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Table of Contents
Year : 2014  |  Volume : 17  |  Issue : 3  |  Page : 200-209
Phenylephrine postconditioning increases myocardial injury: Are alpha-1 sympathomimetic agonist cardioprotective?

1 Department of Pharmacology, University of Athens, 11527 Goudi, Athens, Greece
2 Department of Anaesthesia, General Hospital of Montreal, McGill University, Montreal, Canada
3 Department of Chemistry, Quidd, 50 Ettore Bugatti street, 76800 Saint Etienne du Rouvray, France
4 Department of Chemistry, University of Rouen, Place Emile Blondel, 76821 Mont Saint-Aiginan, France

Click here for correspondence address and email

Date of Submission25-Oct-2013
Date of Acceptance18-Apr-2014
Date of Web Publication3-Jul-2014


Objective: We studied effects of phenylephrine (PHE) on postischemic functional recovery and myocardial injury in an ischemia-reperfusion (I-R) experimental model. Materials and Methods: Rat hearts were Langendorff-perfused and subjected to 30 min zero-flow ischemia (I) and 60 min reperfusion (R). During R PHE was added at doses of 1 μM (n = 10) and 50 μM (n = 12). Hearts (n = 14) subjected to 30 and 60 min of I-R served as controls. Contractile function was assessed by left ventricular developed pressure (LVDP) and the rate of increase and decrease of LVDP; apoptosis by fluorescent imaging targeting activated caspase-3, while myocardial injury by lactate dehydrogenase (LDH) released during R. Activation of kinases was measured at 5, 15, and 60 min of R using western blotting. Results: PHE did not improve postischemic contractile function. PHE increased LDH release (IU/g); 102 ± 10.4 (Mean ± standard error of mean) control versus 148 ± 14.8 PHE (1), and 145.3 ± 11 PHE (50) hearts, (P < 0.05). PHE markedly increased apoptosis. Molecular analysis showed no effect of PHE on the activation of proapoptotic c-Jun N-terminal kinase signaling; a differential pattern of p38 mitogen activated protein kinase (MAPK) activation was found depending on the PHE dose used. With 1 μM PHE, p-p38/total-p38 MAPK levels at R were markedly increased, indicating its detrimental effect. With PHE 50 μM, no further changes in p38 MAPK were seen. Activation of Akt kinase was decreased implying involvement of different mechanisms in this response. Conclusions: PHE administration during reperfusion does not improve postischemic recovery due to exacerbation of myocardial necrosis and apoptosis. This finding may be of clinical and therapeutic relevance.

Keywords: Apoptosis; Ischemia-reperfusion; Myocardial function; Phenylephrine

How to cite this article:
Mourouzis I, Saranteas T, Ligeret H, Portal C, Perimenis P, Pantos C. Phenylephrine postconditioning increases myocardial injury: Are alpha-1 sympathomimetic agonist cardioprotective?. Ann Card Anaesth 2014;17:200-9

How to cite this URL:
Mourouzis I, Saranteas T, Ligeret H, Portal C, Perimenis P, Pantos C. Phenylephrine postconditioning increases myocardial injury: Are alpha-1 sympathomimetic agonist cardioprotective?. Ann Card Anaesth [serial online] 2014 [cited 2020 Sep 20];17:200-9. Available from:

   Introduction Top

Clinical conditions, such as acute coronary syndromes or coronary bypass surgery are leading causes of myocardial injury with cell death and/or apoptosis leading to myocardial loss. [1],[2],[3] Apoptosis may contribute to early functional impairment manifested as myocardial stunning or late cardiac dysfunction due to cardiac remodeling. Apoptosis is shown to reach a nadir at approximately 4 h postoperatively and persists for the first 2 days after cardiac surgery. [4],[5],[6] Based on this evidence, it is suggested that agents with cardioprotective properties may prove suitable for treating hemodynamically compromised patients. [7] Current clinical practice favors use of sympathomimetic drugs to support hemodynamics in various clinical settings due to their effect on enhancing cardiac contractility and controlling peripheral vascular function. [8] More specifically, selective α1-adrenergic agonists like phenylephrine (PHE) can support hemodynamics mainly through vasoconstriction. In high doses, PHE may stimulate β-receptors also. [9],[10],[11] PHE is used for the maintenance of blood pressure during spinal and inhalation anesthesia and for the treatment of vascular failure in shock, shock-like states, and drug-induced hypotension or hypersensitivity. However, α1 adrenergic receptors also exist in cardiomyocytes and their activation may lead to direct effects on the stressed myocardium. [9] This issue, although of clinical relevance, has not been adequately explored. In this study, we explored the effects of PHE on the postischemic contractile function and myocardial injury by using an isolated rat heart model of ischemia and reperfusion.

   Materials and methods Top

A total of 71 Wistar male rats weighing 320-380 g were used for this study. The rats were handled in accordance with the Guide for the Care and Use of Laboratory Animals published by US National Institutes of Health (NIH Pub.No. 8323, Revised 1996). The Ethics Review Board of our university also granted approval for the study.

Isolated heart preparation

Rats were anesthetized with ketamine HCl and heparin 1000 IU was given intravenously before thoracotomy. The hearts were rapidly excised, placed in ice-cold Krebs-Henseleit buffer (buffer composition in mmol/L: Sodium chloride 118, potassium chloride 4.7, potassium phosphate monobasic 1.2, magnesium sulfate 1.2, calcium chloride 1.4, sodium bicarbonate 25, and glucose 11) and mounted on the aortic cannula of the Langendorff perfusion system. The nonworking isolated rat heart preparation was perfused at a constant flow according to the Langendorff technique. The constant flow permits measurement of changes in perfusion pressure and thus determines vascular resistance. Perfusion with oxygenated (95% O 2 /5% CO 2 ) Krebs-Henseleit buffer was established within 60 s after excision of the hearts. The perfusion apparatus was warmed to ensure a temperature of 37°C throughout the experiment. Sinus node was removed and hearts were paced at 320 beats/min with a Harvard pacemaker. The pacemaker was turned off during ischemia. For the measurement of cardiac functions, a balloon was advanced into the left ventricle (LV) through an incision in the left atrium, which was filled with water and connected to a pressure transducer coupled to a Gould RS-3400 recorder. Pressure signals were transferred to a computer using data analysis software (IOX 1.544, Emka Technologies, 59, Ave. général Martial Valin, 75015 Paris-France) which allowed continuous monitoring and recording. [12] The balloon volume was adjusted to produce an initial LV end-diastolic pressure of 6-8 mmHg. The balloon volume was held constant throughout the experiment. Since the balloon was not compressible, the intraventricular volume and the diastolic fiber length (preload) remained constant and the LV contractions, were isovolumic. Thus, the LV peak systolic pressure and the LV developed pressure (LVDP), defined as the difference between LV peak systolic pressure and LV end-diastolic pressure represented indices of systolic function obtained under isometric conditions.

Phenylephrine administration

Phenylephrine (Sigma Chemicals, St Louis MO, USA) was dissolved in normal saline to obtain a stock solution, which was kept at 4°C. Before each experiment a quantity of this solution was dissolved in Krebs buffer to obtain a final concentration of either 1 μM or 50 μM. Pharmacokinetic studies of intravenous (IV) administration have shown that PHE rapidly distributes into the peripheral tissue, which yields a very low plasma concentration. For this reason, the doses selected in our experimental design were not based on pharmacokinetics of IV infusion in the clinical setting. [13] However, these doses are in the range of doses previously described in other experimental studies. [14, 15, 16]

Experimental protocol

This study was conducted in four groups. The isolated control hearts were subjected to 15 min of stabilization, 90 min of uninterrupted perfusion (negative control group; n = 5) or 30 min zero-flow global ischemia, and 60 min of reperfusion (control group; CNT-R60 n = 14), or perfusion with PHE 1 μM or 50 μM in the perfusate, (PHE (1)-R60, n = 10 and PHE (50)-R60, n = 12). In PHE groups, PHE was added to the perfusate from the beginning of the reperfusion and continued until the end of the experiment. LV functions were evaluated in all the hearts; in addition, in control and PHE groups, five samples per group were used for western blotting analysis and five other samples were used for evaluation of apoptosis by optical imaging. Additional experiments were performed to study the pattern of activation of kinase signaling, at 5, 15, and 60 min of reperfusion. The rat hearts in negative perfusion group were continuously perfused in Langendorff preparation for 105 min and were used as negative controls in the evaluation of apoptosis.

Measurement of mechanical function

Left ventricle function was assessed by recording the LVDP and the positive and negative first derivative of LVDP (+dp/dt and -dp/dt). The measurements were made at the end of the stabilization period and at 60 min of reperfusion (postischemic LV function), which indicated recovery of LVDP and was expressed as percentage of the baseline value (LVDP%). Diastolic function was assessed by monitoring isovolumic LV end-diastolic pressure (LVEDP) as a measure of diastolic chamber distensibility. LVEDP60 was measured after 60 min of reperfusion.

Measurement of lactate dehydrogenase release

Coronary effluent was collected from the starting until the end of reperfusion at 60 min. Measurement of LDH activity in the coronary effluent was performed using ELISA kit (Quantichrom LDH Kit, DLDH-100, BioAssay Systems USA). LDH release was expressed per gram of tissue and was used as an index of myocardial injury. [17]

Assessment of pattern of I/R induced pro-apoptotic kinase signaling activation: Protein isolation, sodium dodecyl sulfate-protein polyacrylamide gel electrophoresis (SDS-PAGE) and immunodetection.

Protein expression was measured as previously described. [12],[18] LV tissue was homogenized in the ice-cold buffer containing 10 mM Hepes (pH: 7.8), 10 mM KCl, 0.1 mM EDTA, 0.1 mM ethylene glycol tetra-acetic acid, 0.5 mM PMSF, 1 mM dithiothreitol, and 10 μg/ml leupeptin. 200 μl of 10% Igepal was added and samples were left in ice for 30 min. Homogenization was repeated and the homogenate was centrifuged at 1000 g for 5 min, at 4°C. The supernatant representing the cytosol-membrane fraction was kept at −80°C for further processing. Protein concentrations were determined by the bicinchoninic acid method, using bovine serum albumin as a standard. Samples were prepared for SDS-PAGE by boiling for 5 min in Laemmli sample buffer containing 5% 2-mercaptoethanol. Aliquots of 40 μg were loaded onto 9% (w/v) acrylamide gels and subjected to SDS-PAGE in a Bio-Rad Mini protean gel apparatus. Following SDS-PAGE, proteins were transferred electrophoretically to a nitrocellulose membrane (Hybond ECL) at 100 V and at 4°C, for 1.5 h using Towbin buffer for Western blotting analysis. Subsequently, filters were probed overnight at 4°C with specific antibodies against total p38 mitogen activated protein kinase (MAPK) and dual phospho-p38 MAPK, total c-jun NH2-terminal kinases (JNKs), dual phospho-JNKs, and total Akt and phospho-Akt (Cell Signaling Technology, dilution 1:1000). Filters were incubated with appropriate antimouse (Amersham) or antirabbit (cell signaling) horse-radish peroxidase secondary antibodies and immune-reactivity was detected by enhanced chemiluminescence using Lumiglo reagents (New England Biolabs) and exposed to Hyperfilm paper (Amersham). Immunoblots and gels were quantified using the Alpha Scan Imaging Densitometer (Alpha Innotech Corporation, 14743, Catalina Street, San Leandro, CA). Data were expressed as the ratio of phosphorylated to total protein expression. Equal loading in Western blots has been confirmed by Ponceau staining.

Evaluation of apoptosis by fluorescent probe optical imaging

A specific probe (QCASP 3.2, Quidd, France) which targets the intracellular activated caspase-3 was used as a marker of cell apoptosis as previously described. [19] It is composed of the peptidic sequence Asp-Glu-Val-Asp (DEVD) flanked by a fluorophore (derived from Cy 5.0) and a suitable quencher. The probe is activated upon recognition of its target and emits light at 670 nm when excited at 645 nm. The signal was visualized using fluorescence microscopy (Zeiss Axiovert 25 with Filter Set 50 and Axiocam MRc incorporated). Images were quantified using Image J (National Center for Biotechnology Information, Bethesda, MD) in arbitrary units. The probe was administered directly to the heart at 30 min of reperfusion. Administration of the probe either in perfused hearts or in hearts subjected to ischemia-reperfusion (I-R) showed no effect on LV function. At 60 min of reperfusion, in each group, the LV was isolated, cut into transverse sections and examined in real-time under fluorescence microscopy within 2-4 min.


Values are presented as mean and standard error of mean (SEM). One-way analysis of variance was used for multiple comparisons between groups with the appropriate Bonferroni or Dunnett T3 correction. Unpaired t-test and Mann-Whitney test were used for differences between two groups. A two-tailed test with a P < 0.05 was considered significant.

   Results Top

Effect of phenylephrine on postischemic cardiac function

Baseline indices of LV function are shown in [Table 1]. No difference was found between groups at baseline. Administration of PHE during reperfusion at 1 and 50 μM had no significant effect on recovery of function when compared with control hearts. The LVDP% and LVEDP60 (mmHg) were 35.8% ±3.8% and 67.3 ± 4.4 for CNT-R60; 28.9% ±3.1% and 75.1 ± 4.5 for PHE (1)-R60, and 46.7% ±4.7% and 68.8 ± 3.8 for PHE (50)-R60 hearts, respectively, P > 0.05. However, a significant difference in LVDP% was found between PHE (50)-R60 and PHE (1)-R60 hearts, P < 0.05 [Figure 1]. Furthermore, administration of PHE had no effect on the coronary perfusion pressure during reperfusion (100.1 ± 5.2 mmHg for CNT-R60 vs. 98.3 ± 3.9 and 90 ± 4 for PHE 50-R60, and PHE 1-R60, respectively, P > 0.05).
Figure 1: (a) Recovery of left ventricular developed pressure (LVDP%), (b) LV end-diastolic pressure and (c) lactate dehydrogenase release in control hearts (CNT-R60), in hearts treated with 1 ìM PHE (PHE [1]-R60) and 50 ìM PHE (PHE [50]-R60) after 30 min of zero-fl ow global ischemia and 60 min of reperfusion

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Table 1: LV functional indices at baseline

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Effect of phenylephrine on myocardial lactate dehydrogenase release

Lactate dehydrogenase release (IU/g) in the perfusate was significantly higher in PHE perfusate hearts 102 ± 10.4 in CNT-R60 versus 148.4 ± 14.8 in PHE (1)-R60 and 145.3 ± 11 in PHE (50)-R60 hearts, P < 0.05 [Figure 1]c.

Effect of phenylephrine on myocardial apoptosis

The representative fluorescent signals in subepicardium, mid-myocardium and sub-endocardium layers are shown in [Figure 2]. The signal was significantly increased in all three layers in PHE (1)-R60 and PHE (50)-R60 as compared with CNT-R60 hearts (P < 0.05).
Figure 2: Microscopy images showing myocardial apoptosis detected by fl uorescent probe in different heart layers in control hearts (CNT-R60), in hearts treated with 1 ìM PHE (PHE [1]-R60) and 50 ìM PHE (PHE [50]-R60) after 30 min of zero-fl ow global ischemia and 60 min of reperfusion (Table presenting data of caspase-3 activity after quantifi cation of images obtained by fl uorescent microscopy). Quantification was performed using ImageJ (National Center for Biotechnology Information, Bethesda, MD). Data are expressed as standard error of mean for each myocardial layer in arbitrary units. The number of hearts used for optical imaging were n = 5 for each group (*P<0.05 vs. CNT-R60)

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Pattern of ischemia-reperfusion-induced pro-apoptotic kinase signaling activation

Phosphorylated to total levels of the pro-apoptotic kinases p38 MAPK and JNKs at 5, 15, and 60 min of reperfusion are shown in [Figure 3] and [Figure 4]. The ratio of phospho-JNKs to total-JNKs was similar in all groups at all-time points, P > 0.05. The ratio of phospho-p38 to total p38 MAPK was found to be increased 1.5-fold in PHE (1)-R5 as compared with CNT-R5 and 1.8-fold more in PHE (1)-R60 as compared with CNT-R60, P < 0.05. No difference was found in the ratio of phospho-p38 to total p38 MAPK between PHE (50) treated hearts and CNT hearts at any time point, P > 0.05.

Phosphorylated to total levels of the pro-survival kinase Akt at 5, 15, and 60 min of reperfusion are shown in [Figure 5]. The ratio of phospho-Akt to total Akt was decreased 1.7 fold in PHE (50)-R15 as compared with CNT-R15 and 2.0-fold as compared with PHE (1)-R15, P < 0.05. No difference was found in the ratio of phospho-Akt to total Akt between PHE (1) treated hearts and CNT hearts at any time point, P > 0.05.
Figure 3: Densitometric assessment in arbitrary units of the ratio of phosphorylated p38 mitogen activated protein kinase (MAPK) to total p38 MAPK expression in control hearts (CNT) and in phenylephrine (PHE)-treated hearts with 1 ìM (PHE [1]) and 50 ìM (PHE [50]) after 30 min of zero-fl ow global ischemia and 5 min (R5), 15 min (R15) or 60 min (R60) of reperfusion. Data represent n = 5 hearts per group. (*P < 0.05 vs. CNT-R5) (†P < 0.05 vs. CNT-R60)

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Figure 4: Densitometric assessment in arbitrary units of the ratio of phosphorylated p54 JNK to total p54 c-jun NH2-terminal kinases expression in control hearts (CNT) and in phenylephrine (PHE)-treated hearts with 1 ìM (PHE [1]) and 50 ìM (PHE [50]) after 30 min of zero-fl ow global ischemia and 5 min (R5), 15 min (R15), or 60 min (R60) of reperfusion. Data represent n = 5 hearts per group

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Figure 5: Densitometric assessment in arbitrary units of the ratio of phosphorylated Akt to total Akt expression in control hearts (CNT) and in phenylephrine (PHE)-treated hearts with 1 ìM (PHE [1]) and 50 ìM (PHE [50]) after 30 min of zero-flow global ischemia and 5 min (R5), 15 min (R15) or 60 min (R60) of reperfusion. Data represent n = 5 hearts per group **P < 0.05 versus CNT-R15 and PHE (1)-R15

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   Discussion Top

Sympathomimetic drugs such as β and α-adrenergic agonists can improve hemodynamics in low output states and thus, they are routinely used in clinical practice. However, these agents have been associated with increased arrhythmia risk and adverse outcomes in patients with the heart failure. [20] Sympathomimetics may worsen the oxygen demand/supply balance [10],[11] and induce calcium overload with potential detrimental effects on the myocardium, particularly in the setting of I-R. This study provides evidence that PHE given at reperfusion can exacerbate reperfusion injury. In our experimental isolated rat heart model of ischemia-reperfusion, PHE failed to significantly increase postischemic contractile function. This is probably due to weak inotropic effect of α1-adrenergic PHE on the myocardium as compared with the peripheral vasoconstrictive effect. However, myocardial injury induced by PHE as indicated by increased LDH release during reperfusion could also offset its effect on contractile function.

The mechanisms that increase ischemia-reperfusion-induced apoptosis with PHE addition in the perfusate during reperfusion, remain speculative. It may be secondary to α-1 adrenergic stimulation induced vasoconstriction in the coronary arteries or may be due to a direct effect in the myocardium. However, our data provid no evidence of severe coronary vasoconstriction as indicated by the absence of changes in coronary perfusion pressure during reperfusion. Thus, PHE may have a direct effect on the myocardium and induce apoptosis and cell death. In fact, α-1 adrenergic receptors exist in cardiomyocytes and their activation may lead to direct effects on the stressed myocardium. [9] Furthermore, PHE administration has been used extensively in isolated cardiomyocytes as a model to study the development of pathological hypertrophy and the activation of intracellular kinase signaling (such as extracellular signal-regulated kinases) has been shown to play an essential role in this response. [21],[22] Apoptosis is an energy dependent programmed cell death and thus, is markedly exacerbated upon reperfusion and executed through activation of caspases particularly the caspase-3. [23] Apoptosis is observed after cardiac surgery and myocardial infarction and contributes in reperfusion injury and cardiac dysfunction. [4],[5] In our study, fluorescent probe optical imaging targeting caspase-3 was used as an indicator of apoptosis. This apoptotic index showed a stronger signal in the subepicardium and mid-myocardium and lower subendocardium, indicating a differential transmural pattern of apoptosis after I-R, as previously reported. [19] With this technique both optical imaging and quantitative measurements of the activated caspase-3 can be achieved in real-time under fluorescence microscopy in all myocardial layers. With PHE administration an increased apoptotic signal was observed in all myocardial layers and particularly in the subendocardial layer. Apoptosis appears to be mediated by several mechanisms including the activation of the pro-apoptotic p38 MAPK and JNK kinases. Sustained activation of the so-called pro-death signaling pathways, p38 MAPK or JNKs, results in cellular death/apoptosis while blockade of the I/R induced sustained activation of p38 MAPK is shown to decrease apoptosis and improve recovery of function. [24],[25] On the basis of this evidence, we measured the phosphorylated levels of p38 MAPK and JNK kinases at different time points of reperfusion with and without PHE treatment. Our molecular analysis showed no differences in JNK activation during reperfusion between untreated and PHE treated hearts. However, a differential pattern of p38 MAPK activation was observed with different doses of PHE. With 1 μM PHE, the ratio of phospho-p38 to total p38 MAPK at reperfusion phase was increased, indicating that the detrimental effect of PHE at this dose may involve the activation of p38 MAPK. With 50 μM of PHE, no changes in p38 MAPK activation were observed, implying the involvement of different underlying intracellular signaling in this response. This is probably due to the fact that at high doses, PHE may abolish its selectivity to α-1 adrenergic receptors and could also act on β-adrenergic receptors resulting in differential regulation of kinase signaling pathways. β-1 adrenergic receptor agonists have been shown to induce apoptosis in cultured cardiomyocytes through the activation of protein phosphatases, such as PTEN. [26] Furthermore, β-1 adrenergic stimulation in neonatal rat cardiomyocytes reduced α-1 adrenergic-mediated phosphorylation of target proteins through activation of a protein phosphatase. [27] Thus, it is possible that the stimulation of β-adrenergic receptors by the high dose of PHE at reperfusion induced protein phosphatase activity and resulted in inhibition of p38 MAPK over-activation. The activation of protein phosphatases could have also resulted in inhibition of pro-survival pathways. In accordance with this notion, we observed that the high dose of PHE at reperfusion reduced the activation of the pro-survival Akt pathway.

Strengths and limitations of the study

Our data indicate that agents with predominant α1 adrenergic activity may have detrimental effects in the stressed myocardium that could offset their beneficial effects on the maintenance of blood pressure. Interestingly, we have previously shown that dobutamine, a β1 adrenergic agonist, also exacerbated myocardial injury resulting in reduced post ischemic recovery of function. [28] Here, it should be realized that both these agents seem to be beneficial given before ischemia and can precondition the heart. [9],[16],[29] These data are of therapeutic importance and should be considered in relation to the use of sympathomimetics in clinical settings of I-R such as bypass surgery or myocardial infarction. Further clinical studies are needed to elucidate this issue.

   Conclusion Top

Our study demonstrates that phenylephrine administration during reperfusion does not improve postischemic recovery of myocardial function due to exacerbation of both myocardial necrosis and apoptosis. These data are of important therapeutic relevance and indicate the need for the development of new pharmacological agents to support hemodynamics and induce myocardial protection at the same time.

   References Top

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Correspondence Address:
Iordanis Mourouzis
Department of Pharmacology, University of Athens, 75 Mikras Asias Avenue, 11527 Goudi, Athens
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0971-9784.135850

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