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Anesth Analg 2004;98:595-603
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000100681.15355.AC

CARDIOVASCULAR ANESTHESIA

Amplification by Hyperoxia of Coronary Vasodilation Induced by Propofol

Alexandre Ouattara, MD*,{dagger}, Gilles Boccara, MD PhD*,{dagger}, Patrick Lecomte, MD*,{dagger}, Rachid Souktani, PhD*,{dagger}, Philippe Le Cosquer, MD*,{dagger}, Stéphane Mouren, MD PhD*,{dagger}, Pierre Coriat, MD*,{dagger}, and Bruno Riou, MD PhD*,{ddagger}

*Laboratory of Anesthesiology, Université Pierre et Marie Curie, Paris; {dagger}Department of Anesthesiology and Critical Care, Centre Hospitalier Universitaire Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris; {ddagger}Department of Emergency Medicine and Surgery, Centre Hospitalier Universitaire Pitié-Salpêtrière, Paris, France

Address correspondence and reprint requests to Dr. Alexandre Ouattara, Département d’Anesthésie-Réanimation, Hôpital Pitié-Salpêtrière, 47 boulevard de l’Hôpital, 75651 Paris Cedex 13, France. Address e-mail to alexandre.ouattara{at}psl.ap-hop-paris.fr


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We tested the hypothesis that in vitro coronary and myocardial effects of propofol (10–300 µM) should be significantly modified in an isolated and erythrocyte-perfused rabbit heart model in the absence (PaO2 = 137 ± 16 mm Hg, n = 12) or in the presence (PaO2 = 541 ± 138 mm Hg, n = 12) of hyperoxia. The induction of hyperoxia provoked a significant coronary vasoconstriction (-13% ± 7%). Propofol induced increased coronary vasodilation in the presence of hyperoxia. Because high oxygen tension has been reported to induce a coronary vasoconstriction mediated by the closure of adenosine triphosphate-sensitive potassium channels, we studied the effects of propofol in 2 additional groups of hearts (n = 6 in each group) pretreated by glibenclamide (0.6 µM) and cromakalim (0.5 µM) in the absence and presence of hyperoxia, respectively. The pretreatment by glibenclamide induced a coronary vasoconstriction (-16% ± 7%) which did not affect propofol coronary vasodilation. The pretreatment by cromakalim abolished the amplification of propofol coronary vasodilation in the presence of hyperoxia. Propofol induced a significant decrease in myocardial performance for a concentration >100 µM both in the absence and presence of hyperoxia. We conclude that propofol coronary vasodilation is amplified in the presence of hyperoxia. This phenomenon is not explained by the previous coronary vasoconstriction induced by glibenclamide. However, the pretreatment of hearts by cromakalim abolished the amplification of propofol coronary vasodilation in the presence of hyperoxia. The myocardial effects of propofol were not affected by the presence of hyperoxia.

IMPLICATIONS: Propofol induced a coronary vasodilation that was amplified in the presence of hyperoxia. This phenomenon does not seem to be related to previous coronary vasoconstriction. The myocardial effects of propofol were not significantly modified in the presence of hyperoxia.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
The attractive pharmacokinetic properties of propofol and the use of new anesthetic techniques, such as the target-controlled infusion technique, explain the increased use of propofol. In vivo, propofol induces a decrease in myocardial blood flow and myocardial oxygen consumption (1,2). Although in vitro studies reported significant coronary effects of propofol, these results are variable (3–10). In canine coronary arteries, propofol induces a biphasic change resulting in a vasodilation only at therapeutic (6) or at supratherapeutic (5,10) concentrations. However, some authors reported a dose-dependent vasodilator effect of propofol in several species, including human coronary arteries (4,9,11). In addition, the mechanism of propofol coronary vasodilation is a subject of controversy. For Yamanoue et al. (4) this vasodilation is non-endothelium-dependent on porcine coronary arteries but involves an antagonism of calcium channels. These results are consistent with those reported in canine and human coronary arteries (6,11). However, in rat coronary arteries, propofol induces a significant endothelium-dependent vasodilation that is not mediated by opening of the adenosine triphosphate-sensitive potassium (KATP) channels (3).

Because the administration of oxygen delays the onset of arterial desaturation (12), this maneuver is widely used before the induction of anesthesia. Although no clinical adverse effect has been reported, in vitro, high arterial oxygen tension (PaO2) is not devoid of myocardial and coronary effects (13,14). Indeed, Baron et al. (13) reported that high PaO2 induces coronary vasoconstriction. In vivo, Daniel and Bagwell (15) showed that the high inspired fraction of oxygen induces a decrease in myocardial contractile force in anesthetized open-chest dogs. By modifying the coronary vascular tone, high PaO2 could influence the coronary effects of propofol. Therefore, we tested the hypothesis that in vitro coronary and myocardial effects of propofol (10–300 µM) should be significantly modified in an isolated and erythrocyte-perfused rabbit heart model in the absence or presence of hyperoxia. This model was chosen because the presence of erythrocytes in the medium perfusate allows comparison of physiological PaO2 as well as a high PaO2. Because high oxygen tension has been reported to induce coronary vasoconstriction mediated by the closure of KATP channels (14), we hypothesized that these channels may have a role. Thus, we studied the effects of propofol in 2 additional groups of hearts (n = 6 in each group) pretreated by glibenclamide, an inhibitor of the KATP channels, and cromakalim, an opener of the KATP channels, in the absence and presence of hyperoxia, respectively.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
We used 45 adult New Zealand albino rabbits. Care of the animals conformed to the recommendations of the Helsinki Declaration, and the study was performed in accordance with the regulations of the official edict of the French Ministry of Agriculture.

Perfusate Preparation
The perfusion medium was reconstituted by mixing human erythrocytes (Etablissement Français du Sang, Paris, France) and a modified Krebs-Henseleit bicarbonate buffer containing 118 mM NaCl, 5.9 mM K+, 2.5 mM CaCl2, 0.5 mM MgSO4, 1.17 mM NaH2PO4, 28 mM NaHCO3, 11 mM glucose, 0.9 mM lactate, and 0.5% bovine serum albumin. The erythrocytes were stored at 4°C in our laboratory for no more than 1 week. They were centrifuged and washed with saline (Cell-Saver 3+; Hemonetics, Braintree, MA). The mixture allowed us to obtain a hemoglobin value of approximately 8 g/dL. The reconstituted blood was filtered, then continuously oxygenated with a gas mixture comprising 20% oxygen, 5% carbon dioxide, and 75% nitrogen using a membrane oxygenator (Optima; COBE Cardiovascular, Arvada, CO). After rewarming to 37°C, electrolyte concentrations were adjusted to achieve physiological concentrations and sodium bicarbonate was added to obtain a pH between 7.35 and 7.45.

Heart Preparation
After the rabbits were anesthetized with ether, thoracotomy was performed, and the heart and aorta arch were excised and then rapidly placed in cold (4°C) isotonic saline solution. The pericardium was quickly removed and the aorta was prepared for the cannulation. The heart was mounted on an aortic cannula and retrograde perfusion was begun according to the Langendorff’s technique with a constant hydrostatic perfusion pressure (PP) of 80 mm Hg. As previously described (16,17), the apparatus was modified to reduce red blood cell sedimentation and circuit filling volume. Consequently, the column used to set the PP was replaced by a syringe with a plunger containing mercury and attached to a displacement transducer that controlled the speed of the peristaltic coronary pump reflecting the coronary blood flow (CBF). The coronary driving pressure was measured from the signal pressure obtained from a small catheter that was positioned above the aortic valves and connected to a pressure transducer. The heart rate (HR) was maintained constant by an atrial pacing. The coronary sinus flow was collected by a small catheter inserted into the pulmonary artery. A cannulated fluid-filled balloon connected to a pressure transducer by a rigid catheter was inserted into the left ventricle through a left atrial incision. A 2-mL graduated syringe was connected on this pressure transducer to increase the intraventricular volume. Left ventricular end-systolic pressure, left ventricular end-diastolic pressure, and HR were recorded, and the maximal positive (dP/dtmax) and negative (dP/dtmin) left ventricular pressure derivatives were electronically derived from the left ventricular pressure signal. Because intraventricular volume and HR were held constant during the experiment, dP/dtmax and dP/dtmin reflected inotropic and lusitropic properties, respectively. The whole apparatus was enclosed in a thermostatic chamber at 37.5°C.

Blood Gas and Electrolytes Measurements
PaO2 and venous coronary oxygen tension, arterial and venous coronary carbon dioxide tension, and pH were measured with standard electrodes at 37°C, and the arterial hemoglobin concentration, and arterial and venous coronary saturation were measured with a hemoximeter (BG3 System and IL 482; Instrumentation Laboratory, Saint-Mandé, France). Arterial and venous coronary oxygen content, oxygen extraction (O2 extraction) and myocardial oxygen consumption (MvO2) were derived from the standard formulae. At the onset of each experiment, a sample of the reconstituted blood was withdrawn to determine the concentration of the main electrolytes (Na+, K+, Cl-, HCO3-, and Ca2+).

Experimental Protocol
The experimental protocol for this study is summarized in Figure 1. For all hearts, a recovery period of 20 min in normoxia was present. At the end of this period, a first set of baseline measurements were performed in normoxic conditions (BASELINE 1).



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  		Figure 1. Experimental protocol for the study. All hearts were subjected to a recovery period of 20 min in normoxia. All BASELINE 1 measurements were performed in normoxic conditions. BASELINE 2 measurements were performed after the pretreatment and/or the shift from normoxic to hyperoxic blood according to the group.

 
Comparison of Coronary and Myocardial Effects of Propofol in the Absence and Presence of Hyperoxia.
In the hyperoxia group (n = 12), hyperoxic blood was obtained by shifting from the normoxic gas mixture comprising 20% oxygen, 5% carbon dioxide, and 75% nitrogen to a hyperoxic gas mixture comprising 95% oxygen and 5% carbon dioxide. Because preliminary experiments showed that 5 min was necessary to reach the appropriate PaO2 level, a new equilibration period of 10 min was allowed before obtaining new measurements (BASELINE 2). In the normoxia group (n = 12), a control period of 10 min was used. Then, increasing concentrations of propofol (Diprivan®; AstraZeneca, Rueil-Malmaison, France) were infused to target intracoronary concentrations of 10, 30, 100, and 300 µM throughout, via a plastic valve which was localized only 1 cm above the coronary ostium. The peak of the propofol effect was noted within 5 min. Before and after each propofol infusion, arterial and coronary sinus samples were collected for blood gas analysis. After the end of each propofol infusion, a recovery period was allowed to achieve baseline values. The effects of propofol solvent, 10% Intralipid (Ivélip®; Baxter, Maurepas, France) on myocardial performance, CBF, and MvO2 were studied in additional hearts perfused by normoxic (n = 3) and hyperoxic (n = 3) blood.

Effects of Propofol During Normoxia in the Absence or Presence of Glibenclamide.
Because the result expected by the shift from normoxic blood to hyperoxic blood was coronary vasoconstriction (14), six additional hearts were studied to assess the influence of a previous modification of the coronary vascular tone on propofol coronary vasodilation. After BASELINE 1, 0.6 µM glibenclamide (Sigma-Aldrich, Saint-Quentin Fallavier, France), an inhibitor of the KATP channels, was added to the perfusate. After an equilibration period of 10 min, new measurements of CBF and myocardial metabolism and performance were recorded (BASELINE 2). Then, increased concentrations of propofol (10–300 µM) were perfused in similar conditions as described above. The results were compared with those in the normoxia group. Glibenclamide was dissolved in dimethyl sulfoxide (DMSO) and then diluted in distilled water. The DMSO concentration in the final solution was 0.0001%. We have previously reported that 0.01% DMSO does not significantly change CBF and myocardial performance in this isolated heart model (14).

Influence of the KATP Channels on Propofol Effects During Hyperoxia.
To assess the influence of the KATP channels on the coronary effects of propofol in the presence of hyperoxia, six additional hearts were studied. After BASELINE 1, hyperoxic blood was obtained by shifting from a normoxic to a hyperoxic gas mixture. Simultaneously, 0.5 µM cromakalim (Sigma-Aldrich), an opener of the KATP channels, was added to the perfusate. After a new equilibration period of 10 min, measurements of CBF and myocardial metabolism and performance were performed (BASELINE 2). Then, increased concentrations of propofol (10–300 µM) were infused in conditions similar to that described above. The results were compared with those in the normoxia group. Cromakalim was dissolved in DMSO (final concentration 0.0001%). Because coronary vasodilation was expected by the pretreatment of cromakalim, assessment of coronary effects of propofol could be limited. To eliminate a potential limitation of the increase in CBF, we assessed the endothelium-independent CBF reserve with nitroprusside in three additional hearts, as previously reported (18). Preliminary experiments showed that the maximal CBF was obtained with a coronary concentration of 10-1 µM (data not shown).

Data were expressed as mean ± SD. Comparison of two means was performed using a paired or unpaired Student’s t-test when appropriate. Comparison of several means was performed using repeated-measures analysis of variance for repeated measurements. Interaction analysis revealed whether coronary, myocardial metabolic effects of increased concentrations of propofol were different between the two groups. Post-test analysis was performed using Newman-Keuls test. All P values were two-tailed and a P value < 0.05 was required to reject the null hypothesis.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
There were no significant differences in pH and electrolyte composition of the reconstituted perfusate between the normoxic and hyperoxic groups (pH = 7.36 ± 0.08, Na+ = 140 ± 6 mM, Cl- = 107 ± 6 mM, K+ = 4.4 ± 1.1 mM, HCO3- = 25 ± 3 mM, Ca2+ = 2.18 ± 0.33 mM).

Coronary and Myocardial Effects of Hyperoxia
In the hyperoxic group (n = 12), the shift from normoxic to hyperoxic blood induced a significant increase in the PaO2 that was associated with a significant decrease in CBF (-13% ± 7%, P < 0.05). No significant differences in myocardial performance and MvO2 were found (Table 1).


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  		Table 1. Coronary, Myocardial, and Metabolic Effects of a Shift from Normoxic Blood (BASELINE 1) to Hyperoxic Blood (BASELINE 2) in the Hyperoxia Group (n = 12)
 
Coronary and Myocardial Effects of Propofol in the Absence and Presence of Hyperoxia
The baseline values of CBF were not significantly different between the normoxia group (3.0 ± 0.7 mL · min-1 · g-1, n = 12) and the hyperoxia group (2.7 ± 1.0 mL · min-1 · g-1, n = 12). In the absence of hyperoxia, propofol induced an increase in CBF which was significant at a concentration of 100 µM. The propofol coronary vasodilation was significantly larger in the presence of hyperoxia (Fig. 2). A return to baseline values of CBF was obtained before each perfusion of propofol (data not shown). Propofol vehicle alone induced no significant coronary effects in the absence (n = 3) or presence (n = 3) of hyperoxia (data not shown).



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  		Figure 2. Comparison of propofol effects (10–300 µM) on coronary blood flow (CBF) in the presence (n = 12) and absence of hyperoxia (n = 12) groups. BL = BASELINE 2 values (see text for explanation). CBF was expressed in absolute values (A). CBF was expressed in percentages of baseline value (B). P value refers to between-group comparison. *P < 0.05 versus baseline value. Data are mean ± SD.

 
Before infusion of propofol, only the lusitropic variable (dP/dtmin) was significantly reduced in the presence of hyperoxia (Table 2). Propofol induced a significant decrease in left ventricular end-systolic pressure, dP/dtmax, and dP/dtmin in both groups for a concentration >100 µM. Negative inotropic and lusitropic effects of propofol were not significantly different in both groups. The propofol vehicle alone induced no significant myocardial effects in neither the absence (n = 3) nor presence (n = 3) of hyperoxia (data not shown).


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  		Table 2. Baseline Values and Effects of Propofol on Myocardial Performance in the Normoxia (n = 12) and Hyperoxia (n = 12) Groups
 
On baseline values, only the O2 extraction was significantly greater in the presence of hyperoxia (Table 3). Increased concentrations of propofol were devoid of significant effects on MvO2. Nevertheless, at 300 µM, propofol induced a significant increase in coronary venous oxygen tension and content (Table 3). Additionally, the increased concentrations of propofol induced a significant decrease in O2 extraction. This decrease was not significantly different between groups.


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  		Table 3. Baseline Values and Effects of Propofol on Myocardial Oxygen Consumption in the Normoxia (n = 12) and Hyperoxia (n = 12) Groups
 
Coronary Effects of Propofol in Hearts Pretreated by Glibenclamide in the Absence of Hyperoxia
The pretreatment of hearts by glibenclamide (Fig. 3) induced a significant decrease in CBF (-16% ± 7%, P < 0.05). Subsequently, propofol coronary vasodilation was not significantly different from that observed in hearts in the normoxia group (Fig. 4).



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  		Figure 3. Evolution of coronary blood flow (CBF) and arterial oxygen tension (PaO2) between the two sets of baseline measurements (BASELINE 1 and 2). A, Before and after the shift from normoxic blood to hyperoxic blood in group hyperoxia (n = 12). B, Before and after the addition of 0.6 µM glibenclamide to normoxic blood (n = 6). C, Before and after the shift from normoxic to hyperoxic blood containing 0.5 µM cromakalim (n = 6). *P < 0.05 versus BASELINE 1. Data are mean ± SD.

 


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  		Figure 4. Comparison of coronary vascular effects of propofol between hearts in the absence of hyperoxia (n = 12) and those pretreated by glibenclamide (n = 6) in the absence of hyperoxia. BL = BASELINE 2 values (see text for explanation). Coronary blood flow (CBF) was expressed in absolute values (A). CBF was expressed in percentages of baseline value (B). P value refers to between-group comparison. *P < 0.05 versus baseline value. NS = not significant. Data are mean ± SD.

 
Coronary Effects of Propofol in Hearts Pretreated by Cromakalim in the Presence of Hyperoxia
The shift from normoxic to hyperoxic blood containing cromakalim (0.5 µM) was associated with a significant increase in CBF (Fig. 3). Subsequently, propofol coronary vasodilation was not significantly different from that observed in hearts in the normoxia group (Fig. 5).



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  		Figure 5. Comparison of coronary vascular effects of propofol between hearts in the absence of hyperoxia (n = 12) and those pretreated by cromakalim (n = 6) in the presence of hyperoxia. BL = BASELINE 2 values (see text for explanation). Coronary blood flow (CBF) was expressed in absolute values (A). CBF was expressed in percentages of baseline value (B). P value refers to between-group comparison. *P < 0.05 versus baseline value. NS = not significant. Data are mean ± SD.

 
The endothelium-independent coronary reserve flow induced by 0.1 µM nitroprusside was 383% ± 56%. The corresponding absolute value of CBF was 11.2 ± 2.3 mL · min-1 · g-1, which was not significantly different from the maximal CBF observed in hearts pretreated by cromakalim in the presence of hyperoxia (10.2 ± 1.7 mL · min-1 · g-1).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In the present study, we observed that: 1) propofol coronary vasodilation is amplified in the presence of hyperoxia, 2) this phenomenon is not related to a previous coronary vasoconstriction induced by the presence of hyperoxia but should involve the KATP channels, and 3) the myocardial effects of propofol are not modified in the presence of hyperoxia.

High inspired fractions of oxygen are routinely used during the perioperative period. This procedure, by increasing the oxygen store, allows a delay in the onset of arterial desaturation during the apneic period of induction. Nevertheless, the high level of oxygen tension induced is not devoid of significant cardiovascular effects. In vivo, coronary vasoconstriction induced by a high level of oxygen tension has been reported (15,19). These results have been confirmed by an in vitro study (13). The closure of KATP channels mediates this coronary vasoconstriction (14). The use of a high inspired fraction of oxygen also induces a decrease in myocardial function (15). An interaction between high-level oxygen tension and coronary vasoactive drugs has been previously reported (20).

In vivo, propofol produces a decrease in myocardial blood flow and MvO2 (1,2). Although numerous in vitro studies reported a coronary vasodilation, previous results remain a subject of controversy. In human coronary vessels, propofol induced a dose-dependent vasodilation (11). These results have been confirmed in numerous animal species (4,8,9). Conversely, a biphasic coronary effect of propofol has been reported (5,6,10). Finally, the precise mechanism of propofol coronary vasodilation also remains controversial. For Yamanoue et al. (4), this vasodilation is non-endothelium-dependent on porcine coronary arteries and involves antagonism of calcium channels. These results are consistent with those reported in canine and human coronary arteries (6,11). By contrast, in rat coronary arteries, propofol induces a significant endothelium-dependent vasodilation that is not mediated by opening of the KATP channels (3). Previous studies in various mammalian species, including humans, have suggested that propofol is devoid of significant effects on intrinsic myocardial properties, at least within therapeutic concentrations (7,8,21–25).

The presence of erythrocytes in the perfusate is a clear advantage over other study methodologies. This medium provides physiological values of PaO2 and arterial coronary oxygen content (16) and maintains myocardial metabolism (26). Indeed, Mouren et al. (7) have demonstrated that the myocardial effects of propofol depend on the type of perfusate: a marked negative inotropic effect was observed using Krebs-Henseleit solution, which is associated with poor oxygen transport and altered cardiac function (26), compared with erythrocyte-containing solution (hemoglobin level at 10 g/dL).

During anesthesia, the high level of oxygen tension and propofol exert two opposing effects on coronary vascular tone. No previous study has evaluated coronary and myocardial consequences of this potential interaction. We undertook an in vitro study by using a blood-perfused and isolated heart model. This model presents several advantages because it allows the use of either physiological (100–150 mm Hg) or high-level (400–450 mm Hg) oxygen tension. In contrast, in vitro Krebs-Henseleit models must use only a hyperoxic gas mixture that provides a PaO2 of approximately 500 mm Hg to avoid ischemia of the myocardium. Furthermore, the blood-perfused and isolated heart model allows the assessment of the intrinsic effects of arterial hyperoxia on the coronary vascular tone independent of the autonomic nervous system that may modify the HR and myocardial performance and thus CBF.

In the present in vitro study, arterial hyperoxia was similar to that obtained in clinical studies (27). The decrease in CBF (13% ± 7%) obtained in the hyperoxia group was consistent with that previously reported by Baron et al. (13). Coronary vasoconstriction was abolished with the pretreatment of cromakalim. These findings confirmed the involvement of KATP channels in hyperoxia-induced coronary vasoconstriction (14). In addition, the range of the coronary constriction induced by glibenclamide (16% ± 7%) was similar to that obtained in the hyperoxia group. However, the absence of decrease in CBF by hyperoxia after pretreatment by cromakalim may be related to a major vasorelaxing effect of cromakalim more than specific opening of KATP channels. By using a similar erythrocyte-perfused and isolated heart model with assessment of coronary vascular tone by PP, Mouren et al. (14) reported that coronary infusion of 1 µM cromakalim decreased PP from 80 ± 4 to 27 ± 2 mm Hg. Whereas increased PaO2 was unable to increase PP at this level, 5 µM phenylephrine induced an increase in PP (14). In addition, the pretreatment of heart by nitroprusside induced a similar decrease in PP to 35 ± 14 mm Hg. In contrast, at this level of PP, high PaO2 was still able to increase PP to 52 ± 32 mm Hg. This result previously reported by Mouren et al. (14) suggests that, in the present study, the ability of cromakalim to abolish the decrease in CBF caused by hyperoxia is related to its properties of opening KATP channels.

Propofol induced concentration-related coronary vasodilation during normoxia. This finding concords with those previously reported (3,4,7–9,28). The coronary vasodilation of propofol was significantly enhanced during hyperoxia. Because hyperoxia induced a previous vasoconstriction, we performed additional experiments to determine whether the increased coronary vasodilation could be explained by a previous modification of the vascular coronary tone. Thus, coronary vasoconstriction by glibenclamide was obtained before propofol infusion. In this group, the propofol coronary vasodilation was similar to that obtained in the normoxia group without glibenclamide (Fig. 4). These findings suggest that a previous vasoconstriction does not explain the increase in coronary vasodilation induced by propofol during hyperoxia. These results also suggest that the coronary vasodilation induced by propofol is not mediated by the KATP channels. Our results are consistent with those reported by Park et al. (3) in an in vitro Krebs-Henseleit model of isolated coronary vessels. However, this model used a high oxygen tension which may have interfered with the coronary vascular tone by involvement of the KATP channels.

The pretreatment by 0.5 µM cromakalim abolished the coronary vasoconstriction induced by hyperoxia. Subsequently, propofol-induced coronary vasodilation was not significantly different from that obtained in the absence of hyperoxia. This result suggests the involvement of KATP channels in the amplification of the propofol-induced coronary vasodilation in the presence of hyperoxia.

In an isolated and erythrocyte-perfused rabbit heart preparation, propofol induced a significant myocardial depression only at a concentration >100 µM. Our results are consistent with those reported by Kanaya et al. (23) in the rat and Ismail et al. (24) in the dog. In isolated human atrial muscle, Gelissen et al. (21) observed a negative inotropic propofol effect only at a concentration >100 µM. In the present study, the myocardial effects of propofol were not significantly modified in the presence of hyperoxia. The blood concentration of propofol during anesthesia was assessed between 5 and 80 µM (3). Propofol is highly bound to serum protein and the unbound fraction may be very small. Indeed, the clinical range of the unbound propofol was assessed at approximately 4 µM. In our study, the protein concentration was relatively small (<5 g/L) and the unbound propofol was probably larger. Nevertheless, there are no data to indicate the importance of protein binding during the acute administration of propofol, and thus the precise concentration of propofol at which the heart is exposed during the induction of anesthesia remains unknown. However, from a pharmacological viewpoint, we considered it important to encompass the therapeutic and supratherapeutic concentrations of propofol when assessing its myocardial and coronary effects.

The following points must be considered in the assessment of the clinical relevance of our study: In order to study the direct myocardial effects of propofol on isolated and erythrocyte-perfused heart models, preload and afterload systems are eliminated. In vivo, the cardiovascular depression of propofol is a result of myocardial and systemic vascular effects. Second, this study was performed in the myocardium of the rabbit, and species differences cannot be completely excluded. Third, because the baseline value of CBF in the group pretreated with cromakalim was increased, the subsequent coronary effects of propofol could be limited by the CBF reserve. Nevertheless, we observed that the endothelium-independent CBF reserve (11.2 ± 2.3 mL · min-1 · g-1) was not significantly different from the CBF obtained with the largest concentration of propofol in the group pretreated with cromakalim (10.2 ± 1.7 mL · min-1 · g-1).

In conclusion, in isolated and erythrocyte-perfused rabbit heart, coronary vasodilation induced by propofol was amplified in the presence of hyperoxia. The pretreatment with cromakalim abolished the amplification of propofol coronary vasodilation. In contrast, the myocardial effects of propofol were not affected by the presence of hyperoxia. Although the clinical implication of these findings is unknown, our results emphasize the possible interaction between hyperoxia and anesthetic drugs on coronary circulation. In addition, we examined some mechanisms of coronary vasodilation induced by propofol that will require additional investigation.


   Acknowledgments
 
This study was supported by the Department of Anesthesiology and Critical Care, CHU Pitié-Salpêtrière, Paris.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication September 23, 2003.




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