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Am J Physiol Heart Circ Physiol 289: H2585-H2591, 2005. First published July 8, 2005; doi:10.1152/ajpheart.00400.2005
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Isoflurane induces second window of preconditioning through upregulation of inducible nitric oxide synthase in rat heart

Mayu Wakeno-Takahashi,1 Hajime Otani,2 Shinichi Nakao,1 Hiroji Imamura,2 and Koh Shingu1

1Departments of Anesthesiology and 2Cardiovascular Center, Kansai Medical University, Moriguchi City, Japan

Submitted 22 April 2005 ; accepted in final form 6 July 2005


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The second window of preconditioning (SWOP) induced by inhalation of volatile anesthetics has been documented in the rat heart and is triggered by nitric oxide synthase (NOS), but involvement of NOS in the mediator phase of isoflurane-induced SWOP has not been demonstrated. We tested the hypothesis that isoflurane-induced SWOP is mediated through upregulation of inducible NOS (iNOS). Rats inhaled 0.75 minimum alveolar concentration (MAC) isoflurane, 1.5 MAC isoflurane, or O2 for 2 h. After 24, 48, 72, and 96 h, the isolated heart was perfused with buffer and subjected to 30 min of ischemia followed by 2 h of reperfusion. Inhalation of 0.75 and 1.5 MAC isoflurane significantly limited infarct size after ischemia-reperfusion 24–72 h after isoflurane inhalation. The maximum effect was obtained 48 h after inhalation of 1.5 MAC isoflurane. Postischemic left ventricular function was improved only 48 h after inhalation of 1.5 MAC isoflurane. iNOS expression and activity in the heart were increased 24–72 h after inhalation of 1.5 MAC isoflurane; this increase was less pronounced after inhalation of 0.75 MAC isoflurane. A selective iNOS inhibitor, 1400W (10 µM), abolished iNOS activation and cardioprotection induced 48 h after inhalation of 1.5 MAC isoflurane. These results suggest that isoflurane inhalation induces SWOP after 24–72 h through overexpression and activation of iNOS in the rat heart.

infarct; cardioprotection; volatile anesthetics; ischemic preconditioning

BRIEF PERIODS OF CARDIAC ISCHEMIA and reperfusion exert a protective effect against subsequent, lethal periods of ischemia, a phenomenon termed ischemic preconditioning (IPC) (20). IPC has two distinct phases: an early phase, which lasts from a few minutes to 2–3 h, and a late phase, termed the second window of preconditioning (SWOP), which develops after 12 h and lasts for 72–96 h (1, 2, 17, 19, 34). IPC-like effects have also been observed after administration of various pharmacological agents. Volatile anesthetics, including isoflurane, have been shown to be cardioprotective agents, which confer a first window of preconditioning (6–8, 15, 16, 23, 24, 32).

Whether SWOP is induced by inhalation of isoflurane is a matter of debate. The SWOP effect of isoflurane has been demonstrated in rabbit and rat, but not in dog, hearts (14, 26, 29, 30). Because these previous studies evaluated the SWOP effect of inhaled isoflurane only after 24 h, the time window of SWOP after isoflurane inhalation remains unclear.

The mechanism of ischemia-induced SWOP has been extensively investigated. It has been shown that nitric oxide (NO) synthase (NOS) triggers isoflurane-induced SWOP in the rat (26). On the other hand, a growing body of evidence suggests that inducible NOS (iNOS) plays a crucial role in mediating SWOP (3–5, 10–12, 28). Nevertheless, whether volatile anesthetic-induced SWOP is mediated by iNOS is unknown. Therefore, we have studied the time window of cardioprotection and the role of iNOS in isoflurane-induced SWOP.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animal preparation. Male Sprague-Dawley rats weighing 250–300 g were used in the present study. All experiments were conducted in accordance with National Institutes of Health (NIH) guidelines (21) and were approved by the Animal Care Committee of Kansai Medical University. Rats inhaled 100% O2 or 100% O2 with 0.75 or 1.5 minimum alveolar concentration (MAC, i.e., end-tidal concentration under spontaneous respiration) isoflurane, which is equivalent to 1.05% or 2.1% volume concentration of isoflurane, respectively, in the rat (25), for 2 h. The concentration of isoflurane in a chamber was continuously monitored by using an anesthetic gas monitor (model M1025B, Hewlett-Packard). The rats were placed on a thermoregulating pad for maintenance of rectal temperature at 37°C. Each rat was then allowed to recover in room air (21% O2) and housed until the Langendorff heart perfusion experiments. Rats housed for the same period without inhalation of O2 or isoflurane were used as controls.

Perfusion technique. The control rats (without any treatments) and rats subjected to 24, 48, 72, or 96 h of O2 or isoflurane inhalation were anesthetized with pentobarbital sodium (100 mg/kg ip). After thoracotomy, the heart was rapidly excised, placed in a temperature-regulated heart chamber, and perfused at a constant mean pressure of 70–75 mmHg with Krebs-Henseleit bicarbonate buffer solution containing (in mM) 118 NaCl, 4.7 KCl, 1.2 MgSO4, 25 NaHCO3, 1.2 KH2PO4, 1.8 CaCl2, and 11 glucose, with pH 7.4 at 37°C when equilibrated with 95% O2-5% CO2.

During the stabilization period, a latex balloon was inserted into the left ventricle (LV) through the left atrium to measure isovolumic LV function. The balloon was filled with saline solution to produce a LV end-diastolic pressure of 5–10 mmHg at baseline, and the balloon volume was kept constant throughout the experiment. Coronary flow was measured by timed collection of the coronary effluent. Hearts with LV developed pressures <80 mmHg or heart rates <240 beats/min at baseline were excluded from the study. The animals excluded from the subsequent experiment were one control rat, one rat subjected to 24 h of O2 inhalation, and one subjected to 72 h of 1.5 MAC isoflurane inhalation in the functional study and one rat subjected to 24 h of O2 inhalation and one subjected to 24 h of 0.75 MAC isoflurane inhalation in the biochemical study.

Experimental protocol. First, the cardioprotective effect of inhalation of O2, 0.75 MAC isoflurane, and 1.5 MAC isoflurane 24, 48, 72, or 96 h before Langendorff perfusion studies was compared (Fig. 1). The isolated and perfused hearts were subjected to 30 min of global ischemia followed by 120 min of reperfusion.



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  		Fig. 1. Experimental protocol. O224h, O248h, O272h, and O296h, 24, 48, 72, and 96 h after inhalation of O2, respectively; 0.75Iso24h, 0.75Iso48h, 0.75Iso72h, and 0.75Iso96h, 24, 48, 72, and 96 h after inhalation of 0.75 minimum alveolar concentration (MAC) isoflurane (Iso), respectively; 1.5Iso24h, 1.5Iso48h, 1.5Iso72h, and 1.5Iso96h, 24, 48, 72, and 96 h after inhalation of 1.5 MAC Iso, respectively; O248h-W, 48 h after inhalation of O2 and preischemic treatment with 10 µM 1400W for 15 min; 1.5Iso48h-W, 48 h after inhalation of 1.5 MAC Iso and preischemic treatment with 10 µM 1400W for 15 min.

 
Second, the effect of an iNOS inhibitor, 1400W, on postischemic recovery of LV function and infarct size 48 h after inhalation of O2 or 1.5 MAC isoflurane was studied. 1400W is highly selective for iNOS (IC50 = 2.0 µM) and is 50-fold more potent against iNOS than against endothelial NOS (eNOS) (28). 1400W (10 µM) was administered for 15 min before ischemia.

Isoflurane was purchased from Abbott Laboratories (Abbott Park, IL) and 1400W from Alexis Biochemicals (Carlsbad, CA).

Infarct size measurement. At the end of experiments, the heart was trimmed for removal of the atrium, the right ventricular free wall, and connective tissues and sliced transversely in a plane perpendicular to the apical-basal axis into ~1-mm-thick slices. The slices were immersed in phosphate-buffered saline containing 2% triphenyltetrazolium chloride for 15 min at 37°C and fixed with 10% formaldehyde in 0.1 M phosphate buffer (pH 7.2) at room temperature. The brick-red area was traced using by NIH 1.61 image-processing software (Bethesda, MD), and each digitized image was subjected to equivalent degrees of background subtraction, brightness, and contrast enhancement for improved clarity and distinction. The areas at risk (equivalent to total LV mass), as well as the infarct zones of each slice, were calculated in terms of pixels. The infarct volume was calculated, and the sum of all slices was used to compute a ratio of percent infarct to total LV mass.

iNOS expression. After stabilization of the heart under aerated Langendorff perfusion, the heart was removed from the apparatus, and a 2-mm-thick midventricular slice was frozen with a tissue mount compound in liquid nitrogen for immunohistochemical analysis of iNOS in frozen sections. The rest of the ventricular muscle was immersed in liquid nitrogen for immunoblot analysis of iNOS and iNOS activity assay. Frozen 6-µm-thick sections were fixed in acetone for 10 min at room temperature. Slides were incubated with a rabbit polyclonal iNOS antibody (Santa Cruz Biotechnology, Santa Cruz, CA), diluted 1:100 in PBS containing 1% BSA for 60 min at room temperature. Subsequently, slides were incubated with FITC-conjugated goat anti-rabbit IgG (1:200 dilution) for 60 min at room temperature. Immunofluorescence images of iNOS were obtained by confocal laser microscopy (Olympus, Tokyo, Japan).

For immunoblot analysis, frozen heart tissues were homogenized with a lysis buffer containing 30 mM Tris, pH 7.4, 150 mM NaCl, 1% NP-40, 0.25% sodium deoxycholate, 1 mM EDTA, 0.1 mM phenylmethylsulfonyl fluoride, and a protease inhibitor cocktail (Complete, Roche Diagnostics, Mannheim, Germany). The protein concentration was determined by using a protein assay kit (Bio-Rad Laboratories, Hercules, CA). The lysate samples were separated by 7.5% SDS-PAGE, and the separated proteins were transferred to a polyvinylidene difluoride membrane with a transfer buffer containing 25 mM Tris, 192 mM glycine, and 10% methanol. The membranes were blocked with 5% skim milk and immunoblotted with the anti-iNOS antibody using an enhanced chemiluminescence detection system (Amersham Biosciences, Tokyo, Japan) according to the manufacturer's instructions. The immunolabeling was quantified by densitometric analysis using image-analyzing software (Win Roof, Mitani, Fukui, Japan).

iNOS activity assay. Frozen heart tissues were homogenized in 4 vol of buffer containing 10 mM HEPES, pH 7.2, 0.32 M sucrose, 0.1 mM EDTA, 1 mM DTT, and the protein inhibitor cocktail. The homogenate was centrifuged, and aliquots of the supernatant were incubated for 60 min at 37°C with 1) assay cocktail containing 50 mM L-valine, 1 mM DTT, 0.1 mM NADPH, 0.1 mM tetrahydrobiopterin, 1 mM L-citrulline, 18 µM L-arginine, 2 µM [L-14C]arginine, 1 mM MgCl2, and 0.2 mM CaCl2 in 50 mM KH2PO4, pH 7.2; 2) cocktail plus 1 mM EGTA; or 3) cocktail plus 1 mM EGTA plus 1 mM N-monomethyl-L-arginine to determine the total and Ca2+-independent NOS (iNOS) activity. NOS activity was quantified by measurement of [L-14C]citrulline using a liquid scintillation counter after removal of untreated [L-14C]arginine with 50W-X8 Dowex resin (Muromachi Technos, Tokyo, Japan).

Statistics. Values are means ± SE. Statistical analysis of hemodynamics was performed with analysis of variance for repeated measures followed by Bonferroni's post hoc test. Statistical analysis of infarct size, iNOS expression, and iNOS activity was performed by one-way analysis of variance followed by Bonferroni's post hoc test. P < 0.05 was considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Isoflurane-induced SWOP effect. The SWOP effect 24, 48, 72, and 96 h after inhalation of 0.75 and 1.5 MAC isoflurane was compared. Hemodynamic studies showed that all the parameters of LV function (LV developed pressure, LV end-diastolic pressure, and heart rate) were not significantly different at baseline between groups but were significantly improved during reperfusion only 48 h after inhalation of 1.5 MAC isoflurane (Table 1), although the same dose of isoflurane decreased the LV end-diastolic pressure during reperfusion after 24 h. Coronary flow was 17.5 ± 1.2 ml·min–1·g–1 at baseline in the control group and was not significantly different between groups. Coronary flow was decreased to 12.6 ± 1.0 ml·min–1·g–1 in the control group 30 min after reperfusion but was significantly higher only 48 h after inhalation of 1.5 MAC isoflurane (16.8 ± 1.0 ml·min–1·g–1). Infarct size was significantly smaller 24, 48, and 72 h after inhalation of 0.75 or 1.5 MAC isoflurane than in the control group or the time-matched O2 inhalation group (Fig. 2). However, the infarct size-limiting effect 48 h after inhalation of 1.5 MAC isoflurane was significantly greater than after other protocols of isoflurane inhalation. O2 inhalation had no SWOP effect 24–96 h later. Thus the SWOP effect was most pronounced 48 h after inhalation of 1.5 MAC isoflurane in this experimental model.


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  		Table 1. Postischemic recovery of LV function

 


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  		Fig. 2. Effect of inhalation of Iso on myocardial infarct size. Experimental protocol is shown in Fig. 1. Values are means ± SE of 7 experiments. LV, left ventricle. ¶P < 0.05 compared with control. *P < 0.05 compared with O224h. {dagger}P < 0.05 compared with O248h. {ddagger}P < 0.05 compared with O272h.

 
INOS expression and activity. Immunoblot studies showed no appreciable iNOS expression in the control condition (without treatment) or 48 h after O2 inhalation (Fig. 3, a and b). In contrast, iNOS expression was significantly increased 24 and 48 h after inhalation of 1.5 MAC isoflurane. A significant, but less pronounced, increase in iNOS expression was also noted 72 h after inhalation of 1.5 MAC isoflurane. Immunohistochemical studies confirmed no iNOS expression in the control heart (Fig. 3C) or 48 h after O2 inhalation (Fig. 3d) but an increase in the cytoplasmic region of cardiomyocytes 48 h after inhalation of 1.5 MAC isoflurane (Fig. 3e). A negative control slide, in which the primary antibodies were replaced with nonimmune normal rabbit serum, did not show appreciable immunostaining for iNOS (not shown).



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  		Fig. 3. a: Immunoblot study of inducible nitric oxide synthase (iNOS) protein expression. Experimental protocol is shown in Fig. 1. b: Quantitative analysis of iNOS protein expression. Values are means ± SE of 5 experiments. *P < 0.05 compared with control. c–e: Immunohistochemical analysis of iNOS protein expression in control heart (c); 48 h after O2 inhalation (d), and 48 h after inhalation of 1.5 MAC Iso (e). Scale bars, 20 µm.

 
INOS activity. iNOS and total NOS activity were significantly increased 24 and 48 h after inhalation of 1.5 MAC isoflurane (Fig. 4). The increase, although less pronounced, remained 72 h after inhalation of 1.5 MAC isoflurane. The increase in total NOS activity in these hearts was primarily attributed to the increase in iNOS activity. O2 inhalation had no effect on iNOS and total NOS activity 48 h later. The activation of iNOS 48 h after inhalation of 1.5 MAC isoflurane was inhibited by 1400W. This was associated with a decrease in total NOS activity.



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  		Fig. 4. iNOS and total NOS activity. Experimental protocol is shown in Fig. 1. Values are means ± SE of 5 experiments. *P < 0.05 compared with control. {dagger}P < 0.05 compared with 1.5Iso48h.

 
Effect of 1400W on isoflurane-induced SWOP. 1400W had no significant effect on LV function before ischemia in the heart 48 h after inhalation of O2 or 1.5 MAC isoflurane (Table 2). 1400W did not affect the recovery of postischemic LV function and infarct size (Fig. 5) 48 h after O2 inhalation. However, preischemic treatment with 1400W significantly inhibited the improvement of LV function (LV developed pressure, LV end-diastolic pressure, and heart rate), coronary flow (not shown), and the infarct size-limiting effect 48 h after inhalation of 1.5 MAC isoflurane.


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  		Table 2. Effect of 1400W on postischemic recovery of LV function

 


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  		Fig. 5. Effect of 1400W on infarct size. Experimental protocol is shown in Fig. 1. Values are means ± SE of 7 experiments. *P < 0.05 compared with control. {dagger}P < 0.05 compared with O248h. {ddagger}P < 0.05 compared with 1.5Iso48h.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The salient findings of this study are summarized as follows: 1) Inhalation with 0.75 or 1.5 MAC isoflurane conferred a significant infarct size-limiting effect in an isolated and perfused rat heart model after 24, 48, and 72 h. The most pronounced reduction in infarct size and improvement of LV function were observed 48 h after inhalation of 1.5 MAC isoflurane. 2) The SWOP effect observed 48 h after inhalation of isoflurane was associated with enhanced expression and activity of iNOS in the heart. 3) The SWOP effect of isoflurane was abolished by the pharmacological inhibition of iNOS. These data demonstrate that inhalation of relatively high-dose isoflurane induces the most powerful delayed cardioprotection in the rat heart after 48 h and that overexpression and activation of iNOS in the heart mediate this effect.

Whether SWOP can be induced after exposure to isoflurane has been controversial (14, 26, 29, 30). Tonkovic-Capin and associates (30) demonstrated that inhalation of 1% isoflurane for 2 h conferred significant cardioprotection against LV dysfunction and infarction induced by 30 min of global ischemia and 3 h of reperfusion after 24 h in an isolated and perfused rabbit heart model. Tanaka and associates (29) demonstrated that inhalation of 1 MAC isoflurane 24 h before coronary artery occlusion reduced infarct size in rabbit hearts in vivo. The dose-dependent effect of isoflurane in SWOP was investigated in an isolated and perfused rat heart model by Shi and associates (26), who demonstrated that inhalation of 0.8% isoflurane conferred significant cardioprotection against LV dysfunction and infarction induced by global ischemia and reperfusion after 24 h. However, those investigators failed to observe significant cardioprotection at lower or higher doses of isoflurane. Similarly, inhalation of 1 MAC isoflurane 24 h before coronary artery occlusion was ineffective in reducing infarct size in the dog (14). Although the reason for these variable observations is unclear, it is speculated that the optimal time window of SWOP mediated by inhalation of isoflurane may differ between the species and the experimental models. It has been demonstrated that inhalation of isoflurane induces the SWOP effect after 24 h at least in the rat and rabbit. Nevertheless, the time window of SWOP induced by inhalation of isoflurane has not been investigated. To the best of our knowledge, the present study demonstrated for the first time that isoflurane induces delayed cardioprotection most effectively 48 h after inhalation of 1.5 MAC isoflurane in the isolated and perfused rat heart. Less significant cardioprotection against infarction, but not LV dysfunction, was observed 24–72 h after inhalation of 0.75 MAC or 24–72 h after inhalation of 1.5 MAC isoflurane. The SWOP effect was dissipated after 96 h at 0.75 or 1.5 MAC isoflurane inhalation. The time window of isoflurane-induced SWOP is reminiscent of that induced by IPC (34). Thus isoflurane-induced SWOP may represent a promising alternative to IPC-induced SWOP. However, volatile anesthetics have significant effects on respiratory rate and hemodynamics, especially when the dose of isoflurane is increased. Therefore, the superior SWOP effect induced by 1.5 MAC isoflurane may not solely be ascribed to the volatile anesthetic effect.

NOS is known to play a pivotal role in isoflurane-induced SWOP. It has been demonstrated that eNOS-mediated formation of NO and reactive oxygen species triggers isoflurane-induced SWOP (26). Although it has been shown that isoflurane inhalation produces the overexpression of iNOS and mediates delayed protection against ischemic neuronal injury (13), the role of iNOS in volatile anesthetic-induced SWOP has not been studied in the heart. The present study provided evidence that iNOS is a mediator of isoflurane-induced SWOP in the rat heart. Inhalation of 1.5 MAC isoflurane increased the expression and activity of iNOS after 24–72 h, with maximum activation after 48 h. This time course is correlated with the efficacy of cardioprotection. The activation of iNOS and cardioprotection induced 48 h after isoflurane inhalation was abolished by preischemic treatment with a highly selective iNOS inhibitor, 1400W. The role of iNOS as a mediator of isoflurane-induced SWOP is consistent with the hypothesis that iNOS is a common mediator of late preconditioning induced by ischemic challenges or by pharmacological agents (3–5, 10–12, 28). Although Wang and associates (33) demonstrated that the final stage of SWOP, which occurred 72 h after a repeated brief ischemia and reperfusion, was mediated by neuronal NOS (nNOS), instead of iNOS (33), the present study could not demonstrate a significant increase in Ca2+-dependent NOS (eNOS and/or nNOS) expression and activity 24–96 h after isoflurane inhalation. Thus it seems likely that the contribution of nNOS in the final stage of isoflurane-induced SWOP is relatively minor compared with iNOS in our experimental model.

Although our study suggests that iNOS is a mediator of isoflurane-induced SWOP, the underlying signaling mechanisms involved in cardioprotection were not addressed. It has been demonstrated that cyclooxygenase-2 (COX-2) expression is also upregulated by SWOP and that iNOS and COX-2 act in parallel to mediate late preconditioning (4, 27). The mediator role of COX-2 in isoflurane-induced SWOP has also been demonstrated by Tanaka and associates (29). Although the effector system of isoflurane-induced SWOP has not been elucidated, there is evidence that mitochondrial and sarcolemmal ATP-regulated K+ (KATP) channels play an essential role in mediating delayed cardioprotection afforded by isoflurane (30). These studies suggest that iNOS-derived NO and COX-2-derived prostaglandins activate a downstream signaling cascade, such as protein kinase C, in a cooperative manner, leading to activation of mitochondrial and sarcolemmal KATP channels. Indeed, it has been demonstrated that protein kinase C plays a pivotal role in activation of KATP channels and cardioprotection in early preconditioning (18, 22, 31).

The present study demonstrated that isoflurane induces SWOP against myocardial infarction and LV dysfunction in the rat heart in a dose- and time-dependent manner. This cardioprotective effect is associated with enhanced expression and activity of iNOS and was completely abrogated by selective pharmacological inhibition of iNOS. To the best of our knowledge, this is the first report demonstrating a time window of delayed cardioprotection induced by isoflurane 24–72 h after isoflurane inhalation. Further investigations are warranted to elucidate whether a similar time window of isoflurane-induced SWOP can be observed in other species and experimental models and whether this SWOP effect is relevant in the clinical setting of anesthetic preconditioning.


   FOOTNOTES
 

Address for reprint requests and other correspondence: H. Otani, Cardiovascular Center, Kansai Medical Univ., Moriguchi City 570-8507, Japan (e-mail: otanih{at}takii.kmu.ac.jp)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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