Institute of Physiology, University of Glasgow, Glasgow G12 8QQ. Acute adrenalectomy was performed in three rats through an abdominal incision, following pithing. One rat was pithed having been obtained commercially after adrenalectomy had been performed (Scientific Products, Margate). 936 BRITISH JOURNAL OF ANAESTHESIA Statistical comparisons were made using a paired Student's t test. Drugs used were: gallamine triethiodide (Flaxedil, May & Baker), halothane (Fluothane, I.C.I.), ketamine hydrochloride (Ketalar, Parke Davis), pancuronium bromide (Pavulon, Organon), pentobarbitone sodium (Nembutal, Abbott), phentolamine mesylate (Rogitine, CIBA), reserpine, tyramine hydrochloride (Sigma Laboratories). With the exception of halothane and reserpine, all drugs were administered i.v. (•> BAT Ktort (B) RABBIT RESULTS Lo Pithed rat Ketamine 2-50 mg/kg produced a biphasic effect on arterial pressure, an initial transient (15-s) depressor response, followed by a pressor response which reached a peak at approximately 1 min after injection and decreased to control values by 3—4 min after injection (fig. 1A). The pressor response was maximal at 5 mg/kg, whereas the depressor response increased with increasing dose up to 50 mg/kg. The heart rate was decreased also in a dose-related manner up to 50 mg/kg (table I). The pressor response to ketamine 2,5 and 10 mg/kg was unaffected by phentolamine 2 mg/kg or by pretreatment of the rats with reserpine 2 mg/kg daily i.p. for 3 days (table II). Tyramine 200 j^g/kg, which increased arterial pressure and heart rate in untreated rats, had no effect in these reserpinized animals. 400 Haort Eott (C) CAT nHj 0 -200 H«ort Kaf« FIG. 1. Effects of ketamine 5 mg/kg i.v. on the arterial pressure of the pithed rat, rabbit and cat. (A) Rat. Note that time scale differs from (B) and (c) below, (B) Rabbit. Event marker indicates electrical stimulation of the upper lumbar sympathetic outflow (10 Hz, 20 s). (c) Cat. Event marker indicates electrical stimulation of the upper lumbar sympathetic outflow (10 Hz, 20 s). Note delayed increase in heart rate resulting from release of adrenal catecholamines following sympathetic stimulation. TABLE I. The maximum depressor, pressor and heart rate responses produced by ketamine in pithed animals. P values indicate significance of the difference from pre-injection control values calculated by paired t test Maximum depressor response Systolic pressure Ketamine dose Species (mg/kg) n Rat 2 9 5 15 10 18 Rabbit 20 21 50 19 5 6 %of control 93.8 ±2.7 93.8 ±1.4 0.05 893 0.001 ±1.4 85.9 ±1.4 68.6 ±3.3 75.5 ±2.1 Cat 5 2 >P 76 74 0.001 0.001 0.001 0.001 Diastolic pressure %of control 95.1 ±1.9 89.6 ±2.1 80.8 ±2.2 71.0 ±1.7 49.5 ±2.4 83.2 ±3.9 77 74 >P 0.05 0.001 0.001 Maximum pressor response Systolic pressure %of control %of >P 122.0 0.001 ±4.5 132.8 0.001 ±6.3 130.2 0.001 ±3.1 0.001 0.001 0.001 Diastolic pressure 123.4 0.001 ±3.1 124.5 0.001 ±5.7 control >P 131.2 ±4.8 145.5 ±7.9 147.5 ±4.9 135.5 ±5.0 135.9 ±63 — 0.001 0.001 0.001 0.001 0.001 Heart: rate response %of control 83.3 ±2.7 79.8 ±2.1 73.2 ±2.3 68.6 ±2.7 53.2 + 2.8 89.0 ±2.1 90 87 >P 0.001 0.001 0.001 0.001 0.001 0.001 937 CARDIOVASCULAR EFFECTS OF KETAMINE TABLE II. TTie effect of phentolamine 2 mglkg and of pretreatment with rescrpine 2 mglkg i.p. daily for 3 days on the pressor response to ketamine 2-10 mglkg in the pithed rat. P values indicate significance of the difference from control group calculated by paired t test. Neither phentolamine nor reserpine pretreatment made any significant difference to the values of control arterial pressure, (n.s. = not significant) Control dose (mg/kg) Systolic % control Diastolic % control 2 122.0 ±4.5 132.8 131.2 + 4.8 145.5 ±6.3 ±7.9 5 10 130.2 147.5 ±3.1 ±4.9 Phentolamine 2 mg/kg n Systolic % control Diastolic % control 9 118.3 ±3.2 133.4 129.1 + 5.4 143.6 ±5.2 ±6.8 15 18 128.7 + 3.5 In one rat which had been adrenalectomized chronically and in three which were adrenalectomized acutely, ketamine 5 mg/kg produced pressor responses similar to those obtained in the control Pithed rabbit Ketamine 5 mg/kg produced a short-lived depressor response which was maximal within 30 s and had returned to control values within 2 min. Heart rate was depressed transiently, also. The direct vasopressor response to stimulation of the sympathetic outflow was unaffected 2 min after ketamine 5 mg/kg (table I,fig.1B). Pithed cat As in the rabbit, in two cats studied, ketamine 5 mg/kg produced only a short-lived depressor response and a transient depression of heart rate (table I, fig. lc). Stimulation of the lumbar sympathetic outflow in the cat produced both a direct vasopressor response as a result of stimulation of vasoconstrictor nerves and a delayed response as a result of release of catecholamines from the adrenals which increased both arterial pressure and heart rate. Ketamine 5 mg/kg failed to enhance these responses (fig. lc). DISCUSSION These results demonstrate that ketamine can increase arterial pressure by a direct peripheral mechanism in the rat, but not in the rabbit or cat. In each of the latter two species, however, ketamine can produce a pressor effect in the presence of an intact central nervous system (Wong and Jenkins, 1974; McGrath, MacKenzie and Millar, 1975). The occurrence of a pressor effect following ketamine in the pithed rat, therefore, points to a particular sensitivity of this species rather than a general explanation of the 78 143.7 ±6.8 Reserpine pretreatment n P Systolic % control Diastolic % control 3 n.s. 117.9 135.8 + 6.2 160.0 ±10.2 146.2 ±5.0 3 3 n.s. n.s. ±2.9 154.2 ±10.8 124.8 ±1.5 n P 3 n.s. 5 n.s. 3 rus. mechanism by which ketamine increases arterial pressure in several species. Although the mechanism of the pressor effect of ketamine in the pithed rat is not defined closely by this study, we cannot confirm the suggestion of Chang, Chan and Ganendran (1969) that ketamine releases peripheral catecholamines since, in the experiments described here, the pressor response was unaltered by (1) the a-adrenoceptor blocker phentolamine in a dose sufficient to abolish the response to injected catecholamines or sympathetic nerve stimulation (Gillespie, MacLaren and Pollock, 1970), (2) reserpine pretreatment sufficient to decrease peripheral tissue noradrenaline concentrations to less than 2% (Gillespie and McGrath, 1974) and prevent the indirect sympathomimetic action of tyramine, and (3) adrenalectomy, both chronic and acute. In addition, the heart rate was not increased as it would have been in the presence of increased concentrations of circulating catecholamines (Gillespie, MacLaren and Pollock, 1970). In each of the three species examined, ketamine caused a decrease in arterial pressure and heart rate immediately following injection. This is in accord with the direct negative inotropic and chronotropic effect which ketamine exerts on the myocardium (Dowdy and Kaya, 1968) and which is responsible for the initial decrease in arterial pressure commonly preceding the pressor effect in intact animals (McCarthy et al., 1965; Dowdy and Kaya, 1968; McGrath, MacKenzie and Millar, 1975). In the pithed cat and rabbit this transient decrease of both arterial pressure and heart rate was the only discernible effect of ketamine, while in the rat it was followed by the pressor effect. While these initial depressant effects in the rat were dose-related up to 50 mg/kg, the subsequent pressor effect was maximal at 5 mg/kg. 938 BRITISH JOURNAL OF ANAESTHESIA This indicates that the pressor effect of ketamine is independent of the depressor effect and that at doses in excess of 5 mg/kg the depressant effects predominate. Taken alone, these results do not explain the mechanism of the pressor effect of ketamine in intact animals They do, however, indicate the absence of a direct peripheral component in the rabbit and cat. Similar results have been demonstrated in dogs during extradural anaesthesia (Traber and Wilson, 1969), and in patients with irreversible post-traumatic coma (du Cailar, 1972). Also, it has been suggested from in vitro experiments that ketamine may cause an indirect peripheral potenuation of the effects of sympathetic nerve stimulation by blockade of the uptake of noradrenaline into sympathetic nerve terminals (Montel et al., 1973; Nedergaard, 1973). In vivo, however, ketamine does not potentiate the effects of sympathetic nerve stimulation or noradrenaline in the rat (Clanachan and McGrath, 1975) or the rabbit (McGrath and MacKenzie, unpublished observations). Therefore, this indicates that ketamine exerts its pressor effect by a central rather than a peripheral mechanism in agreement with the findings of Schwartz and Horwitz (1975). ACKNOWLEDGEMENTS Excellent technical assistance was provided by Mr G. M. McCreaddie. We are grateful to Professor J. S. Gillespie and Professor R. A. Millar for their advice and support. J. C. McG. and A. S. C. were respectively in receipt of a fellowship and a scholarship from the Wellcome Trust and J. E. M. of an M.R.C. fellowship. Gillespie, J. S., and McGrath, J. C. (1974). The effect of pithing and of nerve stimulation on the depletion of noradrenaline by reserpine in the rat anococcygeus muscle and vas deferens. Br. J. Pharmacol., 52, 585. MacLaren, A., and Pollock, D. (1970). A method of stimulating different segments of the autonomic outflow from the spinal column to various organs in the pithed cat and rat. Br. J. Pharmacol., 40, 257. McCarthy, D. A., Chen, G., Kaump, D. H., and Ensor, C. (1965). General anesthetic and other pharmacological properties of 2-(0-chlorophenyl)-2-methylaminocyclohexanone H a (CI-581). J. New Drugs, 5, 21. McGrath, J. C , and MacKenzie, J. E. (1976). A pithed rabbit preparation for stimulation of different segments of the autonomic outflow. Br. J. Pharmacol, (in press). Millar, R. A. (1975). Circulatory response to ketamine: dependence on respiratory pattern and background anaesthesia in the rabbit. Br. J. Anaesth., 47, 1149. Montel, H., Starke, K., Gorlitz, B.-D., and Schumann, H. J. (1973). Tierexperimentelle Untersuchungen zur Wirkung des Ketamins auf periphere sympathische Nerven. Anaesthetist, 22, 111. Nedergaard, O. A. (1973). Cocaine-like effect of ketamine on vascular adrenergic neurones. Eur. J. Pharmacol., 23, 153. Schwartz, D. A., and Horwitz, L. D. (1975). Effects of ketamine on left ventricular performance. J. Pharmacol. Exp. Ther., 194, 410. Traber, D. L., and Wilson, R. D. (1969). Involvement of the sympathetic nervous system in the pressor response to ketamine. Anesth. Analg. (Cleve.), 48, 248. Treese, N., Niemezyk, H., and Reuther, P. (1973). Tierexperimentelle Untersuchungen iiber die myokardiale und zentralnervos ausgeloste Wirkung von Ketamin auf das Herz-Kreislauf-System. Anaesthetist, 22, 117. Wong, D. H. W., and Jenkins, L. C. (1974). An experimental study of the mechanism of action of ketamine on the central nervous system. Can. Anaesth. Soc. J., 21, 57. REFERENCES du Cailar, J. (1972). The effects in man of infusion of Althesin with particular regard to the cardiovascular system. Postgrad. Med. J. (Suppl.)—Steroid Anaesthesia, p. 72. Chang, P., Chan, K. E., and Ganendran, A. (1969). Cardiovascular effects of 2-(0-chlorophenyl)-2-methylaminocyclohexanone (CI-581) in rats. Br.J. Anaesth., 41, 391. Clanachan, A. S., and McGrath, J. C. (1975). Effects of ketamine on the peripheral sympathetic nervous system of the rat. Br. J. Pharmacol., 55, 245P. Domino, E. F., Chodoff, P., and Corssen, G. (1965). Pharmacologic effects of CI-581, a new dissociative anesthetic in man. Chn. Pharmacol. Ther., 6, 279. Dowdy, E. G., and Kaya, K. (1968). Studies of the mechanism of cardiovascular responses to CI-581. Antsthetiology, 29, 931. Fischer, K. (1973). Vergleichende tierexperimentelle Untersuchungen zum Kinfluss verschiedenen Narkotica auf das Herz; in Ketamin—Nene Ergebmsse in Forschung und Klmik. (Anaesthetiology and Resuscitation, 69) (eds M. Gemperle, D. Langrehn and H. Kreuscher), p. 11. Berlin: Springer-Verlag. EFFETS CARDIOVASCULAIRES DE LA KETAMINE SUR LES RATS, LAPINS ET CHATS AYANT ETE SOUMIS A UNE ENERVATION RESUME On a etudie les effets de la ketamine administree par voie intraveineuse sur la tension arterielle et la frequence cardiaque de rats, lapins et chats ayant ete soumis a une enervation. Sur ces trois types d'animaux, la ketamine a provoquc une breve diminution de la tension arterielle et de la frequence cardiaque. Chez le rat, mais pas chez les deux autres especes, cette baisse initiate de la tension arterielle a etc suivie par une reponse vasomotrice qui a resiste au blocus de l'adrenorecepteur alpha, a l'epuisement des reserves de la noradrenaline des tissus et a l'adrenalectomie. On en a conclu que la reponse vasomotrice peripherique que Ton a trouvee chez le rat enerv6 est specifique a cette espice, qu'elle n'est pas le resultat du degagement de catecholamines peripheriques et qu'elle n'explique pas l'effet vasomoteur de la ketamine que Ton trouve chez l'homme et chez plusieurs especes d'animaux. 939 CARDIOVASCULAR EFFECTS OF KETAMINE KARDIOVASKULARE WIRKUNGEN VON KETAMIN AUF RATTEN, KANINCHEN UND KATZEN MIT AUSGEBOHRTEM RUCKENMARK EFECTOS CARDIOVASCULARES DE LA KETAMINA EN RATAS, CONEJOS Y GATOS DESCEREBRADOS ZUSAMMENFASSUNG SUMARIO Diese MRirkxingen von Ketamin auf den arteriellen Druck und das Herzminutenvolumen bei Ratten, Kaninchen und Kfltzen mit ausgebohrtem Ruckenmark wurden untersucht. Bei alien drei Spezies kam es zu einem kurzen Abfall des arteriellen Drucks und des Minutenvolumens. Bei Ratten, aber nicht bei den anderen Spezies, war dieser anfangliche Druckabfall von einer Druckreaktion gefolgt, die gegen alpha-Adrenozeptorblockierung resistent war, ferner von einer Verringerung der Noradrenalin-Vorrate im Gewebe und von Adrenalektomie. Es wird geschlossen, dass die peripher vermittelte Druckreaktion speziflsch fur Ratten ist, nicht das Ergebnis der Freisetzung peripherer Katecholamine darstellt, und nicht den Druckeffekt von Ketamin erklart, der beim Menschen und in verschiedenen Tierarten fastgestellt wurde. Se examinaron los efectos de ketamina i.v. en la presion arterial y frecuencia cardiaca en ratas, conejos y gatos descerebrados. En las tres especies la ketamina produjo un breve descenso en la presion arterial y frecuencia cardiaca. En la rata, pero no en las otras dos especies, este descenso initial en la presion arterial fue seguido de una respuesta presora que resistio al bloqueo adrenoceptor-a, la depletion de reservas de noradrenalina histica, y adrenalectomia. Se conduye que la respuesta presora mediada perifericamente hallada en la rata descerebrada es espetifica a esta especie, no es resultado de liberation de catecolaminas perifericas, y no explica el efecto presor de la ketamina hallado en el Hombre y en diversas especies animales.