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Ann Thorac Surg 1997;63:683-688
© 1997 The Society of Thoracic Surgeons

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Original Article: Cardiovascular

Intermittent Warm Blood Cardioplegia Preserves Myocardial ß-Adrenergic Receptor Function

Department of Cardiac Surgery, Medical School of Catanzaro, Catanzaro, and Department of Cardiac Surgery, Medical School of Naples, Naples, Italy

Accepted for publication October 5, 1996.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Background. Left ventricular dysfunction is frequently observed in patients after hypothermic cardioplegic arrest, and often inotropic intervention is necessary for patients to be successfully weaned from cardiopulmonary bypass (CPB). A myocardial ß-adrenergic receptor (ßAR) desensitization has been noted to occur after hypothermic CPB in patients undergoing coronary artery bypass grafting. This randomized study was undertaken to determine the effect of cardioplegic solution temperature on cardiac ßARs.

Methods. Two groups of patients (20 patients in each) scheduled for elective coronary artery bypass grafting underwent CPB with either intermittent warm or cold blood cardioplegia. The density of the ßARs, the proportion of ß_1- to ß_2-adrenergic receptors, and the ßAR coupling capacity to adenylate cyclase were determined in specimens of the right atrial tissue at baseline, during CPB, and after discontinuation of CPB. Plasma concentrations of catecholamines were also measured in both arterial and coronary sinus samples.

Results. In both cardioplegia groups, no significant modification in either the ßAR density or the proportion of ß_1- to ß_2-adrenergic receptors was detected. However, a significant decrease in adenylate cyclase activity after stimulation with isoproterenol was observed in the cold blood cardioplegia group during CPB (p < 0.01) and 30 minutes after its discontinuation (p < 0.05). Moreover, a significant decrease in adenylate cyclase activity during CPB was detected in this group after stimulation with sodium fluoride (p < 0.05), but this pattern was found to be completely reversed by 30 minutes after discontinuation of CPB. No modification in the basal or stimulated adenylate cyclase activity was observed in the warm blood cardioplegia group during or after CPB.

Conclusions. Our results confirm the finding from previous studies of a cardiac ßAR desensitization after hypothermic cardioplegic arrest, and provide evidence of the advantages of intermittent warm blood cardioplegia in preserving the autonomic sympathetic function of the heart.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
In the early era of coronary artery bypass grafting, the appropriate role of the procedure in patients with severe left ventricular dysfunction was quite uncertain and the high operative risk in these patients represented an important contraindication in the minds of many surgeons. During the past decade, however, there has been a significant increase in the number of risk factors in patients with coronary artery disease referred for coronary artery bypass grafting, including advancing patient age, worsening ventricular condition, and an increasing frequency of comorbid diseases. This change in patient demographics has paralleled increasingly aggressive attempts to provide maximal myocardial protection to resuscitate the ischemic myocardium.

Because the inotropic state of the heart muscle is mostly controlled by the ß-adrenergic receptor (ßAR)–adenylate cyclase complex [1], a decrease in ßAR density or an attenuation in the regulatory protein coupling of these receptors with adenylate cyclase, or both, may be implicated as the source of the relative inability of the heart to withstand stress after coronary artery bypass grafting with cardiopulmonary bypass (CPB). It is thus important to determine whether cardiac arrest with cardioplegia can be performed without considerably modifying the efferent sympathetic innervation of the human heart.

This study was designed to compare the effects of intermittent warm and cold blood cardioplegia on the density and functional status of right atrial ßARs in patients undergoing elective coronary artery bypass grafting.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Forty patients scheduled to undergo nonurgent aortocoronary bypass grafting at the Department of Cardiac Surgery of the Medical School of Naples were randomly assigned by hospital number to one of two groups. All patients had angina on effort on admission and were receiving some combination of nitrate vasodilators and calcium-channel blocking agents. No patient in the study was on ß-blocker therapy preoperatively. The two groups were similar in terms of the mean age, male dominance, preoperative hemodynamic data, and the number of coronary arteries revascularized (Table 1). Patients had good left ventricular function, judged on the basis of a preoperative cardiac angiogram (left ventricular ejection fraction, >0.55), and had no evidence of pulmonary disease, judged on the basis of a chest roentgenogram and lung volume.

Cardioplegia Groups
Blood cardioplegic solutions were prepared by mixing four parts of oxygenated blood with each part of hyperkalemic crystalloid solution (SIENA 1) and were delivered by means of a separate circuit consisting of a roller pump (Sarns), a reservoir (Terumo), a heat exchanger–bubble trap (Medtronic Hall, Minneapolis, MN), and an in-line ultrasonic flow probe. The crystalloid solution consisted of 5% dextrose–0.225% NaCl (550 mL), KCL (2 mEq/mL), citrate-phosphate-dextrose (FUI-IX, 50 mL), and 3-mol/L trihydroxymethylaminomethane ([THAM] 200 mL). Cardiac arrest was achieved in all patients by the infusion of a high-potassium (26 mEq/L) blood cardioplegic solution into the aortic root at a rate of 200 to 300 mL/min until diastolic arrest was achieved. The temperature of this initial dose of solution in the warm blood cardioplegia group was 37°C, whereas the temperature of this solution in the cold blood cardioplegia group was 5°C. The body temperature of the patients in the warm blood cardioplegia group was actively warmed to 37°C during bypass. The myocardial septal temperature in the cold blood cardioplegia group ranged from 10° to 15°C, and the esophageal temperature in this group was maintained between 25° and 28°C during the aortic cross-clamp period, with rewarming to 37°C begun during construction of the last distal anastomosis. Reperfusion with warm blood cardioplegic solution before aortic unclamping was never done.

In both groups, 100 to 150 mL of low-potassium (12 mEq/L) cardioplegic solution was infused intermittently into each vein graft after completion of each distal anastomosis and 300 to 400 mL was infused into the aortic root and each completed vein graft after each proximal anastomosis. A total of 1,520 ± 68.1 mL of cardioplegic solution was infused into patients in the cold blood cardioplegia group, compared with 1,780 ± 79.3 mL in the warm blood cardioplegia group (p = not significant).

Study Protocol
A wedge resection specimen was excised from the apex of the right atrial appendage immediately before the atrial cannula was introduced. A second and a third specimen were obtained below the pursestring suture 30 minutes after aortic cross-clamping and 30 minutes after decannulation. The specimens were immediately frozen in liquid nitrogen and stored in it until examination.

Arterial and coronary sinus blood samples were obtained while patients were on CPB 5 minutes after heparinization, at the time of each infusion of cardioplegic solution during the cross-clamp period, immediately (1 minute) after cross-clamp release, 10 minutes after reperfusion, and 30 minutes after discontinuation of CPB. The samples were collected in heparinized, cooled syringes that were immediately capped and stored in ice until separation and analysis. Blood samples were assayed to determine the oxygen and carbon dioxide tension, pH, and oxygen saturation.

The study protocol was approved by the ethics committee of the Medical School of Naples. Informed consent was obtained from each patient.

Hemodynamic Measurements
From the moment patients arrived in the intensive care unit after operation, we monitored the systolic, diastolic, and mean systemic and pulmonary arterial pressures; the mean left atrial pressure; systemic vascular resistance; and cardiac output every 4 hours for 24 hours. We calculated the left ventricular stroke work index and cardiac index using standard formulas. Hemodynamic instability was defined as the need for inotropic agents or mechanical support to maintain the patient's mean arterial blood pressure in the ICU above 70 mm Hg, despite the optimization of preload and afterload and the correction of any metabolic abnormalities.

ß-Adrenergic Receptor Binding Studies
Eighteen to twenty-three milligrams of right atrial tissue was chilled in ice-cold homogenization buffer (10-mmol/L THAM-HCl, 1-mmol/L EDTA; pH, 7.4). The sample was homogenized with a motor-driven glass Teflon Potter homogenizer for 1 minute, diluted to 20 mL with ice-cold 1-mol/L KCl, and stored on ice for 10 minutes. The crude membrane preparation was then incubated in an assay buffer consisting of 4 mL of 0.9% NaCl with THAM (20 mmol/L), MgCl₂ (12.5 mmol/L), and EDTA (ethylenediaminetetraacetic acid; 1.5 mmol/L). Samples were frozen in liquid nitrogen (-70°C) until used for radioligand studies, which were performed within 2 weeks. The ßAR binding studies were performed on the prepared membranes using a method modified from that of Feldman and associates [2]. An aliquot (0.1 mL) of membrane was incubated in a final volume of 250 µL containing ascorbic acid (0.5 mmol/L), bovine serum albumin (60 µg/mL), phentolamine mesylate (0.03 mmol/L), THAM-HCl (12 mmol/L; pH, 7.4; 37°C), 0.05% NaCl, MgCl₂ (7.5 mmol/L), EDTA (0.9 mmol/L), and [¹²⁵I]iodocyanopindolol (0.9 mmol/L). The density of receptors was determined by analyzing the binding of six to nine concentrations of [¹²⁵I]iodocyanopindolol (10 to 250 pmol) in the presence or absence of isoproterenol. The reaction was stopped after 90 minutes of incubation by the addition of 10 mL of 0.9% NaCl, 10 mL of THAM-HCl, and MgCl₂ (12.5 mmol/L), followed by rapid ultrafiltration through Whatman GF/C filters (Whatman Inc., Clifton, NJ). Each filter was then washed with an additional 5 mL of buffer. The radioactivity retained on the filter was determined with a gamma-counter. The maximal number of binding sites and the equilibrium dissociation constant of binding sites were obtained in individual experiments from Scatchard plots determined by linear regression analysis [3]. The proportion of ß₁ and ß₂ receptors was assessed by CGP 20712A–[¹²⁵I]iodocyanopindolol competition curves.

Assay of Adenylate Cyclase
Assays of adenylate cyclase activity were performed using homogenates prepared in the same way as the membranes for binding assays. The homogenates were then resuspended in 1-mmol/L HEPES and 2-mmol/L EDTA and assayed using the method of Salomon and associates [4], as modified by De Blasi and colleagues [5]. Three different incubation conditions were used, as described by Schranz and co-workers [6]. For isoproterenol activation, membranes were incubated for 10 minutes at 37°C in a final volume of 100 µL containing HEPES buffer (40 mmol/L; pH, 7.4), MgCl₂ (5 mmol/L), EDTA (1 mmol/L), guanosine triphosphate (10 µmol/L), 32 P adenosine triphosphate (500 µmol/L), cyclic adenosine monophosphate (100 µmol/L), and an adenosine triphosphate–regenerating system (5-mmol/L phosphocreatine and 50 U/mL of creatine phosphokinase [buffer A]). For sodium fluoride (10 mmol/L) and forskolin (100 µmol/L) activation, membranes were incubated in buffer A without guanosine triphosphate. The reaction was stopped by adding 0.8 mL of THAM-HCl buffer (500 mmol/L; pH, 7.4) containing adenosine triphosphate (40 mmol/L) and cyclic adenosine monophosphate (1.4 mmol/L).

Assay of Catecholamines
Samples were prepared and assayed by high-performance liquid chromatography, as described by Goldstein and associates [7]. Its sensitivity for the detection of norepinephrine was 15 pg/mL, and its sensitivity for the detection of epinephrine was 25 pg/mL.

Statistical Methods
Data are expressed as the mean ± the standard error of the mean. A repeated-measures analysis of variance followed by Scheffé's multiple-comparison analysis was used to test for significant changes over the time course of the study, both within and between groups. An unpaired Student's t test was used when appropriate. Linear regression analysis was used to test relations between independent variables. A p value of less than 0.05 was considered significant.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Operative Data
There were no operative deaths, and no patient sustained a Q-wave myocardial infarction or subendocardial myocardial infarction. In addition, no patients required intraaortic balloon counterpulsation during the postoperative period. The postoperative conditions of the patients in the two groups were comparable. During the first postoperative hours, the systemic vascular resistance was significantly lower in the warm blood cardioplegia group (989 ± 49.5 dynescm^-5) than it was in the cold blood cardioplegia group (1,205 ± 58.4 dynescm^-5; p < 0.01), with similar values on the morning of the first postoperative day. The mean infusion rate of vasodilators during the same period was the same. The cardiac index was significantly higher in patients after normothermic CPB than in patients after hypothermic CPB (3.5 ± 0.08 versus 3.1 ± 0.04 Lmin^-1m^-2; p < 0.01), with no significant difference in the values on the first postoperative day. Three patients in the cold blood cardioplegia group and 2 in the warm blood cardioplegia group required dopamine infusion for the management of the low cardiac output syndrome. There were no differences between the groups with regard to the total volume administered, the mean urinary output, the need for diuretics, and the total fluid balance during the postoperative period.

Right Atrial ß-Adrenergic Receptor Density and Function
Interestingly, the ßAR density was not modified in our patients, regardless of the cardioplegic protection used (Table 2). In addition, no change in the affinity of the ßARs for [¹²⁵I]iodocyanopindolol was detected.

EPINEPHRINE.
Figure 1 shows the pattern of epinephrine levels during the entire sampling period. A significant increase in the plasma epinephrine levels occurred in the arterial and coronary sinus samples in both groups 5 minutes after the start of CPB. The maximum epinephrine levels in both groups were reached at both sampling sites 10 minutes after aortic cross-clamp release. However, the levels were significantly (p < 0.01) higher in the warm blood cardioplegia group at both sampling sites during the entire sampling period. Interestingly, the arterial levels of epinephrine in the cold blood cardioplegia group were significantly (p < 0.01) higher than those in coronary sinus blood during the entire cross-clamp time. This difference was still present 1 and 10 minutes after the release of the aortic cross-clamp, though it failed to reach statistical significance.

View larger version (59K): [in this window] [in a new window]   Fig 1. . Plasma epinephrine and norepinephrine levels in arterial and coronary sinus ( CS) samples (during and after cardiopulmonary bypass) from patients treated with intermittent cold or warm blood cardioplegia. Each bar represents the mean ± standard error of the mean. (base = baseline; 5`cpb = 5 minutes after beginning of cardiopulmonary bypass; 1st, 2nd, and 4th = after the first, second, and fourth cardioplegic infusion; 1`xco and 10`xco = 1 and 10 minutes after cross-clamp removal; 30`pcpb = 30 minutes after discontinuation of cardiopulmonary bypass; 12hpo = 12 hours postoperatively; * = p < 0.01; ** = p < 0.05 versus coronary sinus levels.)

NOREPINEPHRINE.
Figure 1 also shows the pattern of norepinephrine levels during the entire sampling period. The norepinephrine levels paralleled the epinephrine levels during this period, with peak values observed 10 minutes after release of the aortic cross-clamp in both arterial and coronary sinus samples. In a fashion similar to the epinephrine levels, the norepinephrine levels were higher in the warm blood cardioplegia group than they were in the cold blood cardioplegia group during the entire sampling period (p < 0.01). In the cold blood cardioplegia group, significantly higher levels (p < 0.05) of norepinephrine were observed in samples from the arterial sites after the first two cardioplegic infusion. However, after the fourth dose of cardioplegic solution and through the end of CPB, no significant difference in the norepinephrine level was observed at the two sampling sites. The norepinephrine levels in the warm blood cardioplegia group were higher in the arterial samples than they were in those from the coronary sinus, but the difference was not statistically significant.

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
The superiority of blood cardioplegia over cold chemical cardioplegia in protecting the ischemic and reperfused myocardium has been reported [8, 9]. Nevertheless, there is still controversy over whether to use warm or cold blood cardioplegia and intermittent or continuous perfusion. The concept of warm heart protection is attractive because the continuous infusion of warm hyperkalemic blood not only maintains cardiac arrest but also supports aerobic metabolism. Moreover, findings from other studies have also indicated that the protection conferred by blood cardioplegia is diminished at lower temperatures [10]. In practice, however, the continuous infusion of warm blood cardioplegic solution frequently causes the operative field to be obscured and is particularly cumbersome during coronary operations. Lichtenstein and colleagues [11], who originally described the technique, admit to interrupting the infusion of warm blood for up to 15 minutes. Yau and associates [12] also reported that they found it necessary to interrupt the antegrade administration of warm blood cardioplegic solution for 39% of the total cross-clamp time.

The effectiveness of interrupted antegrade warm blood cardioplegia has been thoroughly assessed in recent studies [13, 14]. Further, Calafiore and co-workers [15] found there was a significant difference in the degree of morbidity between a group of patients operated on using warm blood cardioplegia and a group previously operated on using interrupted antegrade cold blood cardioplegia.

Despite important improvements in myocardial preservation techniques, left ventricular function is depressed after CPB. Because the inotropic state of the heart muscle is mostly controlled by the ßAR–adenylate cyclase complex, a decrease in ßAR density or function, or both, may be implicated as the cause of the relative inability of the heart to withstand stress after CPB.

The biological signal triggered by the occupancy of ß-ARs by the agonists is transduced, amplified, and regulated by a family of guanine nucleotide–binding proteins (G proteins), which serve both stimulatory and inhibitory functions. Partial mechanisms underlying a decreased ß-AR agonist–mediated contractile response of myocytes include down-regulation of ß-ARs, decreased levels of stimulatory G protein, increased levels of inhibitory G protein, and defects in the adenylate cyclase itself. Prior studies have demonstrated an uncoupling of human cardiac ßARs during CPB in which hypothermic cardioplegic cardiac arrest was produced by cold solutions [6, 16]. Conversely, Murphy and Armour [17] found no difference in the heart rate, atrial force of contraction, and the right and left ventricular wall systolic pressure increase induced by stimulation of the efferent sympathetic nervous system and by isoproterenol infusion in dogs after 1 hour of normothermic CPB in which the coronary arteries were continuously perfused with normothermic blood. Cavallo and co-workers [18] also demonstrated that myocyte ß-AR responsiveness was reduced from normothermic values after hypothermic cardioplegic arrest. In our study, the reduced adenylate cyclase activity observed after stimulation with 10-mmol/L sodium fluoride (which, in this concentration, is believed to activate predominantly stimulatory G protein with little effect on inhibitory G protein), together with a preserved maximal activation after 100-µmol/L forskolin stimulation (acting predominantly at the catalytic unit of the enzyme), indicates that the enzyme catalytic subunit is not involved in the down-regulation of the ßAR observed in the cold blood cardioplegia group, which seems to be due only to an alteration in the receptor and its regulatory protein. Because we did not measure the level of stimulatory G protein or its function directly, we cannot fully exclude the possibility that changes in the level or function of stimulatory G protein may, at least in part, contribute to the reduction in isoproterenol- and sodium fluoride–stimulated adenylate cyclase activity.

Results from many studies have led to the hypothesis that both the reduction in myocardial ßARs and their subsensitivity to stimulation are a direct consequence of increased exposure to the sympathetic nervous system neurotransmitter norepinephrine [2, 19]. Our study demonstrated an inverse relationship between myocardial catecholamine release and temperature; nevertheless, though higher catecholamine levels were observed in the warm blood cardioplegia group during the entire CPB period, no significant alteration in either ßAR density or function was detected in these patients. Moreover, in the cold blood cardioplegia group, no significant correlation was seen between the degree of ßAR down-regulation and the amount of catecholamine release.

The results of the present study have two important clinical implications. First, they indicate that the modulation of ßAR behavior after CPB may be more complex than was previously thought. Factors other than the ones we investigated may affect ßAR responsiveness. For example, the favorable modulation of the ßAR complex might be due to an overall improvement in cardiac function and hemodynamic status (ie, lower pulmonary capillary wedge pressure and higher stroke volume index). It is also possible, as suggested by Liang and co-workers [20], that ßAR down-regulation occurs only if there is a defect in the norepinephrine concentration in the local synaptic cleft. Thus, ßAR regulation depends not only on the circulating catecholamine levels, but also on neuronally released norepinephrine, local metabolism, and presynaptic uptake mechanisms.

The second implication of this study concerns the status of basal and sodium fluoride–stimulated adenylate cyclase activity after CPB with cold blood cardioplegia. That is, attenuated adenylate cyclase activity in patients receiving cold blood cardioplegic solution could limit the capacity of drugs that affect cyclic adenosine monophosphate metabolism, such as the phosphodiesterase inhibitors, to acutely augment adenosine monophosphate concentrations.

In the present study, changes in ßARs were studied in the right atria. Whether similar changes also occur in human left ventricular ßARs is not known. As already observed by Schranz and co-workers [6], the pattern of changes in ßARs and ßAR agonist activation of adenylate cyclase found in human right atria in this study is very similar to that recently described for canine left ventricular ßARs [21]. Nevertheless, it should be emphasized that changes in the ßAR density and function occurring in the right atrium cannot necessarily be extrapolated to ventricular tissue.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Address reprint requests to Dr Chello, Via S. Giacomo dei Capri 29, 80128 Napoli, Italy.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Pasquale Mastroroberto Vincenzo De Amicis Donato Pantaleo Nicola Spampinato Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chello, M. Articles by Spampinato, N. Search for Related Content PubMed PubMed Citation Articles by Chello, M. Articles by Spampinato, N.