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CARDIOVASCULAR
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin
Received December 18, 2003; accepted March 1, 2004.
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Abstract |
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). Morphine is commonly administered during an acute myocardial infarction as a method of pain relief at a loading dose ranging from 0.06 to 0.11 mg/kg (4–8 mg/70 kg), with additional morphine doses of 0.03 to 0.14 mg/kg administered every 5 to 15 min. Although more uncommon, the total morphine dose in some patients experiencing a myocardial infarction can reach 2 to 5 mg/kg (Antman and Braunwald, 2000). Moreover, morphine is routinely administered during an acute myocardial infarction in combination with nonsteroidal anti-inflammatory drugs to achieve an antithrombotic effect with aspirin doses ranging from 2.3 to 4.6 mg/kg (160–325 mg/70 kg) (Antman and Braunwald, 2000; Hollander, 2000).
Previously, morphine has been shown to mimic ischemic preconditioning when administered to rats before ischemia (Schultz et al., 1997) and also reduce infarct size when given before reperfusion (Gross et al., 2004). However, it is unknown in animal models whether morphine administered after reperfusion can reduce infarct size. Additionally, although patients commonly receive a combination of nonsteroidal anti-inflammatory drugs and morphine in the emergency room during a myocardial infarction, no studies have examined whether aspirin or ibuprofen has an adverse or beneficial effect on morphine-induced infarct size reduction. Although there is strong clinical evidence that aspirin reduces mortality rate from a myocardial infarction after chronic oral administration (Hennekens et al., 1997), it is controversial in animal models as to whether aspirin when given acutely reduces infarct size or is detrimental (Bonow et al., 1981; Lepran et al., 1981; Such et al., 1983; Rossoni et al., 2001). Additionally, a number of animal models have also shown that ibuprofen can reduce infarct size (Jugdutt et al., 1980; Kirlin et al., 1982; Romson et al., 1982). However, it has not been established whether aspirin or ibuprofen reduce infarct size when administered as a single dose just before or after reperfusion. Moreover, aspirin or ibuprofen may interact with morphine because 12-lipoxygenase (12-LO) is an end effector of 
opioid-induced delayed cardioprotection (Patel et al., 2003).
Therefore, the objective of this study was to determine whether morphine, aspirin, or ibuprofen reduces infarct size when administered either 5 min before reperfusion or 10 s after reperfusion and what effect the concomitant administration of aspirin or ibuprofen with morphine has on infarct size reduction. Furthermore, we examined whether subthreshold cardioprotective doses of aspirin or ibuprofen in combination with a subthreshold dose of morphine can reduce infarct size. Last, we determined whether the mechanism of acute infarct size reduction produced by these agents is mediated by 12-LO.
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Materials and Methods |
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Pharmacological Agents
The agents used for this study included morphine sulfate (Sigma/RBI, Natick, MA), aspirin (acetylsalicylic acid; Sigma-Aldrich, St. Louis, MO), and ibuprofen (Sigma-Aldrich). Additional agents included the 12-LO inhibitor baicalein (BIOMOL Research Laboratories, Plymouth Meeting, PA) and the 12-LO metabolite 12-(S)-hydroxyeicosa-5Z,8Z,10Z,14Z-tetraenoic acid [12(S)-HETE; BIOMOL Research Laboratories). Morphine sulfate was dissolved in water. Aspirin, ibuprofen, and 12(S)-HETE were dissolved in 95% ethanol, whereas baicalein was dissolved in dimethyl sulfoxide (DMSO; Sigma-Aldrich) and diluted 1:2 in water.
Experimental Protocols
Infarct Size Studies. Male Sprague-Dawley rats (215–300 g) were obtained from Harlan (Indianapolis, IN) and were used for an in vivo model of ischemia and reperfusion. The general surgical protocol and determination of infarct size have been described in detail previously (Gross et al., 2003). All agents were administered i.v., except 12(S)-HETE, which was delivered through the left atrial appendage via a 30-gauge needle. 12(S)-HETE was administered via the left atrial appendage because it has been shown previously that 12(S)-HETE can be metabolized by the lung (Pace-Asciak et al., 1983). Hemodynamics, including heart rate, mean arterial pressure, and rate pressure product were quantified during baseline, 15 min into ischemia and at 2 h of reperfusion and compared with vehicle-treated rats for each group.
After surgical intervention and stabilization, rats were separated into groups (n = 6–8/group) to undergo the experimental protocols outlined (Fig. 1). For the first part of the study, rats were subjected to treatment with morphine, aspirin, ibuprofen, or ethanol vehicle 5 min before reperfusion. Morphine (0.1, 0.2, and 0.3 mg/kg), aspirin (0.6, 1, and 3 mg/kg), or ibuprofen (0.6, 1, and 3 mg/kg) were administered at three different doses. Second, morphine (0.3 mg/kg), aspirin (3 mg/kg), ibuprofen (3 mg/kg), or ethanol vehicle was administered 10 s after reperfusion.
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To examine the interactions of aspirin and ibuprofen with morphine, aspirin (1 or 3 mg/kg) or ibuprofen (3 mg/kg) was administered 2 min before morphine (0.3 mg/kg) given 5 min before reperfusion. Aspirin or ibuprofen was also administered with morphine (0.2 mg/kg) to determine whether subthreshold doses of these agents that do not individually reduce infarct size are effective when given in combination.
To discern the effects of 12-LO on morphine- or ibuprofen-induced cardioprotection, the 12-LO inhibitor baicalein (3 mg/kg) was administered 10 min before ischemia alone or in combination with morphine (0.3 mg/kg), ibuprofen (3 mg/kg), or morphine (0.2 mg/kg) plus ibuprofen (0.6 mg/kg). A subset of rats also received DMSO vehicle, 10 min before ischemia. Additional rats received 12(S)-HETE (15 µg/kg), 5 min before reperfusion.
Statistical Measurements
All values were denoted as mean ± S.E.M. Statistical significance was determined by performing a one-way analysis of variance with Bonferroni's correction for multiplicity. Values significantly different from vehicle were indicated by ** (P value of < 0.01).
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Results |
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Hemodynamics
Heart rate, mean arterial pressure and rate pressure product were quantified during baseline, 15 min into ischemia, and at 2 h of reperfusion and compared with vehicle-treated rats for each group (Table 1). No significant differences were found for heart rate, mean arterial pressure, and rate pressure product at baseline, 15 min of occlusion, or 2 h of reperfusion for each group compared with vehicle-treated rats for each protocol.
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Infarct Size Studies
Dose Response. Rats treated with morphine (0.1 and 0.2 mg/kg) 5 min before reperfusion demonstrated no significant reduction in infarct size compared with ethanol vehicle (Fig. 2, top, 61.7 ± 1.1, 59.0 ± 1.4 versus 59.1 ± 1.7%, respectively), whereas morphine at a dose of 0.3 mg/kg resulted in a significant reduction in infarct size (Fig. 2, top, 42.3 ± 1.5%**). Rats treated with aspirin (0.6, 1, and 3 mg/kg) 5 min before reperfusion showed no significant reduction in infarct size compared with ethanol vehicle (Fig. 2, middle, 58.6 ± 4.7, 58.1 ± 1.8, 60.7 ± 2.3 versus 59.1 ± 1.7%, respectively). Ibuprofen (0.6, 1, and 3 mg/kg) dose dependently reduced infarct size when administered 5 min before reperfusion compared with ethanol vehicle that was significant only at the highest dose (Fig. 2, bottom, 57.6 ± 2.8, 51.8 ± 2.6, 40.8 ± 2.8** versus 59.1 ± 1.7%, respectively).
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Time of Administration. Both morphine (0.3 mg/kg) and ibuprofen (3 mg/kg), but not aspirin (3 mg/kg), produced significant reductions in infarct size when administered 5 min before reperfusion compared with ethanol vehicle (Fig. 3, 42.3 ± 1.5**, 40.8 ± 2.8**, 60.7 ± 2.3 versus 59.1 ± 1.7%, respectively). The same doses of morphine, ibuprofen, and aspirin administered at 10 s after reperfusion did not affect infarct size compared with ethanol vehicle (Fig. 3; 57.0 ± 5.3, 63.1 ± 1.6, 61.0 ± 1.2 versus 60.0 ± 1.9%, respectively).
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Aspirin or Ibuprofen Interaction with Morphine. Administration of either dose of aspirin (1 or 3 mg/kg) 2 min before morphine (0.3 mg/kg) abrogated morphine-induced cardioprotection compared with ethanol vehicle (Fig. 4; 56.3 ± 1.1, 55.7 ± 0.9 versus 59.1 ± 1.7%, respectively). In contrast, ibuprofen (3 mg/kg) had no effect on morphine-induced infarct size reduction when administered 2 min before morphine (Fig. 4, 43.7 ± 1.3%**). Doses of morphine (0.2 mg/kg), aspirin (0.6 mg/kg), and ibuprofen (0.6 mg/kg) administered 5 min before reperfusion produced no reduction in infarct size compared with ethanol vehicle (Fig. 5, 59.0 ± 1.4, 58.6 ± 4.7, 57.6 ± 2.8 versus 59.1 ± 1.7%, respectively). Interestingly, concomitant administration of aspirin (0.6 mg/kg) with morphine (0.2 mg/kg) did not result in a reduction in infarct size, whereas administration of ibuprofen (0.6 mg/kg) with morphine (0.2 mg/kg) reduced infarct size compared with ethanol vehicle (Fig. 5, 53.1 ± 4.8, 43.9 ± 1.6** versus 59.1 ± 1.7%, respectively).
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12-LO as a Mediator of Morphine or Ibuprofen-Induced Cardioprotection. Morphine (0.3 mg/kg), ibuprofen (3 mg/kg), and concomitant administration of morphine (0.2 mg/kg) plus ibuprofen (0.6 mg/kg) reduced infarct size when administered 5 min before reperfusion compared with DMSO vehicle (Fig. 6, 42.3 ± 1.5**, 40.8 ± 2.8**, 43.9 ± 1.6** versus 59.7 ± 1.5%, respectively). Administration 10 min before ischemia of baicalein abrogated the reduction in infarct size produced by morphine (0.3 mg/kg), ibuprofen (3 mg/kg), and morphine (0.2 mg/kg) plus ibuprofen (0.6 mg/kg) compared with DMSO vehicle (Fig. 6, 51.0 ± 4.6, 64.0 ± 2.1, 57.5 ± 1.8 versus 59.7 ± 1.5%, respectively). Baicalein alone administered 10 min before ischemia had no effect on infarct size compared with DMSO vehicle (Fig. 6, 61.3 ± 0.9 versus 59.7 ± 1.5%, respectively). Administration of 12(S)-HETE (15 µg/kg), 5 min before reperfusion also reduced infarct size compared with DMSO vehicle (Fig. 6, 45.2 ± 2.5** versus 59.7 ± 1.5%, respectively) and ethanol vehicle administered before reperfusion (45.2 ± 2.5** versus 59.1 ± 1.7%, respectively).
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Discussion |
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The protection afforded by morphine when given 5 min before reperfusion in this study and our previous study was found to produce similar infarct size-reducing capabilities compared with morphine administered 10 min before ischemia (Gross et al., 2004). Moreover, morphine administration is required before reperfusion to obtain a reduction in infarct size, indicating a role for morphine in preserving the myocardium from reperfusion injury.
Ibuprofen administered 5 min before reperfusion reduced myocardial infarct size at 3 mg/kg, whereas administration 10 s after reperfusion produced no effect. Similar effects were seen in dogs where ibuprofen was infused at higher doses than those used in our study and continued for several hours during both the ischemia and reperfusion periods (Jugdutt et al., 1980; Kirlin et al., 1982; Romson et al., 1982). Hence, our study refines the window of protection for ibuprofen as being beneficial when administered just before reperfusion. Previous studies in cats show a beneficial effect of ibuprofen as indicated by a reduction of creatine phosphokinase release, a restoration of S-T segment elevation, and prevention of proteolysis (Lefer and Polansky, 1979). Furthermore, studies in isolated rat hearts have also shown that ibuprofen improves functional recovery (Karmazyn, 1986). However, conflicting reports have shown that ibuprofen does not improve functional recovery of isolated feline and pig hearts (Romson et al., 1982; Clement et al., 1990). Although there is conflicting evidence suggesting that ibuprofen may not improve cardiac functional recovery, our data and those of others suggest that ibuprofen reduces infarct size in different animal models and that the cardioprotective benefits of ibuprofen likely extend to humans (Walinsky et al., 1983).
Conflicting results have also been reported for the role of aspirin in cardioprotection. Although some reports have found a beneficial effect of aspirin to reduce infarct size (Such et al., 1983; Rossoni et al., 2001), others have shown no effect (Bonow et al., 1981; Lepran et al., 1981). The differences between these studies are likely attributed to the duration of aspirin administration before a myocardial infarction, because chronic administration of aspirin before ischemia and reperfusion reduced infarct size (Such et al., 1983; Rossoni et al., 2001), whereas acute administration up to 1 h before ischemia demonstrated no reduction of infarct size (Bonow et al., 1981; Lepran et al., 1981). These latter studies, in addition to our findings, would further suggest that the cardio-protection afforded by aspirin is attributed to its antithrombotic effects that occur more than 1 h after aspirin administration (Hirsh et al., 1992); however, when aspirin is administered acutely during ischemia or reperfusion, there is no immediate beneficial effect on infarct size (Bonow et al., 1981; Lepran et al., 1981). It is unknown whether prophylactic treatment of aspirin will abrogate acute morphine-induced infarct size reduction; however, it has been suggested that aspirin may diminish the beneficial effects of angiotensin-converting enzyme inhibitors in humans (Przyklenk and Heusch, 2003).
No other studies have examined the interactions of aspirin or ibuprofen with morphine and its ability to reduce infarct size. Surprisingly, our results suggest that aspirin abrogates morphine-induced cardioprotection, whereas ibuprofen does not effect morphine-induced cardioprotection. Furthermore, the simultaneous administration of these agents, at doses that do not reduce infarct size individually, are effective in combination. Since both morphine and ibuprofen at their highest doses induced similar reductions in infarct size compared with the concomitant administration of ibuprofen and morphine, it would also indicate that the mechanism of infarct size reduction is saturated and a similar pathway of cardioprotection exists for both morphine and ibuprofen.
The ability of morphine or ibuprofen to protect the myocardium when given before reperfusion, but not after reperfusion, may involve a reduction in free radical generation, an event found to be most prominent during the first 10 min of reperfusion (Garlick et al., 1987; Zweier et al., 1989). The generation of oxygen-derived free radicals (OFRs) has also been found to damage membrane lipids during reperfusion (Ambrosio et al., 1991). Interestingly, the conversion of arachidonic acid to 12-HETE has been shown to be attenuated by generation of OFRs, whereas conversely, scavengers of OFRs have been found to cause an elevation of 12-HETE (Muller and Gawlik, 1997). The recovery of left ventricular developed pressure by 12(S)-HETE was also blocked by the mitochondrial KATP channel antagonist 5-hydroxydecanoic acid (Chen et al., 1999). The mitochondrial KATP channel has previously been identified as a source of free radical generation (Pain et al., 2000) and suggests perhaps an interaction occurs between the KATP channel, OFRs, and 12-HETE.
Several different types of 12-LO exist, including leukocyte, epidermal, and platelet 12-LO. Interestingly, leukocyte 12-LO knockout mice abolished ischemic preconditioning-induced infarct size reduction, and these mice also show an increased sensitivity to ADP-induced platelet aggregation (Johnson et al., 1998; Gabel et al., 2001). 12-HETE administration to leukocyte 12-LO-deficient mice also reversed ADP-induced platelet aggregation (Johnson et al., 1998). The human homolog of rat leukocyte 12-LO is the 15-lipoxygenase enzyme that produces 15-HETE as a product (Watanabe et al., 1993). Addition of ibuprofen to human peripheral blood polymorphonuclear leukocytes was found to selectively activate 15-lipoxygenase enzyme and increase 15-HETE concentrations (Vanderhoek and Bailey, 1984). Production of 15-HETE was elevated 9-fold for polymorphonuclear leukocytes treated with ibuprofen; however, aspirin and indomethacin only produced a mild 1.5- to 2-fold elevation in 15-HETE.
The results of our study must be considered with potential limitations, including the extension of these findings from rats to humans. Many additional agents, such as thrombolytics, 
blockers, and nitroglycerin, are also commonly given during or before reperfusion (Antman and Braunwald, 2000). Hence, the ability for morphine or ibuprofen to reduce infarct size in the presence of additional agents commonly given during a myocardial infarction is unknown. The pharmacological agents used in this study may have additional nonspecific effects; however, the doses of ibuprofen and aspirin given were similar to those commonly administered in the clinic. Ibuprofen and aspirin were also administered intravenously, rather than orally. Although 12-HETE was not measured in this study, we previously showed that the selective opioid agonist SNC-121 [4-[(
((2S,5R)-4-propyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide] elevated 12-HETE production during reperfusion in a model of delayed infarct size reduction (Patel et al., 2003).
These data suggest that timely administration of morphine or ibuprofen before reperfusion may attenuate reperfusion injury and reduce infarct size during an acute myocardial infarction. This study also suggests that acute aspirin administration is detrimental to morphine-induced cardioprotection. Furthermore, ibuprofen, instead of aspirin, may be more beneficial to patients during an acute myocardial infarction because of its ability to reduce infarct size both individually and in combination with morphine. These data also implicate 12-HETE in morphine- and ibuprofen-induced infarct size reduction.
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Acknowledgements |
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Footnotes |
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ABBREVIATIONS: 12-LO, 12-lipoxygenase; HETE, hydroxyeicosa-5Z,8Z,10Z,14Z-tetraenoic acid; DMSO, dimethyl sulfoxide; OFR, oxygen-derived free radical.
Address correspondence to: Dr. Garrett J. Gross, Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226. E-mail: ggross{at}mcw.edu
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