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Anesth Analg 2006;103:274-280 © 2006 International Anesthesia Research Society doi: 10.1213/01.ANE.0000230389.76351.0C
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Abstract |
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 Top Abstract IntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION: Female gender confers cardioprotection against ischemia-reperfusion injury, in part because estrogen enhances nitric oxide production by endothelial nitric oxide synthase (eNOS). Whether ischemic preconditioning occurs in females remains controversial. Delayed myocardial preconditioning by isoflurane is mediated by eNOS in male rabbits, but whether females are similarly protected by isoflurane is unknown. We tested the hypothesis that gender-specific reductions in myocardial infarct size occur in female rabbits, but that this inherent cardioprotection abrogates further beneficial effects of isoflurane-induced delayed preconditioning.
METHODS: Rabbits (n = 115) underwent a 30 min coronary artery occlusion and 3 h reperfusion with or without a 2 h administration of 1.0 minimum alveolar concentration isoflurane one day before experimentation. Rabbits received saline or a nonselective, selective inducible, or selective neuronal NOS inhibitor [N-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg), aminoguanidine (AG, 300 mg/kg), or 7-nitroindazole (7-NI, 50 mg/kg), respectively].
RESULTS: Isoflurane reduced infarct size in males (mean± sd, 26 ± 5% of the left ventricular area at risk) versus saline (45 ± 2%). L-NAME, but not AG or 7-NI, abolished isoflurane-induced protection in males (41 ± 9, 24 ± 4 and 22 ± 2%, respectively). Infarct size was reduced, and eNOS protein expression was greater, in female versus male rabbits. Infarct size was unchanged in female rabbits with, versus without, isoflurane pretreatment (27 ± 9 and 27 ± 10%, respectively). L-NAME, but not AG or 7-NI, increased infarct size with or without isoflurane pretreatment in females.
CONCLUSIONS: Female gender-induced reductions in infarct size are mediated by eNOS, but remote isoflurane exposure (1.0 MAC) before ischemia and reperfusion does not produce additional cardioprotection in vivo.
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Introduction |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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The risk of cardiovascular disease is substantially less in premenopausal women as compared to men of similar age (1). This difference in risk is multifactorial in origin, but has been primarily related to the beneficial effects of estrogen on several factors associated with cardioprotection, including lipoprotein profile, coagulation factor-fibrinolytic protein balance, antioxidant production, and vasodilator synthesis (2). These effects are mediately primarily at the transcriptional level, but a clear nongemonic relationship between estrogen and nitric oxide (NO) metabolism has been established that also plays an important role in the gender specificity of cardiovascular risk (3). Estrogen stimulates expression of endothelial NO synthase (eNOS) (4,5), regulates basal endothelial NO release (6), and facilitates binding of heat shock protein 90 to eNOS (7), an action known to markedly enhance the activity of the enzyme (8). These estrogen-induced genomic and eNOS-mediated protective mechanisms are associated with a substantial reduction in myocardial cellular damage, attenuation of the inflammatory response to tissue injury, preservation of left ventricular function, and improved survival after ischemia-reperfusion in females (9,10).
Despite the strong evidence that estrogen exerts cardioprotective effects, there are conflicting data about whether myocardial ischemic preconditioning occurs in females. Female gender did not affect the antiarrhythmic effects of ischemic preconditioning (11) nor impair opioid-induced late preconditioning in rats (12), but other studies suggest that preconditioning may be attenuated (13) or does not occur in females (14) because females are already relatively protected from injury. The effect of gender on volatile anesthetic-induced preconditioning has not been examined. Our laboratory recently demonstrated that delayed myocardial preconditioning produced by isoflurane is triggered and mediated by eNOS in male rabbits concomitant with enhanced eNOS transcription and translation (15). In the current investigation, we tested the hypothesis that gender-specific protection against myocardial infarction occurs in adult female as compared to male rabbits as a result of eNOS upregulation. We further tested the hypothesis that this inherent female-specific cardioprotection abrogates further beneficial actions of isoflurane-induced delayed preconditioning in vivo.
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METHODS |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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All experimental procedures and protocols used in this investigation were reviewed and approved by the Animal Care and Use Committee of the Medical College of WI. Furthermore, all conformed to the Guiding Principles in the Care and Use of Animals of the American Physiologic Society and were in accordance with the Guide for the Care and Use of Laboratory Animals.
Administration of Isoflurane and Surgical Preparation
Male or female New Zealand white rabbits weighing between 2.5 and 3.0 kg were placed in an induction chamber 24 h before acute experimentation as previously described (15). After inhaled induction, anesthesia was maintained with 1.0 minimum alveolar concentration (MAC) isoflurane (2.1%) in an air-oxygen mixture during spontaneous ventilation. The concentration of isoflurane inside the induction chamber was continuously measured with an infrared anesthetic analyzer that was calibrated with known standards before and during experimentation. Anesthesia was discontinued after 2 h, and emergence was allowed to occur. Each rabbit was then housed overnight before experimentation on the following day. Rabbits with or without previous exposure to isoflurane were anesthetized with IV sodium pentobarbital (30 mg/kg). A tracheostomy was performed through a ventral midline incision, and the trachea was cannulated. The lungs of each rabbit were mechanically ventilated using an air-oxygen mixture (fractional inspired oxygen concentration = 0.33). Heparin-filled catheters were inserted into the right carotid artery and the left jugular vein for measurement of heart rate and mean arterial blood pressure, and fluid or drug administration, respectively. A left thoracotomy was performed at the fourth intercostal space. A prominent branch of the left anterior descending coronary artery (LAD) was identified, and a silk ligature was placed around this vessel approximately halfway between the base and apex for the production of coronary artery occlusion and reperfusion. IV heparin (500 U) was administered immediately before LAD occlusion. Coronary artery occlusion was verified by the presence of epicardial cyanosis in the ischemic zone, and reperfusion was confirmed by observing an epicardial hyperemic response. Hemodynamics were continuously recorded on a polygraph throughout each experiment.
Experimental Protocol
The experimental design is illustrated in Figure 1. Baseline hemodynamics and arterial blood gas tensions were recorded 30 min after instrumentation was completed. All rabbits underwent a 30 min LAD occlusion followed by 3 h of reperfusion. In 16 groups (n = 7 or 8 per group), male or female rabbits with or without previous exposure to isoflurane were randomly assigned to receive 0.9% saline (control), the nonselective NOS inhibitor N-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg), the selective inducible (iNOS) antagonist aminoguanidine hydrochloride (AG, 300 mg/kg), or the selective neuronal (nNOS) inhibitor 7-nitroindazole (7-NI, 50 mg/kg). L-NAME was dissolved in 0.9% saline and administered as an IV infusion over 10 min beginning 20 min before LAD occlusion. AG was dissolved in 0.9% saline, the pH of the solution was adjusted to 7.4 with 0.1N NaOH, and the mixture then injected subcutaneously 1 h before coronary occlusion. 7-NI was dissolved in dimethylsulfoxide and administered into the peritoneum 1 h before coronary occlusion. We have previously demonstrated that dimethylsulfoxide does not affect systemic hemodynamics nor alter myocardial infarct size in an identical rabbit model (15,16). AG and 7-NI have been shown to be selective inhibitors of iNOS and nNOS, respectively, at the doses used in the current investigation (17,18).
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Determination of Myocardial Infarct Size
Myocardial infarct size was measured as previously described (19). Briefly, the LAD was reoccluded at the completion of each experiment and 3 mL of patent blue dye was injected IV. The left ventricular area at risk for infarction was separated from surrounding normal areas (stained blue), and the 2 regions were incubated at 37°C for 20 min in 1% 2,3,5-triphenyltetrazolium chloride in 0.1 M phosphate buffer adjusted to pH 7.4. Infarcted and noninfarcted myocardium within the area at risk were carefully separated and weighed after storage overnight in 10% formaldehyde. Myocardial infarct size was expressed as a percentage of the area at risk. Rabbits that developed intractable ventricular fibrillation and those with an area at risk <15% of total left ventricular mass were excluded from subsequent analysis.
Immunohistochemistry
Left ventricular tissue samples were also obtained from 2 separate groups of male and female rabbits (n = 5 per group) that were anesthetized and instrumented as described above but were neither pretreated with isoflurane nor subjected to coronary artery occlusion and reperfusion. Hearts were rapidly excised and the left ventricle was isolated and frozen in liquid nitrogen (-70°C) for subsequent immunohistochemistry analysis as previously described (20). Transverse cryostat sections (5 µm) of the left ventricle were mounted on positively charged Colorfrost Plus microscope slides (Fisher Scientific, Pittsburgh, PA). Sections were fixed for 20 min in 100% acetone at 20C and rinsed with phosphate-buffered saline. Sections were incubated with a 1:50 dilution of mouse monoclonal primary eNOS antibody (Biomol, Plymouth Meeting, PA) in phosphate-buffered saline at 37°C for 30 min. Sections were washed 3 times for 5 min with phosphate-buffered saline. Sections were subsequently incubated with 1:200 dilution of biotinylated anti-mouse secondary antibody (Amersham Pharmacia, Piscataway, NJ) in phosphate-buffered saline at 37°C for 30 min. Sections were washed again 3 times for 5 min with phosphate-buffered saline before conjugation with 10 µg/mL streptavidin-labeled fluorescein isothiocyanate (Pierce, Rockford, IL) at 37°C for 15 min. Nuclear staining was achieved with 1 µM TO-PRO-3 (Molecular Probes, Eugene, OR) at room temperature for 2 min. Images were obtained using a laser fluorescence imaging system and a confocal microscope. Use of the 40x objective yielded a 400x end magnification. A Krypton-Argon laser was used for excitation wavelengths of 488 and 633 nm, and the emitted fluorescence was determined after long pass filtering at corresponding wavelengths of 520 and 661 nm for fluorescein isothiocyanate and TO-PRO, respectively. Approximately 50 images were obtained from each rabbit heart. eNOS-positive structures were counted using the MetaMorph Imaging program (Universal Imaging, Downingtown, PA).
Statistical Analysis
Statistical analysis of data within and between groups was performed with analysis of variance (ANOVA) for repeated measures followed by the Student-Newman-Keuls test. Changes were considered statistically significant when P < 0.05. All data are expressed as mean ± sd.
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RESULTS |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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One hundred-fifteen rabbits were instrumented to obtain 112 successful infarct size experiments. One female rabbit was excluded from the control group because the left ventricular area at risk was <15% of the total left ventricular mass. Two male rabbits (L-NAME alone) were excluded because intractable ventricular fibrillation occurred during coronary artery occlusion. Arterial blood gas tensions were maintained within the physiologic range during administration of isoflurane in all groups (data not shown).
Baseline hemodynamics were similar within and between male and female groups (Tables 1 and 2). Compared with male rabbits, heart rate and mean arterial blood pressure were reduced under baseline conditions in female rabbits pretreated with AG and those receiving AG after remote exposure to isoflurane, respectively. However, no differences in rate-pressure product were observed between male and female groups at baseline. Rate-pressure product was lower during LAD occlusion in female versus male rabbits receiving AG in the absence or presence of isoflurane. Decreases in heart rate and rate–pressure product occurred during reperfusion in most experimental groups. Female rabbits pretreated with AG demonstrated a reduced rate-pressure product 60 and 120 min after reperfusion as compared to male rabbits. No other differences in hemodynamics were observed between male and female groups during reperfusion.
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Body weight, left ventricular mass, area at risk weight, and the ratio of area at risk to left ventricular mass were similar between groups (data not shown). Isoflurane pretreatment in male rabbits reduced infarct size (26 ± 5% of the left ventricular area at risk) as compared with control (45 ± 2%; Fig. 2). Administration of L-NAME, AG, or 7-NI alone did not affect infarct size (43 ± 11, 41 ± 7, and 43 ± 3%, respectively). L-NAME, but not AG or 7-NI, abolished isoflurane-induced cardioprotection in male rabbits (41 ± 9, 24 ± 4 and 22 ± 2%, respectively).
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significantly (P < 0.05) different from corresponding male rabbits.Myocardial infarct size was significantly less in female as compared to male rabbits under control conditions (27 ± 10 versus 45 ± 2%, respectively). In contrast to the findings in male rabbits, administration of isoflurane did not affect infarct size in female rabbits (27 ± 9%). L-NAME, but not AG or 7-NI, increased infarct size in the absence and presence of isoflurane pretreatment in female rabbits (Fig. 2). Basal expression of eNOS protein was greater in female than male rabbits in the absence of isoflurane pretreatment or ischemia and reperfusion (Fig. 3).
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DISCUSSION |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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The results of the current investigation demonstrate that healthy adult female rabbits are relatively protected against myocardial infarction as compared to their male counterparts. Pretreatment with L-NAME but not AG or 7-NI abolished these differences in irreversible ischemic injury, implicating eNOS in this gender-specific cardioprotection. These pharmacological data are supported by the basal upregulation of eNOS protein expression observed in female as compared to male rabbits, independent of subsequent coronary artery occlusion and reperfusion.
Several investigations have established a strong link between estrogen and eNOS expression and activity in females (5–7), similar to the findings of upregulation of eNOS observed in females in the current investigation. The current results also demonstrate that administration of L-NAME, but not AG or 7-NI, before prolonged coronary artery occlusion and reperfusion in male rabbits abrogated reductions in myocardial infarct size produced by prior exposure to the volatile anesthetic on the previous experimental day. These data support our previous findings (15) indicating that isoflurane-induced delayed preconditioning is mediated by eNOS in male rabbits. In contrast to the findings in males, remote administration of 1.0 MAC isoflurane did not produce cardioprotection in female rabbits. These results indicate, for the first time, that isoflurane-induced delayed preconditioning is gender-specific. This gender difference most likely occurred because females were already relatively protected against ischemia-reperfusion injury, and exposure to isoflurane did not provide any additional cardioprotection under these circumstances.
The influence of gender on preconditioning phenomena has not been extensively studied, and the results remain controversial (9). Ischemic preconditioning reduced ventricular ectopy and the incidence of ventricular fibrillation occurring in response to prolonged coronary artery occlusion and reperfusion to a similar extent in female as compared to male rats (11). Administration of a selective 
1-opioid agonist 24 h before a 20 min episode of global ischemia and reperfusion augmented recovery of left ventricular developed pressure to equivalent degrees in isolated hearts obtained from young female as compared to male rats (12). These data suggested that gender does not affect opioid-induced late preconditioning. In contrast, preconditioning produced by the Salmonella typhimurium lipopolysaccharide endotoxin was attenuated in isolated female rat hearts as compared to those of their male counterparts (13). In addition, ischemic preconditioning failed to provide additional protection to Langendorff-prepared female mouse hearts (14). Notably, female hearts displayed enhanced functional recovery and reduced myocardial necrosis as compared to male hearts in the absence of preconditioning in this study (14), and the authors concluded that the failure of female rabbits to respond to ischemic preconditioning was related to this underlying gender-specific protection. The current findings support the results of this latter study (14) as remote administration of isoflurane did not provide additional cardioprotection beyond baseline reductions in myocardial infarct size observed in female rabbits.
The current results must be interpreted within the constraints of several potential limitations. The current investigation was performed in barbiturate-anesthetized, acutely instrumented rabbits in vivo, in contrast to the rat or mouse isolated heart preparations used in other studies (11–14) of the gender-dependence of preconditioning. Thus, the discrepancies between the current results and those obtained by other investigators (11,12) may be related to differences between animal species or experimental preparation. Whether similar results occur in humans is also unknown and may not be inferred from the current results. AG and 7-NI have been shown to be selective inhibitors of iNOS and nNOS, respectively, at the doses used in the current investigation (17,18). Nevertheless, dose-response relationships to these selective inhibitors were not performed, and the possibility that these drugs may have inhibited other protein kinases involved in myocardial protection cannot be completely excluded. Higher doses of these drugs may have produced nonselective actions. The relative lack of effect of AG and 7-NI on myocardial infarct size also did not assure the efficacy of these NOS inhibitors in rabbits in the current investigation. The route, timing, and duration of administration of NOS inhibitors was heterogenous, and these pharmacokinetic factors may have influenced the results. Plasma concentrations of L-NAME, AG, and 7-NI were also not determined. Currently available eNOS antagonists may affect other NOS isoforms and, as a result, experiments were not conducted using these drugs. The current results also require qualification because we did not specifically measure NO production by eNOS, iNOS, or nNOS, nor did we determine the biochemical activity of these NOS isoenzymes in rabbit left ventricular myocardium. Finally, we did not quantify eNOS transcription or translation in the current investigation.
We did not conduct dose- or temporal-responses to isoflurane in the current investigation. Pitcher et al. (13) recently suggested that the preconditioning threshold may be higher in females as compared to males. Thus, it remains possible that a higher dose or a more prolonged period of administration of isoflurane may have produced delayed preconditioning in female rabbits. The current investigation used a 30 min LAD occlusion in order to produce myocardial infarction in male and female rabbits. Whether isoflurane-induced delayed preconditioning may occur in female rabbits subjected to more prolonged periods of coronary artery occlusion is also unknown and will require further study to ascertain. Serum estradiol concentrations were not specifically measured in the current investigation, but substantially greater estradiol concentrations have been reported in adult female as compared to male rabbits (21). Myocardial infarct size is determined primarily by the size of the left ventricular area at risk and extent of coronary collateral perfusion. The left ventricular area at risk was similar between groups. Coronary collateral bloodflow is minimal in rabbits (22). Thus, it is unlikely that differences in collateral perfusion between groups account for the observed results, but coronary collateral bloodflow was not specifically quantified in the current investigation. The reductions in myocardial infarct size occurred independent of changes in major determinants of myocardial oxygen consumption (Table 1). Nevertheless, coronary venous oxygen tension and myocardial oxygen consumption were not specifically determined.
In summary, the current results indicate that healthy adult female rabbits are relatively protected against myocardial infarction as compared to male rabbits under baseline conditions concomitant with enhanced eNOS expression. This decrease in irreversible ischemic injury observed in female rabbits was abolished by pretreatment with L-NAME, but not AG or 7-NI. These pharmacological results implicate eNOS, but not iNOS or nNOS, as a critical mediator of gender-induced cardioprotection. The current findings confirm our previous results (15) by demonstrating that isoflurane-induced delayed preconditioning is mediated by eNOS in male rabbits. In contrast, remote isoflurane exposure before ischemia and reperfusion did not produce additional cardioprotection in female rabbits, most likely because females are already relatively protected from injury. Thus, the current results suggest that isoflurane-induced delayed preconditioning is gender-specific at 1.0 MAC.
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Footnotes |
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This work was supported in part by National Institutes of Health grants HL 054820 (to Dr. Warltier), GM 008377 (to Dr. Warltier), GM 066730 (to Dr. Warltier), and HL 063705 (to Dr. Kersten) from the United States Public Health Service (Bethesda, MD) and by a grant (to Dr. Chiari) from the Foundation GROUPAMA (Paris, France).
Accepted for publication May 24, 2006.
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