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Anesth Analg 2006;103:815-821 © 2006 International Anesthesia Research Society doi: 10.1213/01.ane.0000237284.30817.f6
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Abstract |
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 Top Abstract IntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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BACKGROUND: We investigated the involvement of central and peripheral opioid receptors (OR) in the cardioprotective effects of fentanyl (FENT) in a model of myocardial ischemia/reperfusion injury associated with pharmacologically induced sympathetic overactivity in anesthetized rabbits.
METHODS: Central sympathetic stimulation was achieved through intracerebroventricular injection of l-glutamate in animals submitted to 35 min of coronary occlusion followed by 120 min of reperfusion. Rabbits received naloxone HCl intracerebroventricularly or naloxone methiodide IV, a quaternary compound that does not cross the blood–brain barrier, 5 min before FENT treatment (5 or 50 µg/kg, IV).
RESULTS: Infarct area was reduced only by FENT 50 (from 51% ± 2% to 24% ± 2%). This protective effect was abolished by peripheral (42% ± 4%), but not central, OR blockade (32% ± 3%). The number of premature ventricular complexes during the ischemic period (54 ± 3) was reduced by FENT 50 (19 ± 7), an effect blunted by central (40 ± 3) but not peripheral (18 ± 7) blockade of OR. During reperfusion, the number of premature ventricular complexes (134 ± 50) was reduced to 9 ± 5 by FENT 50 and was prevented by central (42 ± 4) as well as peripheral (20 ± 11) OR blockade. The mortality rate (50%) and incidence of ventricular tachycardia (55%) were completely abolished by FENT 50.
CONCLUSIONS: We conclude that fentanyl's effects for limiting myocardial ischemic injury are mediated via peripheral ORs while opioid's antiarrhythmic actions are mediated via central OR agonism.
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Introduction |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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The cardioprotective effects of opioid receptor (OR) agonists have been consistently demonstrated in different models of ischemia/reperfusion (I/R) injury in vivo as well as in vitro (1). For example, morphine has been shown to reduce the size of experimental myocardial infarction via an OR-KATP channel-linked mechanism (2). This cardioprotective effect is similar to the mechanism for ischemic preconditioning, in which brief periods of coronary artery occlusion before a prolonged ischemic insult reduce the degree of irreversible tissue damage and slow the rate of adenosine triphosphate depletion (3). Further, low doses of intrathecal morphine (0.3 and 1 µg/kg) have been found to elicit cardioprotective effects against myocardial I/R through the modulation of the sympathetic nervous system activity (4), thus suggesting the additional role of the central nervous system in the cardioprotective effect of opioid drugs.
Fentanyl is a synthetic derivative of morphine with a 1000-fold analgesic potency that is widely used for patients with cardiovascular disease. Clinical and experimental evidence suggest that most of the cardiovascular effects of fentanyl are due to an action on central sites leading to modulation of the sympathetic outflow to the periphery (5–7). These effects are mediated by ORs acting on brainstem nuclei corresponding to the region of the vasomotor center of the rostral ventrolateral medulla (8–10).
We recently demonstrated that fentanyl has antiarrhythmic and antiischemic actions in an experimental model of myocardial ischemia resulting from inhibition of nitric oxide synthesis in the setting of central sympathetic overactivity. In that study, the IV administration of fentanyl (5–50 µg/kg) reduced the incidence of ventricular tachyarrhythmias as well as of electrocardiographic changes indicative of myocardial ischemia (11). Nevertheless, in this model of global myocardial ischemia resulting from pharmacologically induced coronary vasoconstriction, it was not possible to quantify the extent of myocardial ischemia/necrosis. Moreover, considering that opioid-induced cardioprotection may be related to the activation of central and/or peripheral ORs, it was important to determine the site(s) of action involved in the cardioprotective effects of fentanyl.
Thus, the purpose of this study was to investigate the involvement of central versus peripheral ORs in the cardioprotective effects of IV-administered fentanyl, using a model of myocardial I/R injury associated with pharmacologically induced central sympathetic overactivity.
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METHODS |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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All procedures were approved by the Oswaldo Cruz Foundation Animal Welfare Committee and were consistent with the United States National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publication No. 85–23, revised 1996). New Zealand albino rabbits of either sex (2.5–3.5 kg, n = 68) were housed under controlled conditions of light (12-h light–dark cycle) and temperature (22°C ± 1°C) with free access to water and standard rabbit food until the day of the experiment. The animals were anesthetized with sodium pentobarbital (40 mg/kg) administered through the marginal vein of the ear. Anesthesia was maintained with a continuous IV infusion of 15 mg/kg/h of pentobarbital. After induction of anesthesia a tracheotomy was performed, the trachea was intubated and neuromuscular blockade was induced with pancuronium bromide (1 mg/kg IV) and the right femoral vein was catheterized for administration of drugs. The lungs of the rabbits were artificially ventilated with room air, using a small animal ventilator (Ugo Basile, Model 7025, Biological Research Apparatus, Varese, Italy) at a rate of 25 strokes per minute and tidal volume of 10 mL/kg. Arterial pH, Pco2, and Po2 were monitored using a blood gas analyzer system (ABLTM 5, Radiometer Copenhagen, Denmark) and maintained within a normal physiologic range. Arterial blood was sampled for analysis at baseline, 15 min after coronary artery occlusion, and 15, 60, and 120 min after myocardial reperfusion. Central temperature was monitored with a rectal probe (Harvard Apparatus, Boston, MA), and the body temperature was kept at 38.0°C ± 0.5°C with a homeothermic blanket system. Arterial blood pressure was continuously monitored through a catheter placed in the abdominal aorta via the right femoral artery. Left ventricular pressure was measured with a high fidelity micromanometer-tipped catheter size 4F (Millar mikro-tip catheter model SPR-249, Millar instruments, TX) placed in the left ventricle via the right carotid artery. The analog pressure signals were digitized with a sampling frequency of 1 Hz using data acquisition software (Heamodyn. for Windows, Hugo Sachs Elektronik, March-Hugstetten, Germany). Measurements were made of the maximum rate of rise of left ventricular pressure (+dP/dtmax), mean arterial blood pressure, and lead II electrocardiogram.
The head of the animal was fixed in a stereotaxic frame (Unimécanique, Epinay/Seine, France), a craniotomy was performed to permit the positioning of a metal needle into the left lateral ventricle (12), and the needle was then fixed to the skull with dental cement. Drugs were injected via the intracerebroventricular (ICV) route in a constant volume of 50 µL in a time period of 1 min, using a Hamilton microliter syringe (Hamilton, Bonaduz AG, Switzerland) connected to a drug-filled polyethylene tube. At the end of each experiment, 50 µL of Evans blue dye was injected ICV. The brain was then removed postmortem and dissected to evaluate whether administered drugs had diffused properly throughout the ventricular space.
A left thoracotomy was performed, the pericardium opened, and the left coronary vein and artery were identified immediately under the left atrial appendage. A 6-0 polypropylene ligature was placed around the left descending coronary artery close to its origin and the ends of the suture were threaded through a propylene tube to form a snare.
After a baseline period of 30 min, the animals were submitted to 35 min of regional myocardial ischemia followed by 120 min of reperfusion. One minute after coronary ligature, the animals received 15 µmol l-glutamate ICV to trigger central sympathetic overactivity. To determine whether the systemic treatment with fentanyl reduced myocardial injury and ventricular arrhythmias, animals were randomly assigned to receive an IV injection of saline (control group, CTL) or fentanyl 5 or 50 µg/kg (FENT 5 or 50, respectively). Premature ventricular complexes (PVCs) occurring during the I/R periods were recorded and ventricular tachycardia (VT) was considered to consist of a run of at least five PVCs. To evaluate the effects of fentanyl (50 µg/kg) in the presence of central or peripheral OR blockade, two other groups of animals were pretreated either with ICV naloxone hydrochloride (Sigma Chemical Co., St. Louis, MO) in a dose 100-times lower than the IV one required to antagonize opioid-induced reduction of infarct size in rabbits (13,14) (NALHCl; 825 nmol prime dose and 0.4 µmol each 20 min ICV) or IV naloxone methiodide (Sigma Chemical Co.), a quaternary chemical analog of naloxone that does not cross the blood–brain barrier (NALMETH, 12.9 mg/kg IV in bolus and 30 mg/kg/h IV infusion). Considering that quaternary naloxone compounds are less potent than NALHCl, the dose of 12.9 mg/kg of the methiodide salt (FW 469.3) was chosen because it provided a naloxone equimolar dose to the 10 mg/kg dose of hydrochloride salt (FW 363.8). Further, because quaternary compounds may have about 10 min duration of action (15), a bolus dose was administered immediately before the onset of ischemia and a maintenance dose of 30 mg/kg/h was continuously infused throughout the experimental period. The diagrammatic representation of the experimental protocols is depicted in Figure 1. After myocardial reperfusion, the animals received an IV bolus dose of 5.000 IU of heparin and the hearts were excised and rapidly transferred to a modified Langendorff apparatus and perfused with normal saline to remove blood elements. The coronary snare was then re-tightened and a 0.25% solution of Evans blue dye was infused to delineate the myocardial area at risk (AAR). The hearts were frozen and then cut into approximately 2-mm-thick transverse slices and stained with triphenyl tetrazolium chloride (1% TTC w/v in sodium phosphate buffer, pH 7.4, 37°C) as described previously (2,4). The myocardial AAR and the infarct area were identified under white light, photographed, (Coolpix 5000, Nikon, Japan) and quantified by planimetry (Image J, NIH image, USA). The volumes of infarcted myocardium and myocardium AAR were calculated by multiplying the planimetered areas by the slice thickness.
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All results are expressed as mean ± sem. Comparisons between the hemodynamic variables within the same experimental groups were made with repeated measures analysis of variance, while comparisons between groups were performed with two-way analysis of variance. Student–Newman–Keuls post test was used to localize the significant differences. Non-normally distributed data were analyzed using Kruskal–Wallis test followed by Dunn's multiple comparisons test. Fisher's exact test was used to compare the incidence of VT and mortality. P-values of <0.05 were considered statistically significant. All calculations were made by computer-assisted analysis using a commercially available statistical package (Graphpad Instat, Graphpad Software, San Diego, CA).
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RESULTS |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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Forty-two of 68 animals concluded the study (26 rabbits died during the period of I/R) and only data from the surviving animals were included in results concerning hemodynamic, electrocardiographic, and histologic variables. The total number of rabbits was used only in the evaluation of the mortality rate.
Hemodynamic Variables
There were no significant differences in the mean basal values of hemodynamic variables among the different experimental groups (Table 1). Pretreatment with ICV NALHCl did not induce significant alterations in the hemodynamic variables but systemic treatment with NALMETH induced a significant hypotensive effect that was accompanied by a significant reduction in +dP/dtmax. When administered systemically, fentanyl in the lower dose (5 µg/kg) did not induce significant alterations in any hemodynamic variable. In the higher dose (50 µg/kg) fentanyl significantly reduced +dP/dtmax without significantly reducing arterial blood pressure. We observed a significant cardiodepressive effect during the reperfusion period in most experimental groups, characterized by arterial hypotension accompanied by reduced +dP/dtmax. In contrast, in the FENT 50 group and NALHCl group the hemodynamic parameters were preserved during the entire reperfusion period (Table 1).
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Histologic Parameters
There were no differences in the mean size of the myocardial AAR and myocardial infarction areas among groups (data not shown). Infarct area produced by I/R injury was significantly reduced only by the higher dose of fentanyl (50 µg/kg IV, P < 0.001). This protective effect of fentanyl was abolished by the peripheral OR blockade induced by NALMETH pretreatment (Fig. 2) but it was not affected by central OR blockade with NALHCl. The infarct areas of the different experimental groups expressed as a percentage of the AAR are shown in Figure 2.
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Ventricular Arrhythmias
Myocardial ischemia induced by coronary ligature and sympathetic activation was characterized by PVCs and VT. The mean number of PVCs observed in the CTL group during the ischemic period was significantly reduced in the group of animals treated with FENT 50 (54 ± 3 vs 19 ± 7, P < 0.01; Fig. 3). The antiarrhythmic effect of fentanyl during the ischemic period was blunted by central (NALHCl, 40 ± 3 PVCs) but not peripheral (NALMETH, 18 ± 7 PVCs) OR blockade (Fig. 3). Reperfusion also triggered ventricular arrhythmia in all groups. The mean number of PVCs during the reperfusion in the CTL group was 134 ± 50; in the FENT 5 group was 23 ± 8; in the FENT 50 group was 9 ± 5 (P < 0.01 versus CTL and P < 0.05 versus NalHCl); in the NALMETH group was 20 ± 11; and in the NALHCl ICV group was 42 ± 4 (Fig. 3). Thus, the antiarrhythmic effect of fentanyl during reperfusion was blunted both by central and peripheral OR blockade.
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Myocardial reperfusion elicited VT in the majority of the animals of the control group. The incidence of VT was not reduced in the FENT 5 group but was totally abolished by the higher dose of fentanyl (FENT 50). In the presence of both central and peripheral blockade of ORs, the incidence of VT after treatment with FENT 50 was not different from that of the CTL group (Fig. 4).
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Mortality
Half of the control group animals died before the end of the reperfusion period (Fig. 4). Mortality was not affected by FENT 5 but was totally prevented by treatment with FENT 50. In the presence of peripheral blockade of ORs (NALMETH group) the mortality rate after treatment with FENT 50 was of 25%. In the presence of central blockade of ORs (NALHCl) the mortality rate after treatment with FENT 50 was identical to that observed in the CTL group.
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DISCUSSION |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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The results of this study demonstrate that systemic administration of fentanyl elicits cardioprotective effects involving the simultaneous activation of central and peripheral ORs. The antiischemic effects of fentanyl observed in our experimental model are most likely due to a peripheral action of the drug, whereas its antiarrhythmic effects during ischemia, but not during reperfusion, result from an action in the central nervous system. Our results also show that fentanyl abolished mortality resulting from myocardial ischemia and sympathetic overactivity via its central nervous system antiarrhythmic effects.
Fentanyl modulates cardiovascular function, mainly by reducing sympathetic activity, and this effect does not seem to be secondary to analgesia or other sensory depressant effects of the drug, but rather to an action on central opioid-sensitive mechanisms regulating cardiovascular function (8,9,16,17). Moreover, the stimulation of central µ-ORs protects the heart against the arrhythmogenic action of catecholamines in I/R injury (18). ORs of the µ- and 
-subtypes share 58% homology in their amino acid sequence (19) and have been identified on pre- and postsynaptic neurons and in the spinal intermediolateral cell column, where their activation can modulate the autonomic response (20).
We have previously shown that fentanyl effectively prevents life-threatening ventricular arrhythmias in anesthetized rabbits (11). Our present results demonstrate that antiarrhythmic effects induced by fentanyl (50 µg/kg) in the model of I/R injury are prevented by the central blockade of ORs, thus confirming the involvement of central pathways in the antiarrhythmic effects of fentanyl. In the present study, naloxone methiodide, an OR antagonist that does not cross the blood–brain barrier, was used to investigate the involvement of peripheral ORs on the cardioprotective effects elicited by the systemic administration of fentanyl. The peripheral blockade of ORs did not influence the antiarrhythmic effect of fentanyl during ischemia, but partially reversed its protective effects observed during the reperfusion period. These latter results can be explained by the involvement of sympathetic overactivity in the genesis of ventricular arrhythmias during myocardial ischemia (21) while during the early reperfusion period local factors such as reactive oxygen species play a major role (22). It is also noteworthy that the antiarrhythmic effects of fentanyl were confirmed using two dissimilar experimental models of myocardial ischemia, i.e., pharmacologically induced coronary vasoconstriction (11) and regional ischemia induced by coronary artery occlusion (present study).
Our results also showed that the reduction of infarct area elicited by the 50 µg/kg dose of fentanyl was most likely mediated by peripheral mechanisms, since the systemic pretreatment of the animals with naloxone methiodide prevented this antiischemic effect of fentanyl. In opposition, the blockade of central ORs with ICV naloxone hydrochloride, although preventing the antiarrhythmic effect of fentanyl, did not significantly affect fentanyl-induced reduction of infarct area. This antiischemic effect of fentanyl, which besides the classical action on µ-receptors is also able to stimulate - and 
-ORs (23), could have resulted from the activation of cardiac ORs. The synthesis and release of endogenous opioids induced by myocardial ischemia is a well-demonstrated phenomenon (1) and may be a regulatory mechanism that counteracts the effects of catecholamines released during ischemia, thus reducing the size of the infarcted area. Attempts to characterize OR subtypes in the mammalian myocardium agreed on the existence of both - and -receptors and were discordant for the presence of µ-receptors. In this context, the reduction of infarct area induced by opioid agonists in animal studies has been attributed to activation of cardiac -ORs (1,23). Kato and Foex (24) demonstrated that fentanyl has cardioprotective effects mediated by both -ORs and protein kinase C in a model of myocardial I/R injury in vitro. On the other hand, studies using positron emission tomography demonstrated the presence of both µ- and -ORs in the human heart (25), suggesting a possible synergic cardiac effect of these subtypes of ORs. Additionally, the presence of µ-ORs in the human heart supports the clinical use of fentanyl and its analogs in the cardioprotection of patients presenting with coronary artery disease.
Interestingly, when central ORs were blocked with a low dose of naloxone hydrochloride, fentanyl was no longer able to reduce mortality, but it still elicited a significant reduction of infarct area. The high mortality rate observed in this group may be related to the synergism of two events that trigger sympathetic overactivity: central ORs blockade with naloxone associated with the activation of glutamatergic receptors with l-glutamate. On the other hand, when the rabbits were systemically pretreated with naloxone methiodide, fentanyl still reduced the mortality rate by 50%, although this cardioprotective effect did not reach statistical significance. It is also noteworthy that myocardial infarct area in this latter group was similar to that observed in the control group. Taken together, these results suggest that the activation of central ORs with fentanyl is the critical event for reducing the mortality rate, at least in the experimental model used in the present study.
The current results must be interpreted within the constraints of potential experimental limitations. Myocardial infarct size is determined primarily by the size of the AAR and extent of coronary collateral perfusion. In the present study, both AAR and left ventricular size were similar in the control and treated groups. Moreover, rabbits have been shown to have little if any coronary collateral bloodflow (26). Thus, it appears unlikely that differences in collateral perfusion among groups account for the observed results.
In conclusion, the results of the present study strongly suggest that, besides its classical analgesic properties, fentanyl, an opioid agonist widely used in clinical anesthesia, has additional protective actions against cardiac events induced by central sympathetic overactivity associated with myocardial ischemia. This cardioprotective effect is essentially characterized by antiarrhythmic and antiischemic actions involving central as well as peripheral ORs and confirms the importance of the use of opioid drugs in the management of patients with ischemic heart disease who undergo anesthesia and surgery.
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Footnotes |
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Accepted for publication June 21, 2006.
Supported by grants from CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior), CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico), and Oswaldo Cruz Institute.
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