Ann Thorac Surg 1999;68:1219-1224
© 1999 The Society of Thoracic Surgeons
Original Articles
Phenylephrine induces delayed cardioprotection against necrosis without amelioration of stunning
Kourosh Baghelai, MDa,
Laura J. Graham, BSa,
Andrew S. Wechsler, MDa,
Emma R. Jakoi, PhDa
a Division of Cardiothoracic Surgery, Department of Surgery, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia, USA
Address reprint requests to Dr Baghelai, Division of Cardiothoracic Surgery, Department of Surgery, Medical College of Virginia, 1200 East Broad St, PO Box 981239, Richmond, VA 23298;
e-mail: kbaghela{at}hsc.vcu.edu
Presented at the Forty-fifth Annual Meeting of the Southern Thoracic Surgical Association, Orlando, FL, Nov 12–14, 1998.
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Abstract
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Background. 
-Adrenergic stimulation induces protection in reperfused ischemic (I/R) myocardium 24 hours later. We tested the hypothesis that phenylephrine improves dysfunction after global I/R by limiting cell death not stunning.
Methods. Rabbits were pretreated with either phenylephrine or vehicle. Twenty-four hours later, isolated hearts underwent either 45 (infarction protocol) or 20 minutes (stunning protocol) of global ischemia before 2 hours of reperfusion (n = 6 per group). Cell death was determined by triphenyl tetrazolium chloride staining (infarction) and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) (apoptosis).
Results. Compared with vehicle, phenylephrine pretreatment improved post-I/R-developed pressures in hearts after infarction (53.2 ± 4.0 vs 35.8 ± 4.1 mm Hg, p = 0.01) but not stunning protocol (64.3 ± 8.9 vs 57.7 ± 6.2 mm Hg, p = NS). The improved developed pressure was due to better diastolic recovery. Systolic pressures were similar between groups. Phenylephrine markedly decreased infarction (9.0 ± 1.9% vs 40.8 ± 1.8% for vehicle, p < 0.001) and TUNEL-positive staining. Stunned hearts of either group had less than 3% infarction and no apoptosis.
Conclusions. Phenylephrine pretreatment 24 hours before global I/R improves function by limiting infarction but not stunning.
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Introduction
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Induction of delayed and long-lasting protection against global ischemia/reperfusion (I/R) injury is of particular interest as it may apply to the care of patients undergoing open heart surgical procedures. This has been the subject of intense research in recent years. Several studies have shown delayed cardioprotection against I/R by cytokines, heat shock, endotoxin, and prostaglandin analogues [1–4]. The involvement of the -adrenergic pathway in induction of acute preconditioning in various experimental models has been shown [5, 6]. Delayed tolerance against global I/R injury occurs after administration of norepinephrine [7]. This protection appears to be mediated via the -adrenoceptors and requires protein synthesis [8].
Myocardial stunning is defined as reversible contractile dysfunction without cellular necrosis. It is the predominant manifestation of injury after global I/R as it occurs during cardiopulmonary bypass and is responsible for significant morbidity and mortality. Therefore, the clinical applicability of pharmacologic interventions designed to confer delayed cardioprotection against global ischemia depends on their ability to ameliorate stunning. Recent reports have shown nitric oxide mediated delayed preconditioning against regional stunning and infarction by repeated cycles of brief I/R [9, 10]. It is not known whether the delayed cardioprotection conferred by the pharmacological interventions mentioned above only reduces infarction or ameliorates stunning.
Additionally, apoptosis or programmed cell death has been implicated in I/R-induced myocardial injury experimentally and clinically after cardioplegic arrest [11, 12]. Recent, reports have demonstrated decreased apoptosis after acute ischemic preconditioning of the rat heart [13]. Unpublished data from our laboratory have shown that -adrenergic agonist administration 24 h before global I/R reduced infarction and apoptosis. However, the significance of this process in stunned myocardium is not known. The purposes of this study were: (1) to test for presence of apoptosis in globally stunned myocardium; and (2) to test the hypothesis that -adrenergic agonist administration confers delayed tolerance to global I/R-induced infarction but not stunning.
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Material and methods
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Materials
New Zealand white rabbits of either gender (weight 3 to 4 kg) were fed a standard diet. The animal protocol was reviewed and approved by the Animal Care and Research Committee of the Medical College of Virginia/Virginia Commonwealth University. All animals received humane care in compliance with the "Guide for Care and Use of Laboratory Animals" (NIH Publication No. 85-23, revised 1985). Unless otherwise specified, all chemicals and reagents were obtained from Sigma Chemical Company (St. Louis, MO).
Experimental design and groups
The experimental model consisted of the bolus administration of either the -adrenergic agonist, phenylephrine (n = 12, 50 µg/kg iv) or equivalent volume of vehicle (n = 12, 5% Dextrose in water iv) via the marginal vein of the ear. Preliminary experiments demonstrated a nearly 50% increase in mean arterial blood pressure after bolus administration of phenylephrine. The hypertensive effect was significant and transient, lasting for approximately 15 minutes, confirming -adrenoceptor activation. There were no significant changes in heart rate. Twenty-four hours later, rabbits were randomly assigned to the infarction or stunning protocol, and their isolated hearts underwent ex vivo global I/R (n = 6 per group) as described below. The infarction protocol consisted of a 45-minute period of normothermic global ischemia followed by 120 minutes of reperfusion. In the stunning protocol, isolated hearts were subjected to a 20-minute ischemic period followed by reperfusion (Fig 1). The left ventricles (LV) were then harvested for determination of infarction by triphenyl tetrazolium chloride (TTC) staining. Apoptosis was demonstrated by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL).
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Fig 1. Treatment protocols used for the infarcted and stunned hearts. The zero time is the onset of global ischemia. Hearts were harvested at the end of reperfusion for TTC staining and TUNEL. Arrows represent pretreatment with phenylephrine or vehicle.
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Ischemia/reperfusion of the isolated rabbit hearts
Experiments were performed using an isovolumically beating isolated rabbit heart preparation as previously described by our group [14]. Hearts were perfused with modified Krebs-Henseleit buffer (NaCl 103 mM, KCl 4.0 mM, KH2PO4 1.2 mM, NaHCO3 30 mM, MgSO4 1.2 mM, NaEDTA 0.4 mM, lactate 1.0 mM, dextrose 11 mM, palmitic acid, 0.4 mM, and albumin 4g%) containing bovine erythrocytes at a hematocrit of 40%. Briefly, 24 h after pretreatment with either phenylephrine or vehicle, rabbits were heparinized (1,000 U/kg iv) and anesthetized with a mixture of Ketamine and Xylazine (50 and 25 mg/kg, respectively, im). A thoracotomy was performed followed by cardiectomy in rapid sequence. Retrograde coronary perfusion was established via the aortic root (100 cm H2O), with total ischemic period less than 30 seconds. Through an opening in the left atrial appendage, an apical LV vent was placed. A water-filled latex balloon connected to a pressure transducer and chart recorder (Gould Inc, Cleveland, OH) was placed in the LV through the mitral valve and secured using a purse-string silk ligature. The pulmonary artery was cannulated for collection of coronary venous flow, and contact LV pacing electrodes were placed. The instrumented isolated heart was then submerged in 37°C physiologic saline. Blood gas measurements were performed before and periodically during the experiment, and kept within normal physiological range. Hearts were paced at 180 beats per minute (bpm) (SD9 Stimulator; Grass Instrument Co, Quincy, MA). All hearts underwent 60 minutes of equilibration, during which time LV balloon volume was incrementally increased to achieve a stable diastolic pressure of 8 to 10 mm Hg. The balloon volume was kept constant throughout the rest of the experiment. The hearts then underwent I/R according to either the infarction or stunning protocol as described above. Physiologic data including heart rate, diastolic pressure, systolic pressure, and coronary flow were measured at the end of equilibration, ischemia, and every 15 minutes during reperfusion.
Triphenyl tetrazolium chloride staining
To evaluate the presence of cellular necrosis, TTC staining was performed according to the method of Fishbein and associates [15]. This method has been extensively used and validated in numerous experiments.
Hearts were briefly perfused with chilled saline at the end of the reperfusion period, followed by division of LV tissue into approximately five 5-mm-thick transverse slices. LV sections were submerged in 1% TTC solution for 20 minutes (37°C) followed by fixation in 10% formalin for 60 min, and then digitally scanned (ScanJet 6100C; Hewlett Packard, Palo Alto, CA). Viable tissue stains bright brick red in this assay, in contrast to the pale white color of infarcted LV. Digital images were then analyzed using SigmaScan (Jandel Scientific, San Rafael, CA) for determination of infarcted areas.
TUNEL
The middle LV section of one heart from each group (total of four) was fixed for TUNEL. LV slices were immersed in 5% paraformaldehyde for 60 minutes (at 23°C), and then impregnated with 30% sucrose in phosphate-buffered saline (4°C) over night. Slices were frozen in liquid nitrogen and cryosectioned. Ten- to fifteen-micron sections were assayed by TUNEL staining according to the manufacturer’s instructions (Apoptosis Detection System; Promega, Madison, WI) and visualized by fluorescence microscopy (25x lens, 0.8NA; Zeiss, Thornwood, NY). Nuclei positive for apoptosis appear bright white against a dark nonfluorescent background.
Data analysis
All data are expressed as mean ± standard error of the mean (SEM). Developed pressure (DP) is calculated as systolic minus diastolic pressure at each time point. The percent infarcted area is calculated as the ratio of the infarcted to total area at risk. Significant differences between experimental groups are determined by Student’s t test, with p values less than 0.05 considered significant.
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Results
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Contractile behavior after the infarction protocol
The systolic and diastolic pressures of isolated hearts subjected to the infarction protocol 24 hours after pretreatment with either phenylephrine (PHEinf) or vehicle (VEHinf) are summarized in Figure 2. Whereas the systolic, diastolic, and developed pressures at the end of the equilibration period did not differ between groups, the PHEinf hearts developed significantly less ischemic contracture at the end of the ischemic period (45 minutes) compared with VEHinf (31.7 ± 5.5 vs 51.0 ± 5.3 mm Hg, p = 0.03). The recovery of systolic pressure throughout the reperfusion period was similar between the groups. However, the PHEinf hearts demonstrated marked improvement in diastolic recovery during the entire reperfusion period. The LV end diastolic pressures (LVEDP) for the PHEinf hearts were significantly lower compared with VEHinf hearts at the same time points in the reperfusion period. At 120 minutes of reperfusion, the LVEDP for the PHEinf hearts was 25.0 ± 3.7 vs 42.7 ± 4.5 mm Hg for the VEHinf hearts (p = 0.01). The DP for the PHEinf group was significantly increased compared with VEHinf throughout the entire reperfusion period. The DPs at the end of reperfusion for the PHEinf and VEHinf hearts were 53.2 ± 4.0 and 35.8 ± 4.1 mm Hg, respectively (p = 0.01) (Fig 3).
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Fig 2. Left ventricular systolic and diastolic pressures (mean ± SEM) for the isolated hearts subjected to the infarction protocol. Note the 45-minute ischemic period beginning at time 0. *Significant values (t test) compared with DIA (VEH) at the same time point. (SYS = systolic pressure, DIA = diastolic pressure, VEH = vehicle pretreated, PHE = phenylephrine pretreated).
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Fig 3. The developed pressures (mean ± SEM) at end-equilibration and end-reperfusion for the isolated hearts pretreated by either phenylephrine or vehicle 24 hours before global ischemia (p value by t test).
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Contractile behavior after the stunning protocol
The systolic and diastolic pressures of isolated hearts subjected to the stunning protocol 24 hours after pretreatment with either phenylephrine (PHEstun) or vehicle (VEHstun) are summarized in Figure 4. No significant differences in systolic, diastolic, and developed pressures at the end of the equilibration period were found between the groups. The PHEstun hearts developed greater ischemic contracture at the end of the 20-minute ischemic period compared with VEHstun (18.7 ± 7.7 vs 7.3 ± 0.3 mm Hg); however, the difference was not statistically significant. Similarly, the recovery of systolic pressure throughout the reperfusion period was slightly better for the PHEstun hearts but was not significant between groups. The LVEDPs for both PHEstun and VEHstun were similar at all time points throughout the reperfusion period and returned to preischemic levels by the end of the reperfusion (8.0 ± 2.6 and 5.0 ± 1.2 mm Hg, respectively, p = 0.36). The DPs at the end of reperfusion for the PHEstun and VEHstun groups were 64.3 ± 8.9 and 57.7 ± 6.2 mm Hg, respectively (p = 0.57) (Fig 3).
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Fig 4. Left ventricular systolic and diastolic pressures (mean ± SEM) for the isolated hearts subjected to the stunning protocol. Note the 20-min ischemic period beginning at time 0. (SYS = systolic pressure, DIA = diastolic pressure, VEH = vehicle pretreated, PHE = phenylephrine pretreated).
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Infarction after global I/R
To evaluate the effect of phenylephrine pretreatment on ischemic tolerance, the fraction of infarcted myocardium was compared between groups (Fig 5). In isolated hearts pretreated with phenylephrine and then subjected to 45 min of global ischemia followed by reperfusion, infarction was significantly decreased compared with the vehicle pretreated group, (9.0 ± 1.9% vs 40.8 ± 1.8%, p < 0.001). In contrast, in the stunned hearts, myocardial infarction detected by TTC staining comprised less than 3% of the total myocardium without significant difference between groups (Fig 5). When found, the infarcted areas in the stunned groups were limited to scattered small regions in the subendocardium and the distal papillary muscles.
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Fig 5. The ratio (mean ± SEM) of the infarcted to at risk myocardium as determined by tetrazolium staining after treatment with either vehicle or phenylephrine for both infarction and stunning protocols (p values by t test).
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Apoptosis after global I/R
The presence of apoptosis was assessed in all groups using TUNEL. Photomicrographs indicate that apoptotic nuclei were found only in hearts subjected to 45 min of ischemia followed by reperfusion (infarction protocol). Both the signal intensity and the number of TUNEL-positive nuclei are markedly decreased in the phenylephrine pretreated group (Fig 6D) compared with vehicle-pretreated hearts (Fig 6C). There are few apoptotic nuclei observed in the stunned hearts regardless of pretreatment with either vehicle or phenylephrine (Fig 6A, 6B).
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Fig 6. Apoptotic nuclei (arrows): (A) vehicle-pretreated/stunned; (B) phenylephrine-pretreated/stunned; (C) vehicle-pretreated/infarcted; (D) phenylephrine-pretreated/infarcted (25x 0.8 numerical aperture [NA]).
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Comment
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In this study, we have demonstrated that a single bolus of intravenous phenylephrine administered to rabbits confers cardioprotection against global I/R infarct-producing injury in isolated hearts 24 hours later. The greater developed pressure is due to better diastolic recovery. This protection is associated with significant reduction in infarcted myocardium. We have also shown that the observed cardioprotection disappears when the severity of the I/R-induced injury is reduced such that the myocardium is stunned without any cellular necrosis.
Preconditioning renders the myocardium more tolerant to I/R injury after a brief episode of stress. The initial window of preconditioning is immediate in onset and short-lived, making it of limited utility in the clinical settings of myocardial I/R injury such as during open heart surgical procedures. Delayed cardioprotection has been described after brief episodes of I/R as well as pharmacological interventions. The second window of preconditioning appears as early as 6 hours, peaks around 24 to 48 hours, and disappears by 168 hours [8]. his time course makes it a potentially useful modality for surgical cardioprotection. Recent reports have implicated involvement of the -adrenoceptors in development of delayed cardioprotection against global I/R in isolated rat hearts [7, 8]. However, it is not clear whether the -adrenoceptor-mediated delayed cardioprotection involves amelioration of stunning as well as reduction of infarction.
In the present study, we examined the effect of in vivo administration of an -adrenergic agonist (phenylephrine) on functional recovery of isolated rabbit hearts after global I/R protocols that separately produced contractile dysfunction with or without infarction. The vehicle-pretreated isolated hearts that underwent I/R according to the infarction protocol had severe depression in contractile function, as demonstrated by near 70% reduction in DP (Fig 3). Postischemic functional recovery was significantly improved by phenylephrine pretreatment. Examination of postischemic systolic and diastolic pressures reveals nearly identical systolic function throughout the reperfusion period for both PHEinf and VEHinf hearts (Fig 2). In contrast, phenylephrine pretreatment abrogated the development of contracture during ischemia by nearly 50%. This indicates that phenylephrine-mediated delayed cardioprotection is operative during ischemia and before reperfusion. PHEinf hearts demonstrated markedly improved resolution of the elevated LVEDP throughout the reperfusion period. The improved diastolic recovery of the PHEinf hearts seems to account for the observed improvement in DP. We then looked at the extent of cellular necrosis in the hearts that underwent I/R according to the infarction protocol. TTC staining of the LV from the VEHinf hearts revealed that approximately 40% of the myocardium at risk sustained infarction. Pretreatment with phenylephrine reduced the extent of the irreversible injury by nearly 75% (Fig 5). TTC staining was the only method used for determination of infarction. Other histological characteristics of necrosis develop with longer reperfusion periods and were not examined in this study. The reduction in infarction in PHEinf occurred in parallel to the observed improved diastolic recovery, resulting in the higher postischemic contractile function. This is highly suggestive that the improved functional recovery observed in the pretreated hearts is secondary to the reduction in infarcted myocardium and not amelioration of stunning. Reduced infarction results in improved myocardial compliance and reduced ventricular stiffness. In an isovolumic preparation where the dimensions of the ventricular cavity are fixed, reduced stiffness translates into decreased measured diastolic pressures. This could serve as the mechanism by which reduced infarction selectively ameliorated diastolic recovery in this model.
Recent reports studying delayed cardioprotection have shown that multiple cycles of brief regional I/R improve contractile recovery of regionally stunned myocardium 24 to 48 hours later [16]. However, the effect of -adrenergic-mediated delayed cardioprotection on the recovery of globally stunned myocardium in the absence of cellular necrosis is not known. We utilized a model of global I/R due to the inherent difficulties in reproducible induction of regional stunning and accurate measurements of regional function. Additionally, assessments of global function extrapolated from regional data are often unreliable. In order to better delineate the effect of -adrenergic pretreatment on I/R-induced global myocardial stunning, we submitted the vehicle (VEHstun)- and phenylephrine (PHEstun)-pretreated isolated rabbit hearts to global I/R according to the stunning protocol. The infarcted myocardium for VEHstun and PHEstun hearts by TTC amounted to less than 3% of the at-risk myocardium (Fig 5). Despite minimal infarction, the stunning protocol produced significant depression of contractile function represented by reduced post-I/R DPs (Fig 3). However, phenylephrine pretreatment, 24 hours before I/R, failed to significantly augment contractile recovery of the globally stunned myocardium (Fig 3). Examination of the postreperfusion systolic and diastolic pressures revealed a slight trend for higher systolic pressures for the PHEstun hearts without statistical significance. The elevated LVEDP rapidly returned to preischemic levels after onset of reperfusion in both groups (Fig 4).
To better characterize the disparity in the effectiveness of delayed -adrenergic preconditioning preventing infarction versus ameliorating stunning, we examined myocardial samples for presence of apoptosis (programmed cell death). Apoptosis is enzymatic fragmentation of nuclear DNA leading to cell death without disruption of plasma membranes. Previous work from our laboratory has demonstrated a reduction in number of apoptotic nuclei after phenylephrine pretreatment in an infarct-producing global I/R preparation. TUNEL staining confirmed the presence of numerous apoptotic nuclei in VEHinf (Fig 6C) that decreased in number by phenylephrine pretreatment (Fig 6D). In contrast, there were no detectable apoptotic nuclei in either vehicle- or phenylephrine-pretreated stunned hearts. These data demonstrate that apoptosis does not occur early in I/R-induced globally stunned myocardium. It appears that delayed -adrenergic preconditioning protects the myocardium from programmed cell death as well as infarction, but fails to protect the stunned myocardium where neither infarction nor apoptosis is present. TUNEL assays are limited in accurately detecting only the apoptotic nuclei secondary to potential nonspecific reactions. The TUNEL data in this study represent only one section of the ventricle and are preliminary and qualitative in nature. Future dedicated studies are needed to fully characterize the role of apoptosis using DNA laddering and other cellular assays.
Our data differ from the reports of delayed preconditioning against infarction and stunning by multiple brief episodes of I/R that seems to involve nitric oxide and protein kinase C [9, 10, 16]. The in vivo response to myocardial I/R is a complex phenomenon involving activation of several intramyocardial and systemic mechanisms. Pharmacological -adrenergic stimulation simulates only one of these responses, which may not necessarily duplicate all the cellular events evoked by I/R. Additionally, the intracellular derangements responsible for the pathogenesis of cell death can differ from the ones responsible for stunning and not necessarily occur along the same continuum. Consequently, activation of the same cellular pathway protects against one and not the other. For example, adrenergic signaling appears to mediate the increased expression of phosphodiesterases 24 hours after administration of a prostaglandin analogue, thereby accelerating hydrolysis of cyclic nucleotides during a subsequent prolonged ischemic period [17, 18]. This will limit accumulation of intracellular calcium and the subsequent cellular membrane injury leading to cell death, thus explaining the antiinfarct effect of -adrenergic-delayed preconditioning. However, there are no data suggesting involvement of these mechanisms in protection against stunning. These data together with ours suggest that pharmacological preconditioning, such as -adrenergic stimulation, may only partially evoke the protective effects of ischemic preconditioning.
Previous studies have implicated increased expression of heat-shock proteins (HSP) in models of I/R-induced delayed cardioprotection against stunning [19]. Increased expression of HSPs has also been shown to occur in experiments of norepinephrine-induced delayed preconditioning against infarction [7]. Association of increased HSP expression with preconditioning against both infarction and stunning made HSPs unlikely candidates responsible for the differential protection observed in the current study.
In summary, we have shown successful delayed preconditioning by phenylephrine against infarction and apoptosis induced by global I/R. The observed improvement in contractile recovery was secondary to improved diastolic recovery resulting from a reduction in noncontractile infarcted myocardium. The beneficial effects of phenylephrine pretreatment disappeared with the shorter ischemic period inducing only stunning. This suggests that the cellular processes involved in preconditioning against infarction are different from those governing cardioprotection against stunning. Consequently, interventions designed to recruit the endogenous myocardial protective mechanisms in the field of cardiac surgery need to be evaluated for their ability to ameliorate stunning independent of their antiinfarction effects.
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Abstract
Introduction
