158 2006 CPS and SIMM

Acta Pharmacologica Sinica 2006 Feb; 27 (2): 158164

Full-length article

Role of norepinephrine in development of short-term myocardial hiber-nation

Zuo-lin FU1, 3, Yi-bai FENG1, Hong-xia XU1, Xin-ping ZHANG1, Chun-zhi SHI1, Xiang GU1

1The Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022,China; 2Guizhou Provincial Peoples Hospital, Guiyang 550002, China

IntroductionNorepinephrine (NE) is the main transmitter released from

sympathetic nerve terminals; it plays an important role inmodulating the course of myocardial ischemia. Hibernationof the myocardium is defined as a condition of persistentmyocardial dysfunction at rest due to reduced coronary bloodflow, which can be partially or completely restored to normalby improving blood flow[1]. Hibernating myocardium consti-tutes the main part of recovery of heart function after reperfu-sion in patients with coronary heart disease, and is thoughtto be an important sign for revascularization in these pa-

tients[4]. Myocardial hibernation is thought to be an endog-enous cardioprotective phenomenon characterized by ad-aptation to myocardial ischemia[13]; however, to date, themechanisms responsible for the development and mainte-nance of hibernation remain unclear. The role of NE in thedevelopment of myocardial hibernation also remains unclear.In the the present study, the role of NE in the developmentof short-term hibernation was investigated in isolated rathearts. Myocardial infarction is often accompanied by anincrease in NE in the myocardial and circulating system,which may play a role in the development of myocardialhibernation, so the effect of exogenous NE on the develop-

AbstractAim: To investigate the role of norepinephrine in the development of short-termmyocardial hibernation. Methods: Hearts were removed from rats and set up asisometrically beating or short-term hibernation models. The hearts were perfusedwith modified Krebs-Henseleit buffer under a controlled perfusion pressure. Themyocardial ultrastructure was examined, and the content of ATP, phosphocreatine,and glycogen in myocardium, the extent of myocyte apoptosis, and the amount ofBcl-2 and Bax products were determined after 120-min ischemia assessed by TUNELand immunocytochemistry. Results: There was no significant difference be-tween the reserpinized hearts and the NS control group with respect to heartfunction, myocardial ultrastructure, ATP, phosphocreatine, or glycogen content,myocyte apoptosis, or amount of Bax or Bcl-2 products. However, relative to thenormal saline group, in the norepinephrine-treated hearts, heart function, andmyocardial ultrastructure deteriorated significantly, apoptosis and amount of Baxproduct increased significantly, and the ATP, phosphocreatine, and glycogencontent decreased significantly, as did the amount of Bcl-2 product. Conclusion:Myocardial norepinephrine does not contribute to the development of short-termhibernation, but that exogenous NE can induce progressive decreases in coro-nary flow and cardiac performance, which might result from the increases inapoptosis and necrosis. Norepinephrine may be an important factor in the dete-rioration of myocardial structure and function during hibernation, and that anti-adrenergic treatment may be helpful for the development and sustainment of short-term myocardial hibernation.

Key wordsnorepinephrine; dobutamine; myocardialischemia; myocardial reperfusion; myo-cardial stunning; myocardium; left ventri-cular function; lactic acid; coronary circula-tion

3 Correspondence to Dr Zuo-lin FU.Phn 86-27-8572-6423.E-mail fuzuolin@163.net

Received 2005-04-22Accepted 2005-08-19

doi: 10.1111/j.1745-7254.2006.00245.x

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ment of short-term myocardial hibernation was alsoinvestigated.

Materials and methodsHeart preparation Male Sprague-Dawley rats (200250 g,

8 groups, n=6 rats/group) were pretreated with heparin(2 000 U/kg, ip), followed by sodium pentobarbitone (50 mg/kg,ip). After confirmation of complete anesthesia, the heartswere rapidly excised through a midline incision and immedi-ately immersed in ice-cold modified Krebs-Henseleit buffer.Within 2 min, the hearts were perfused in a retrograde man-ner through the aorta, the vena cava and pulmonary veinswere ligated, and the left ventricle was cannulated with afluid-filled latex balloon through an incision in the left atrium.After the balloon was inserted into the left ventricle, theballoon was inflated to an end-diastolic pressure of about 6mmHg (1 mmHg=0.133 kPa), and the left ventricular pressurefrom the balloon was measured by using low-compliancetubing, an MLT844 physiological pressure transducer, andan Octal Bridge amplifier (AD Instruments, Castle Hill,Australia). Hemodynamics were recorded on a Dell com-puter (Dell) using Chart software (v4.2.2, AD Instruments,Castle Hill, Australia) for Microsoft Windows. All heartswere paced at 300 beats per min throughout by using a pac-ing electrode secured to the right atrium. The basic perfu-sion fluid was a phosphate-free modified Krebs-Henseleitbuffer containing 11 mmol/L glucose and having the follow-ing ionic composition[5] (in mmol/L): 144.0 Na+, 6.0 K+, 2.5Ca2+, 130.0 Cl, 1.2 SO42, 25.0 HCO3, and 0.5 Na2EDTA. Thebuffer was gassed with 95% O2, 5% CO2, was temperaturecontrolled at 37 C by 2 water baths, and the pH was ad-justed to 7.4. The hearts were kept in a glass water-heatedjacket, which kept the surrounding air temperature at 37C.The basic perfusion pressure was 90 cmH2O, and the low-flow perfusion pressure was 15 cmH2O. Coronary flow wasmeasured by using timed collections of the coronary efflu-ent with graded glass cylinders throughout the protocol,and aliquots of perfusate were collected for lactate dehydro-genase (LDH) analysis. Samples for the estimation of LDHwere collected in chilled tubes and stored at -20 C untilassayed by colorimetry.

All animals were provided by the Experimental AnimalCenter of Tongji College, Huazhong University of Scienceand Technology, and received humane care in compliancewith the principles outlined in the Guide for the Care and Useof Laboratory Animals.

Protocol After equilibrium was reached in the 20-minperfusions, hearts were divided into 8 groups as follows:

group I: hearts were perfused under a constant pressure of90 cmH2O for 150 min; group II: hearts were switched to thelow-flow ischemia mode, and reperfused for 30 min after 120min of low-flow ischemia; group III: hearts were switched tolow-flow ischemia and a dose of 1106 mol/L dobutamine in100 L of water[5] was injected into a side arm immediatelyabove the aortic cannula after 120 min of low-flow ischemia;group IV (NS group): 0.9% sodium chloride (7 mL/kg, ip, 24 hbefore experiment)-treated hearts were switched to the low-flow ischemia mode and after 120 min of low-flow ischemia,the apical part of each heart was cut off on ice and immedi-ately put into fixation solution, and the remaining part wasfreeze-clamped and stored in liquid nitrogen for biochemicalanalysis; group V (reserpine group): reserpinized hearts(reserpine, 7 mg/kg, ip, 24 h before experiment; GuangdongBanmin Pharmaceutical Co) were studied as in group IV; groupVI (NE group): hearts were studied as in group IV except forthe presence of norepinephrine L-bitartrate (75 ng/mL, Sigma-Aldrich, St Louis, USA) in perfusion. Depletion of NE storesin the hearts of reserpinized rats was measured by testingthe effect of tyramine (5 g/mL, Sigma-Aldrich, St Louis,USA) in the perfusion buffer on the heart rates of spontane-ously beating hearts (group VII)[6]. The same measurementswere carried out for the hearts of non-reserpinized controlanimals (group VIII).

Myocardial ultrastructure examination The apical partof each heart was cut down on ice and immediately put intoa 2.5% glutaraldehyde fixation solution at 4 C. Thesubendocardium was subdivided into tissue blocks of 1 mm3,which were again put into the fixation solution for 30-minoscillation and fixation. Electron microscope slices were pro-duced according to routine methods for the preparation oftransmission electron microscope specimens. Ultrathin sec-tions were stained with uranyl acetate and lead citrate forexamination on a transmission electron microscope.

In situ terminal deoxynucleotidyl transferase-mediateddUTP nick end labeling The left ventricle was immersion-fixed in 10% neutral formalin and embedded in paraffin. Se-rial sections of 3-m thickness were produced. Apoptosiswas detected by using the terminal deoxynucleotidyl trans-ferase-mediated dUTP nick end-labeling (TUNEL) techniquewith an in situ cell death detection kit (AP, Roche, Germany)according to the manufacturers instructions. The numbersof TUNEL-positive cardiomyocytes were counted by 2 blindedobservers using microscopes with an eyepiece grid(magnification, 400) using the HPIAS-2 000 image analysissystem. Five different visual fields were counted in eachslice. The cardiomyocytes that had blue-stained nuclei wereTUNEL-positive cardiomyocytes. TUNEL-positive nuclei

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that could not be definitively confirmed to have myocyteorigins were excluded. The extent of apoptosis was expressedby normalizing the results to the number of myocyte nucleiper visual field in each sample.

In situ immunohistochemistry for Bcl-2 and Bax expres-sion Each specimen was cut into 5-m sections. The sec-tions were deparaffinized with two 5-min changes of xyleneand two 3-min changes of 100% alcohol. The slides werethen washed in distilled water, and intrinsic peroxidase ac-tivity was inhibited with 3% hydrogen peroxide. After beingrinsed, the slides were treated with 5% normal serum in0.01 mol/L phosphate buffered saline for 10 min to blocknonspecific binding. The sections were then incubated atroom temperature overnight with monoclonal mouse anti-human Bcl-2 oncoprotein or monoclonal mouse anti-humanBax oncoprotein (Beijing Zhongshan Biotechnology Co) atdilutions of 1:50 (for both). The sections were then rinsedwith phosphate buffered saline and incubated with biotin-conjugated goat antimouse IgG (Beijing Zhongshan Biotech-nology Co) for 30 min. After being rinsed, the sections wereincubated for 25 min, then after further rinsing, they wereincubated for 30 min with a S-A/HRP work solution at 37 C,then stained with diaminobenzidine (DAB) solution. Eachsection was photographed under a microscope with an eye-piece grid (magnification, 400) using the HPIAS-2 000 im-age analysis system. Twenty randomly chosen visual fieldsfor each group were used for computer-based automatic cal-culation of the mean absorbance of areas of immunopositiveexpression.

Biochemical analysis Adenosine 5'-triphosphate (ATP)concentration in myocardium was determined by using a bi-oluminescence method as described by Sperlagh andKrisztina et al[7,8]. A luminometric method based on the lu-ciferin-luciferase reaction was used to quantify ATP in myo-cardium by using an ATP assay kit (Beyotime Bio-technology). The concentration of phosphocreatine in myo-cardium was determined by using the reverse phase-highperformance liquid chromatography (RP-HPLC) methodsdescribed by Zhang et al[9]. The phosphocreatine standardwas from Sigma-Aldrich. The concentration of glycogen inmyocardium was determined with a chemistry colorimetrymethod by using a glycogen detection kit (Nanjing JianchengBioengineering Institute, Nanjing, China).

Detection of LDH LDH leakage from each heart was mea-sured in the coronary effluent with a linked-enzyme spectro-photometric assay by using a lactate dehydrogenase kit(Zhongsheng Beikong Bio-technology and Science), as de-scribed by Bergmeyer[10]. LDH leakage was expressed asinternational units of LDH released per min per gram wet

heart.Data reduction and statistical analyses The pressure-

rate product (PRP), which is the product of heart rate and leftventricular developed pressure, was calculated and used toassess the mechanical function, because it provides a methodfor quantification of the performance of a heart (for compari-son with the same heart at a different time or with otherhearts).

All data were expressed as meanSD. Students pairedor unpaired t-test was used to assess the differences be-tween any 2 groups, and analysis of variance was used toassess differences among groups using SPSS 12.0 for Win-dows. P

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to 285.7 beat/min; P>0.05), which indicated that myocardialNE was depleted in reserpinized rats.

Myocardial ultrastructure Cardiac muscle fibers in theNS group and reserpine group were abundant, with regulararrays of myofibrils closely arranged within the sarcomere.The mitochondria were intact and had no swelling ordisruption. The amount of glycogen in the mitochondriadecreased, but cardiac muscle fibers and mitochondria fromthe NE group were significantly different from those in theother groups. The differences included a loss of myofibrillarcontent, myofibrillar disarray, and mitochondrial swelling,disruption and vacuolation. The glycogen content in themitochondria decreased significantly (Figure 1, Table 3).

Injury to myocardial cell membranes LDH leakage wasused to assess injury sustained by the myocardial cellmembrane. The rate of LDH leakage was 14.83.0, 13.83.8,and 22.55.4 mUmin-1g-1 after 120-min ischemia in the NSgroup, reserpine group, and NE group, respectively. Therewas no significant difference between the former 2 values,but compared with the NS group, the rate of LDH leakagewas significantly higher in the NE group (P

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Table 4 . Changes in coronary flow (mL/min). n=6. MeanSD.aP>0.05, bP0.05). These values were significantly lowerin the NE group compared to the other 2 groups (P

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tion matching. The existence and adaptive nature of short-term hibernation has been accepted, but the existence ofperfusion-contraction matching over prolonged periods oftime (chronic hibernation) has been questioned, and chronichibernation has been suggested to be a result of repetitiveor cumulative myocardial stunning[3,12,13].

In our perfusion pressure-controlled isolated rat heartmodel, low-flow ischemia induced sustained hypo-contraction, that is, sustained perfusion-contraction match-ing during which there was no morphological or biologicalevidence of myocardial injury: the PRP recovered to controllevels after reperfusion, and hearts retained their respon-siveness to dobutamine. These observations accord withthose for short-term hibernating myocardium[5,14]. Our ex-periments were performed in isolated buffer-perfused rathearts, a model that allows the function of myocardial NEduring the development of short-term hibernation to bestudied, and the degree and composition of coronary flow,heart rate, temperature, and myocardial function to be toprecisely controlled in the absence of systemic neuroendo-crine changes.

Role of myocardial NE in the development of short-termhibernation The observed reduction in myocardial contrac-tile function during hibernation is not regarded as the con-sequence of a sustained energetic deficit, but instead as aregulatory event that serves to avoid an energetic deficitand to maintain myocardial integrity and viability[5,14]. Inthis active adaptation, activation of ATP-dependent potas-sium channels and increases in the concentration of intersti-tial adenosine are not involved in the development of short-term myocardial hibernation. In a study by Heusch et al itwas suggested that a decrease in transient calcium and cal-cium responsiveness might contribute to the developmentof short-term hibernation[15]. Whereas the density of myo-cardial adrenoceptors has been shown to be reduced inchronic animal models of myocardial hibernation[17] orstunning, adrenoceptor density and affinity was unalteredin short-term hibernating myocardium after 90 min of moder-ate ischemia[16], which is consistent with our present results.In our short-term hibernation model in isolated rat heart, therewas no significant difference between the NS group and re-serpine group with respect to contraction function, coro-nary flow, ATP content, phosphocreatine content, glycogencontent, myocardial ultrastructure, LDH leakage, apoptosisof myocytes according to TUNEL, or the amount Bax/Bcl-2products, suggesting that myocardial NE may not contrib-ute to the development of short-term hibernation, and thatthere might not be significant myocardial NE release duringshort-term hibernation, because significant NE release may

injure myocytes[6,17,18]. Effect of exogenous NE on short-term hibernation Al-

though short-term hibernation has been mimicked both invitro and in vivo, there are many significant differences be-tween them. Among these differences is the in vitro ab-sence of neural or hormonal factors that have an importantrole in the regulation of cardiac performance and metabolicprocesses. NE is the main transmitter released from sympa-thetic nerve terminals and is an important component ofblood. During myocardial infarction, the concentration ofNE increases not only in the damaged myocardium but alsoin the circulating system because of increased peripheralreleases from the pain, anxiety and reflex activation of thesympathetic nerve system. The excessive activation of thesympathetic nerve system is an important factor in acceler-ating ventricular remodeling and delayed heart failure. NEcan increase cardiac performance, but it may also increaseoxygen cost and apoptosis or injury to myocytes, decreasecardiac performance, injure the adaptation mechanism, anddestroy the development of hibernation. In the presentstudy, NE induced significant increases in cardiac perfor-mance despite producing no significant change in coronaryflow during normal perfusion, but it induced significant de-creases both in cardiac performance and coronary flow after120 min ischemia, suggesting that the concentration of NEthat induces increases in cardiac performance during normalperfusion induces decreases in cardiac performance duringhibernation. ATP, phosphocreatine, and glycogen contentwas significantly lower in the NE group than in the NS group,suggesting that the balance of energy metabolism and per-fusion-contraction matching was destroyed by high con-centrations of NE.

Myocyte loss may occur in 2 distinct ways in themyocardium: apoptosis and necrosis. In our experiments,the proportion of apoptotic myocytes as observed by TUNELwas significantly greater in the NE group relative to the NSgroup, suggesting that a high concentration of NE mightinduce apoptosis of myocytes during hibernation, whichcould partially explain why NE induced the decrease in car-diac performance during hibernation. The bcl-2 proto-oncogene diagfamily is critical in the control of apoptosis. Ithas been proposed that cell viability after an apoptotic stimu-lus may depend on the ratio of Bcl-2 to Bax[19]. The meanabsorbance of Bcl-2 immunopositive expression was signifi-cantly lower in the NE group than in the NS group, and themean absorbance of Bax products was significantly higherin the NE group relative to the NS group, which indicatesthat NE increases the expression of Bax and decreases theexpression of Bcl-2 during hibernation. The Bcl-2/Bax ratio

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became smaller, suggesting that the Bcl-2/Bax ratio may havean important role in the apoptosis of myocytes induced byNE during hibernation. It has been reported that NE inducedthe apoptosis of myocytes mainly by activating the 1 recep-tor[20], and mitogen-activated protein kinase and the reactiveoxygen species mechanism may also have a role[21,22]. In thepresent study, NE not only induced the apoptosis ofmyocytes, but also induced injury to the myocardial cellmembrane and caused changes in the ultrastructure of themyocardium, suggesting that NE may also induce necrosisin myocardium during hibernation. Another important rea-son why NE induces apoptosis and necrosis is that the de-crease in coronary flow resulted in a decrease in energy sup-ply to the myocardium, which might induce survivingmyocytes to undergo apoptosis or necrosis[23].

The present study indicated that NE induced progres-sive decreases in coronary flow and cardiac performance,which might result from increases in apoptosis and necrosis,suggesting that NE may be an important factor in the dete-rioration of myocardial structure and function duringhibernation, and that anti-adrenergic treatment may be help-ful in the development and sustainment of short-termhibernation. However myocardial NE may not contribute tothe development of short-term hibernation.

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