Department of Anesthesia and Intensive Care, Pitié-Salpétrière Hospital, Paris, France *Corresponding author: Département dAnesthésie-Réanimation chirurgicale, St Antoine Hospital, 184 rue du Fbg St Antoine, F-75012 Paris, France
Accepted for publication: September 25, 2001
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Abstract |
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Methods. Rabbit hearts were perfused by a Langendorf technique with red blood cells mixed with modified KrebsHenseleit buffer. Coronary blood flow (CBF), oxygen consumption and myocardial performance were evaluated during exposure to 0.5, 1 and 2 rabbit minimum alveolar concentrations of halothane, desflurane and isoflurane. Thereafter, the same protocol was applied with the addition of NG-nitro-L-arginine (L-NNA), indomethacin or a combination of both inhibitors.
Results. Similar and significant increases in CBF were observed with increasing concentrations of isoflurane and desflurane. In contrast, CBF did not change with halothane. The combination of the two antagonists abolished desflurane-induced vasodilation, whereas it did not change the isoflurane-mediated increase in CBF. Halothane-induced vasoconstriction was observed in the presence of a combination of indomethacin with L-NNA.
Conclusions. Halothane and desflurane induce the release of vasodilating prostaglandins and NO in rabbit coronary arteries. In contrast, these mediators are not involved in the coronary vasodilating properties of isoflurane.
Br J Anaesth 2002; 88: 399407
Keywords: anaesthetics volatile, halothane; anaesthetics volatile, isoflurane; anaesthetics volatile, desflurane; heart, vascular endothelium; pharmacology, nitric oxide; hormones, prostaglandins
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Introduction |
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The mechanisms of these coronary effects are complex and not yet fully understood. The vascular endothelium, in producing vasorelaxant substances such as nitric oxide (NO) and prostaglandins (PGs), might be involved in the vasomotor properties of halogenated agents. This hypothesis has been investigated mainly for halothane and isoflurane. Several conflicting results have led to the conclusion that endothelium-dependent vasodilating factors are released6 7 or not released8 by coronary vessels exposed to halothane or isoflurane. The role of vasodilating substances released from the endothelium in desflurane-induced coronary vasodilation has not been investigated.
Because endothelial functions may be severely impaired in several cardiovascular diseases that are frequently encountered in operative patients,9 the magnitude of endothelium-dependent coronary vasomotricity related to exposure to halogenated agents needs to be evaluated. We studied (i) the nature of the direct effects of halothane, isoflurane and desflurane on the coronary vasculature in isolated red blood cell-perfused hearts, and (ii) whether the cyclooxygenase and NO pathways are involved in these effects.
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Material and methods |
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Heart preparation
New Zealand albino male rabbits (22.5 kg) were anaesthetized with ether. After thoracotomy, the heart and aortic arch were excised rapidly and immersed in cold isotonic saline solution. The pericardium was removed quickly under immersion and the aorta was prepared for cannulation. The heart was mounted on an aortic cannula. Aortic retrograde perfusion at a constant hydrostatic perfusion pressure (7080 mm Hg) was started according to the Langendorf technique, as described in detail previously.10 The apparatus was modified to reduce red blood cell sedimentation and filling pressure of the circuit and to enable the continuous recording of coronary blood flow. The column used to set the perfusion pressure was replaced by a syringe with a plunger containing mercury. The plunger was attached to a displacement transducer that controlled the speed of the coronary pump. Mean coronary perfusion pressure was recorded by means of a signal pressure obtained from a small catheter located above the aortic valves and connected to a pressure transducer (Statham P23Db: Spectramed, Bilthoven, The Netherlands). The whole apparatus was enclosed in a thermostatic chamber at 37°C. Coronary venous drainage was collected through a small catheter inserted in the pulmonary artery. A cannulated fluid-filled balloon connected to a pressure transducer (model P23Db; Statham) by a rigid catheter was placed in the left ventricle through a left atrial incision. The intraventricular balloon was inflated to maintain constant left ventricular volume. Left ventricular systolic and end-diastolic pressures (LVSP and LVEDP respectively) and heart rate were recorded, and maximal positive and negative left ventricular pressure derivatives (dP/dtmax and dP/dtmin) were derived electronically from the left ventricular signal. Because intraventricular volume was held constant, dP/dtmax and dP/dtmin were inotropic and lusitropic indices respectively. Atrial pacing maintained a constant heart rate.
Perfusate preparation
Packed human red blood cells (outdated for no longer than 1 week) stored at 4°C were used to prepare the perfusate. After centrifugation, the buffy coat and plasma were discarded and erythrocytes were washed twice with 150 mM NaCl solution. The blood was reconstituted by mixing red blood cells in a modified bicarbonate buffer containing (in mM) Na+ 130, K+ 5, free Ca2+ 2.5, MgSO4 1.17, NaHCO3 28, glucose 7 and human serum albumin 0.5%. The reconstituted blood was filtered through a 40 µm filter (model SQ 40S; Pall Ultipor: Pall Biomedical, St Germain en Laye, France) to eliminate polymorphonuclear cells and avoid microaggregate formation. The blood was then oxygenated using a membrane oxygenator with the following gas mixture: oxygen 20%, carbon dioxide 5%, nitrogen 75%. After rewarming (37°C), electrolyte concentrations were adjusted to achieve physiological concentrations and sodium bicarbonate was added to obtain standard acid balance.
Blood gas measurements
Arterial and coronary venous oxygen pressures (P
O2), carbon dioxide pressures and pH were measured at 37°C (BGE; Instrumentation Laboratory, St Mandé, France). Arterial haemoglobin concentration and arterial and coronary venous saturations were measured with an oximeter (Co-oximeter 482; Instrumentation Laboratory). Arterial and coronary venous oxygen contents and myocardial oxygen consumption (MvO2) were derived using standard formulae.
Administration of halogenated agents
A fraction of the perfusate was withdrawn and equilibrated through a second membrane oxygenator with halothane, desflurane or isoflurane over a 20-min period. Anaesthetic gases were administered using agent-specific vaporizers adjusted to deliver calculated anaesthetic concentrations. This circuit was connected to the perfusion circuit by a tap. The concentrations studied were 0.5, 1 and 2 rabbit minimum alveolar concentrations (MAC) for the three agents. The white rabbit MAC has been determined as 1.39% for halothane,11 8.9% for desflurane12 and 2% for isoflurane.11 Delivered anaesthetic concentration was monitored continuously using an infrared analyser (5250 RGM; Datex-Ohmeda, Limonest, France) connected to the oxygenator gas exit.
Halogenated anaesthetic concentration measurements in the blood perfusate
Blood samples (n=36) were withdrawn to determine the inflow perfusate concentrations corresponding to 0.5, 1 and 2 rabbit MACs of the three anaesthetics. Concentrations were measured by gas chromatography (Girdel S30 [Giravion Dorand, Suresnes, France] equipped with a Porapack Q [Touzart and Matignon, Courtaboeuf, France], 5080 mesh, 200 cm column).
Experimental procedure
After aortic cannulation, each experiment included a 1-h period of stabilization. After baseline measurements had been made, infusion of the perfusate containing 0.5 MAC of halothane, desflurane or isoflurane was started. Arterial and venous samples were withdrawn for blood gas analysis during steady state in the last minute of exposure to anaesthetic. The control perfusate was reinfused and a return to control values was obtained before infusion of 1 and 2 MAC concentrations.
This procedure was applied to four different subgroups: (i) without inhibitor, (ii) in the presence of 30 µM NG-nitro-L-arginine (L-NNA), (iii) with 1.4 µM indometacin, and (iv) with both antagonists. After the hearts had been allocated at random among the halogenated agents, they were further assigned randomly to one of the subgroups of antagonists.
We planned to perform 10 experiments in each subgroup. In total, 120 experiments were performed (four subgroups of 10 animals for each anaesthetic drug).
Drugs
L-NNA (Sigma, St Louis, MO, USA) was used as an inhibitor of NO synthase. Indomethacin (Sigma) was used as an inhibitor of the cyclooxygenase pathway. Indomethacin and L-NNA were added to the perfusate containing halogenated gas to obtain the appropriate concentrations. The concentrations used were 1.4 and 30 µM for indomethacin and L-NNA respectively, which correspond to values validated in this model.13 14
Statistical analysis
Comparisons between halothane, desflurane and isoflurane without inhibitors used two-way analysis of variance (NCSS; Deltasoft, Melan, France). The between factor considered was the halogenated agent, and the within factor was the concentration of the anaesthetic. When an interaction was found between the two factors, two-way analysis of variance was again performed for pairwise comparisons.
In the three groups, one-way analysis of variance was used to test whether the control condition was regained between different anaesthetic concentrations.
Two-way analysis of variance was performed to test the effects of inhibitors on the responses to halogenated agents. The between factor considered was the inhibitor and the within factor was the concentration of the anaesthetic. When an interaction was found, two-way analysis of variance was again performed for pairwise comparisons between the inhibitor subgroups (L-NNA, indomethacin and L-NNA+indomethacin) and the control group.
One-way analysis of variance was used to test whether the control condition was regained between each anaesthetic in each subgroup.
Results are expressed as mean (SD). For all tests, the level of significance was fixed at P<0.05.
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Results |
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Electrolyte concentrations, pH, blood gases and haemoglobin values in the perfusates were not significantly different among groups (Table 1).
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Coronary effects of halothane, desflurane and isoflurane
CBF did not change with halothane (Fig. 1). In contrast, isoflurane and desflurane induced a significant increase in CBF (P<0.01) (Fig 1). This increase in CBF was similar for isoflurane and desflurane.
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Indomethacin or L-NNA given alone did not change the coronary effects of halothane and desflurane (Fig. 1). In contrast, when both inhibitors were administered simultaneously, the coronary response to halothane and desflurane was changed significantly (Fig. 1). Indeed, halothane induced coronary vasoconstriction (Fig. 1) whereas the desflurane-induced vasodilation was prevented by the combination of indomethacin and L-NNA (Fig. 1). The coronary vasodilatory effect of isoflurane was not affected by either L-NNA or indomethacin given alone or by the combination of these inhibitors (Fig 1).
Similar concentration-dependent decreases in LVSP, dP/dtmax, dP/dtmin and MvO2 were observed with the three anaesthetics in the presence of the endothelial inhibitors (Tables 2 and 3). LVEDP did not change either during administration of the inhibitors or after administration of halogenated agents (Table 2).
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Discussion |
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Many factors could influence coronary responses to halogenated anaesthetic agents. Some of the conflicting results in the literature could be related to indirect haemodynamic effects of anaesthetic agents,15 to the conditions of the experiment (isolated non-perfused preconstricted or prevasodilated vascular rings versus whole perfused coronary network),16 to the size of the coronary vessel under consideration,16 to neurovegetative influences3 or to the magnitude or rate of variation in concentration of halogenated anaesthetics.17 18 Several of these factors can be ruled out in the present study, which was carried out in a non-ejecting isolated heart model with constant heart rate, preload and perfusion pressure, and without any interaction with the autonomic nervous system. As our group has demonstrated previously that the effect of anaesthetic agents on the coronary circulation and myocardial performance depends on the type of perfusate used in the experiment,19 we chose to use isolated hearts perfused with a buffer containing red blood cells. The presence of red blood cells in the perfusate is important in the study of coronary circulation because the oxygen tension and content and baseline coronary blood flow are closer to physiological values.19 20 Previous work by our group has demonstrated that the endothelium-dependent and endothelium-independent coronary response,21 as well as the coronary reserve,22 are preserved in the blood-perfused model. Furthermore, a recent study demonstrated that the release of endothelial mediators by the vessels may be affected markedly by the absence of red blood cells.23
The rabbit coronary circulation is appropriate for the study of the influence of NO and PG pathways in the vasodilatory effects of anaesthetic agents because these mediators have been clearly demonstrated to be involved in the rabbit endothelium-dependent coronary vasodilation.13 14 24 25
In the present study, we found that both myocardial performance and oxygen consumption decreased similarly with the three anaesthetic agents tested. This allowed us to exclude the possibility that the observed differences in coronary blood flow could be related to differences in myocardial metabolic demand.
In agreement with other studies in in vivo models2 and in isolated hearts,26 isoflurane increased coronary blood flow significantly in our model. We observed an increase in CBF close to that reported by Crystal and colleagues after gradual coronary administration of isoflurane in chronically instrumented dogs.18 The mechanism of the vasodilatory action of isoflurane remains to be determined. It has been suggested that isoflurane stimulates the release of a vasodilating prostanoid from the isolated rat aortic vascular endothelium.17 In rabbit coronary microvessels, isoflurane vasodilation of conductance arteries is mediated by endothelium-dependent PGs and NO, whereas isoflurane causes endothelium-dependent constriction in the distal part of the coronary vascular bed.7 In indomethacin-treated rats, part of the coronary vasorelaxant effect of isoflurane has been ascribed to the secretion of NO.6 However, other investigators came to the opposite conclusionthat NO does not mediate coronary vasodilation induced by isoflurane.8 This discrepancy could be related to differences in experimental protocol (whole animal or isolated vascular rings) or to differences in regional circulation or to the size of the coronary vessels.7 Indeed, Park and colleagues demonstrated heterogeneous vasomotor responses, involving different endothelium-dependent mechanisms, according to the size of the coronary vessels and their preconstricted state.7 16 In the present study, we investigated the global effect of halogenated agents on the whole coronary network. The increase in CBF mediated by isoflurane was not affected by the presence of indomethacin or L-NNA, either alone or in combination. Consequently, it can be concluded that the isoflurane-induced increase in CBF was not mediated by NO or PGs. This result is in accordance with that found by Crystal and colleagues in chronically instrumented dogs.8 Many recent studies have suggested that isoflurane-induced coronary vasodilation may be related to opening of the adenosine triphosphate-sensitive potassium channels (KATP channels).27 28
We found that the coronary vasodilating ability of desflurane was similar to that of isoflurane. This assumption is in accordance with the observations of others.2 29 30 The mechanisms underlying the coronary vasodilating properties of desflurane have been poorly studied. In particular, the role of endothelium-dependent mechanisms remains to be determined. In the present study, we found that simultaneous administration of indomethacin and L-NNA completely prevented the increase in CBF induced by desflurane. Interestingly, this effect was not blocked by either indomethacin or L-NNA when administered alone. This point deserves further discussion. As shown by Berti and colleagues in the coronary circulation of rabbits, it is possible that the effect of the inhibition of either the NO or the cyclooxygenase pathway can be counterbalanced by amplification of the other.25 In conscious dogs, enhancement of the cyclooxygenase pathway may supplement altered NO synthesis to allow vasodilation of the coronary bed.31 The hypothesis that L-NNA and indomethacin given alone are not effective in blocking the NO and cyclooxygenase pathways respectively can be ruled out because we demonstrated a significant decrease in CBF (corresponding to an increase in coronary resistance) after administration of these antagonists. As has been described in other models, no additive effect on basal resistance is observed when these two inhibitors are administrated simultaneously.32
Unchanged CBF with halothane has already been shown in numerous studies.3 33 We observed a decrease in CBF in the presence of NO and PG synthase inhibitors. In isolated rat aortic vascular rings, Stone and Johns demonstrated that halothane induced vasoconstriction in the presence of indomethacin.17 In addition, the vasorelaxant effect of halothane was found to be abolished by indomethacin in rat diaphragm vessels.34 It has been shown that blockade of the NO pathway induces a significant increase in coronary resistance during halothane exposure.6 Thus, it can be hypothesized that the stability of CBF under halothane anaesthesia can be related to a balance between two opposite effects: an endothelium-dependent vasodilatory effect, which is blunted by the endothelial inhibitors, and a vasoconstrictive effect. This vasoconstrictive effect may be related indirectly to its negative inotropic property5 or to the release of an endothelium-dependent constricting factor, as has been shown recently in the pulmonary circulation.35 A direct vasoconstricting effect of halothane on coronary vascular smooth muscle is unlikely because halothane-induced vasodilation was found in coronary vessels without endothelium.36
In conclusion, marked differences in the mechanisms of the coronary response to halothane, desflurane and isoflurane were found in the rabbit heart. The cyclooxygenase and NO pathways are not involved in isoflurane-induced vasodilation. In contrast, a major part of the vasodilation induced by desflurane is related to the simultaneous release of vasodilating PGs and NO. In the presence of indomethacin and L-NNA, halothane induced coronary vasoconstriction.
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Acknowledgements |
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References |
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