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Ann Thorac Surg 1999;68:1567-1572
© 1999 The Society of Thoracic Surgeons

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Original Articles

Bradykinin pretreatment improves ischemia tolerance of the rabbit heart by tyrosine kinase mediated pathways

^a Division of Cardiothoracic Surgery, The Children’s Hospital of Buffalo, Buffalo, New York, USA
^b Department of Surgery, The State University of New York at Buffalo, Buffalo, New York, USA

Address reprint requests to Dr Rosenkranz, Division of Cardiothoracic Surgery, The Children’s Hospital of Buffalo, 219 Bryant St, Buffalo, NY 14222
e-mail: erosenkranz{at}chob.edu

Presented at the Thirty-fifth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 25–27, 1999.

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. Depressed myocardial performance is an important clinical problem after open-heart surgery. We hypothesized that: (1) pretreating the heart with bradykinin improves postischemic performance, and (2) bradykinin activates protein tyrosine kinase (TK).

Methods. Twenty-seven adult rabbit hearts underwent retrograde perfusion with Krebs-Henseleit buffer (KHB) followed by 50 min of 37°C cardioplegic ischemia with St. Thomas’ cardioplegia solution (StTCP). Ten control hearts received no pretreatment. Ten bradykinin-pretreated hearts received a 10-minute infusion of 0.1 µM bradykinin-enriched KHB and cardioplegic arrest with 0.1 µM bradykinin-enriched StTCP. Seven others received 40 µM Genistein (Research Biochemicals, Natick, MA), a selective inhibitor of TK, added to both the 0.1-µM bradykinin-enriched KHB and 0.1-µM bradykinin-enriched StTCP solutions.

Results. Bradykinin pretreatment significantly improved postischemic myocardial performance and coronary flow (CF) compared with control (left ventricular developed pressure: 53 ± 5 vs 27 ± 4 mm Hg; +dP/dt_max: 1,025 ± 93 vs 507 ± 85 mm Hg/s; CF: 31 ± 3 vs 22 ± 2 mL/min; p < 0.05). Inhibition of TK with Genistein prevented this improvement in myocardial function, resulting in recovery equivalent to untreated controls.

Conclusions. Bradykinin pretreatment may be an important new strategy for improving myocardial protection during heart surgery. The molecular mechanism of action may be similar to those activated by ischemic preconditioning.

	Introduction

Top Abstract Introduction Material and methods Results Comment References

 
Open heart operations require a period of elective cardioplegic arrest to facilitate the surgical repair. Although current methods of inducing and maintaining arrest using hyperkalemic cardioplegia solutions are effective, postreperfusion depression of myocardial performance remains an important cause of postoperative morbidity and mortality. In 1986, Murry and associates [1] described the phenomenon of ischemic preconditioning in dogs, in which a brief period of regional myocardial ischemia made the heart more resistant to infarction from a subsequent, prolonged period of ischemia. This observation has been confirmed in all animal species, including humans [2]. The molecular mechanisms responsible for ischemic preconditioning are presently incompletely understood, although several studies have shown that protein kinase C (PKC) and protein tyrosine kinase (TK) activation are required for preconditioning to occur [3–6]. Several mediators released from the ischemic myocardium during ischemia and reperfusion, including adenosine and bradykinin [7], can induce the preconditioned state when given exogenously before a period of prolonged ischemia. These observations led us to conclude that pharmacologic preconditioning combined with hyperkalemic cardioplegia might be a strategy to reduce or prevent postreperfusion myocardial depression after surgical procedures.

This study tests the hypotheses that: (1) pretreating the heart with bradykinin before a period of cardioplegic ischemic arrest improves postreperfusion myocardial function, and (2) bradykinin pretreatment of the heart activates molecular pathways that are associated with the preconditioning phenomenon, including activation of protein TK.

	Material and methods

Top Abstract Introduction Material and methods Results Comment References

 
Experimental model
Animals were cared for in accordance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" (NIH publication 85-23, revised 1985). The protocols used in this study were approved by the Institutional Animal Care and Use Committee of the State University of New York at Buffalo School of Medicine and Biomedical Sciences.

New Zealand white rabbits (1.5 to 2.0 kg) were used in this study. Rabbits were anesthetized with sodium pentobarbital (60 mg/kg, iv), anticoagulated with heparin (2,000 U/kg, iv), and the heart was rapidly exposed. The aorta was cannulated and the heart was retrogradely perfused in situ to avoid ischemia. The heart was then excised and mounted in an organ chamber on a Langendorff perfusion system. The heart was retrogradely perfused at 75 mm Hg with a modified Krebs-Henseleit buffer (KHB) with the following composition (mM/L): NaCl 118, NaHCO₃ 25, KHPO₄ 1.2, KCl 4.7, MgSO₄ 1.2, CaCl₂ 1.8, and glucose 11.0. The KHB was equilibrated with 95% O₂ and 5% CO₂, adjusted to a pH of 7.35 to 7.4 at 37°C and filtered with a 5-µm filter (Gilman Scientific, Inc, Ann Arbor, MI). Right ventricular myocardial temperature was measured with a thermistor needle probe (Mallinckrodt, Inc, St. Louis, MO) and was maintained at 37°C throughout the experiment by regulation of the organ chamber temperature. Our Langendorff apparatus permits instantaneous change of the perfusion fluids from standard KHB to one containing different pharmacological substances or cardioplegia solution by adjusting an inlet valve to the aortic perfusion cannula.

Measurements
Mean coronary flow (mL/min) was measured by timed collection of effluent from the right ventricle exiting the heart from the severed pulmonary artery. Isovolumetric measurement of left ventricular performance was made using a compliant latex balloon connected to a pressure transducer, inserted in the left ventricle (LV) across the mitral valve. A calibrated syringe attached to the pressure transducer system was used to fill the balloon with a volume of saline needed to maintain a left ventricular end diastolic pressure (LVEDP) of 10 mm Hg during measurement of baseline left ventricular performance. This same balloon volume was used for subsequent measurements of left ventricular performance after reperfusion. Left ventricular performance was assessed by measurement of left ventricular developed pressure (LVDP, mm Hg) and left ventricular end-diastolic pressure (LVEDP, mm Hg). Positive and negative first derivatives of LVDP (+dP/dt and -dP/dt, mm Hg/s) were calculated as indices of ventricular contractility and compliance, respectively. Analog pressure data from the LV balloon were continuously recorded on an eight-channel recorder (Gould Instrument Systems, Cleveland, OH) and converted to a digital signal for on-line data recording and computation (MacIntosh IICx; Apple Computer, Cupertino, CA; LabView, National Instruments Corp, Austin, TX). Continuous pressure measurements were sampled at specific time points in each experiment (Fig 1) by taking an average of 15 cardiac cycles for calculation of parameters of left ventricular performance. Hearts failing to generate an LVDP greater than 80 mm Hg, or a coronary flow (CF) greater than 25 mL/min during the stabilization phase of the experiment were excluded from further study.

View larger version (19K): [in this window] [in a new window]   Fig 1. Experimental protocol. Group 1 hearts received no pretreatment before arrest with St Thomas’ cardioplegia solution (StTCP). Group 2 hearts were pretreated with bradykinin (BK) before arrest with StTCP supplemented with BK. Group 3 hearts were pretreated with Genistein (Gen) and BK pretreatment before arrest with StTCP supplemented with both BK and Gen. (Hatched bars = ischemic period; KHB = Krebs-Henseleit Buffer.)

All hearts underwent 50 minutes of cardioplegic arrest induced with St. Thomas’ cardioplegia solution of the following composition (mM/L): NaCl 110, KCl 16, CaCl₂ 1.5, NaHCO₃ 10, glucose 10. The cardioplegia solution was then gassed with 95% O₂ and 5% CO₂, and the pH was adjusted to 7.4 at 37°C. The Langendorff perfusion column was clamped and 50 mL of 37°C cardioplegia solution was infused at 60 mm Hg via a separate perfusion column. The time to mechanical arrest was recorded. Group 1 hearts (control) received unmodified cardioplegia solution. Group 2 hearts received 0.1 µM bradykinin-enriched cardioplegia solution. Group 3 hearts received 0.1 µM bradykinin-enriched cardioplegia solution, which also contained 40 µM Genistein. All hearts were then reperfused with KHB for 60 minutes. Postreperfusion LV performance and CF were recorded continuously and compared between pretreatment groups at 60 minutes of reperfusion.

Drugs
Bradykinin was purchased from Sigma Chemical Corp (St. Louis, MO). Genistein was purchased from Research Biochemicals Inc (Natick, MA). Bradykinin and Genistein were dissolved in distilled water and were diluted to a final concentration in KHB or St. Thomas’ cardioplegia solution.

Statistical analysis
Data are presented as mean and standard error of the mean. One-way analysis of variance (ANOVA) was used for repeated measures and followed by the Student-Neumann-Keuls test for multiple pairwise comparisons (SigmaStat; SPSS, Inc, Chicago, IL). The paired t-test was used for within-group analysis to test for drug effects on functional parameters prior to ischemia. A p value less than 0.05 was considered statistically significant.

	Results

Top Abstract Introduction Material and methods Results Comment References

 
Preischemic cardiac function
There were no significant differences in baseline LV performance between group 1 (control hearts), group 2, and group 3 (bradykinin-pretreated hearts) (Figs 2 through 5). In group 2, 10 minutes of bradykinin infusion resulted in a significant increase in CF and slight increase in LVDP (Figs 2 and 6). In pilot studies (data not shown), administration of Genistein alone had no effect on LV performance or CF either before or after ischemia compared with untreated control hearts. In group 3, however, Genistein pretreatment prevented the increase in CF seen after bradykinin pretreatment alone (Fig 6).

View larger version (19K): [in this window] [in a new window]   Fig 2. Recovery of left ventricular developed pressure (LVDP). Bradykinin slightly increased LVDP during pretreatment and significantly improved recovery throughout the period of reperfusion. Genistein completely blocked the salutary effect of bradykinin pretreatment. Data points represent the mean ± the standard error of the mean. (BK = Bradykinin; Gen = Genistein.)

View larger version (17K): [in this window] [in a new window]   Fig 3. Recovery of left ventricular contractility (+dP/dt). Bradykinin pretreatment significantly improved the recovery of contractility compared with control hearts. Genistein prevented this recovery. Data points represent the mean ± the standard error of the mean. (BK = Bradykinin; Gen = Genistein.)

View larger version (17K): [in this window] [in a new window]   Fig 4. Recovery of left ventricular end diastolic pressure (LVEDP). LVEDP rose significantly in all hearts during ischemia and declined during reperfusion. LVEDP was significantly lower throughout reperfusion in Bradykinin-pretreated hearts. Genistein prevented this recovery. Data points represent the mean ± the standard error of the mean. (BK = Bradykinin; Gen = Genistein.)

View larger version (18K): [in this window] [in a new window]   Fig 5. Recovery of left ventricular compliance (-dP/dt). Bradykinin pretreatment significantly improved the recovery of compliance compared with control hearts. Genistein prevented this recovery. Data points represent the mean ± the standard error of the mean. (BK = Bradykinin; Gen = Genistein.)

View larger version (18K): [in this window] [in a new window]   Fig 6. Recovery of coronary flow (CF). Bradykinin increased CF during pretreatment and significantly improved its recovery throughout the period of reperfusion. Genistein completely blocked the salutary effect of bradykinin pretreatment. Data points represent the mean ± the standard error of the mean. (BK = Bradykinin; Gen = Genistein.)

Postischemic recovery of diastolic function
The continuous recovery of LVEDP and -dP/dt_max in the three study groups are presented in Figures 4 and 5, respectively. LVEDP remained at baseline level in all groups during the stabilization and pretreatment intervals. During cardioplegic ischemia,LVEDP rose significantly in all groups and then gradually declined during the 60-minute period of reperfusion. Ventricular compliance, as measured by -dP/dt_max, showed a gradual rise during reperfusion.

Bradykinin pretreatment in group 2 hearts significantly improved the recovery of both LVEDP and -dP/dt_max throughout the reperfusion period compared with the group 1 control hearts. At 60 minutes of reperfusion, group 2 hearts had a significantly lower LVEDP (28 ± 3 vs 52 ± 5 mm Hg, p < 0.01) and a higher -dP/dt_max (669 ± 60 vs 368 ± 65 mm Hg/s, p < 0.05) then group 1 hearts. In group 3, Genistein prevented the salutary effect of bradykinin on the recovery of diastolic ventricular function. At 60 minutes of reperfusion, LVEDP (47 ± 4 vs 52 ± 5 mm Hg) and -dP/dt_max (450 ± 50 vs 368 ± 65 mm Hg/s) did not differ between group 3 hearts and group 1 control hearts.

Postischemic recovery of vascular function
Figure 6 shows the profile for the recovery of CF in the three groups. Bradykinin pretreatment improved the recovery of CF throughout the entire period of reperfusion. At the end of 60 minutes of reperfusion, the recovery of CF was significantly enhanced in group 2 bradykinin-pretreated hearts, compared with group 1 control hearts. Pretreatment of group 3 hearts with Genistein eliminated the effects of bradykinin on the recovery of CF throughout the entire period of reperfusion. There were no significant differences in the recovery of CF at the end of 60 minutes of reperfusion between group 3 and group 1 hearts.

	Comment

Top Abstract Introduction Material and methods Results Comment References

 
This study was designed to simulate the clinical problem of inadequate myocardial protection leading to depression of postoperative ventricular function. We chose a period of 50 minutes of warm cardioplegic ischemia based on pilot studies, which demonstrated that a single dose of 37°C St. Thomas’ cardioplegia solution resulted in significant myocardial depression after this duration of ischemia. The results of the present study demonstrate that pretreating the heart with bradykinin before 50 minutes of cardioplegic ischemia with bradykinin-enriched cardioplegia solution significantly improved postischemic ventricular function compared with untreated control hearts. Our results suggest that pretreating the heart with bradykinin improved postreperfusion ventricular function by activating molecular pathways that require activation of protein TK. When we pretreated hearts with a specific inhibitor of this TK, Genistein, the benefit of bradykinin pretreatment was lost. These pathways may be the same as those activated during ischemic preconditioning.

Cardioprotective effects of bradykinin
Bradykinin is a member of a family of kinins that are peptides released by the myocardium during ischemia [10], and it is activated by cleavage from a precursor peptide catalyzed by the enzyme kallikrein. The heart has an intrinsic kallikrein-kinin system that under normal circumstances produces very low concentrations of bradykinin in the plasma. Active bradykinin is rapidly degraded (< 15 seconds), principally by kininase II, which is the same enzyme as angiotensin-converting enzyme (ACE) [11].

Bradykinin exerts several cardioprotective effects, including an increase in coronary blood flow [12], an improvement in ventricular performance [8], a decrease in reperfusion arrhythmias [9], a reduction in lactate dehydrogenase and creatine kinase release [13], a reduction in tissue ATP depletion [13], and a reduction in infarction size. These beneficial effects occur via stimulation of the bradykinin B₂ receptor [14]. Bradykinin may also play an important role in protecting the human heart from ischemia. ACE inhibitors reduce infarct size and mortality associated with myocardial ischemia [11, 15] by increasing the level of bradykinin in coronary sinus blood [16].

There is accumulating evidence that bradykinin improves myocardial tolerance to ischemia through molecular mechanisms associated with ischemic preconditioning. Bradykinin occupancy of the B₂ receptor results in G-protein-linked activation of phospholipase C (PLC), generation of diacylglycerol (DAG), and activation of protein kinase C (PKC) [17]. These observations suggest that bradykinin works using a signal transduction pathway similar to that associated with ischemic preconditioning.

Proposed molecular mechanisms of bradykinin pretreatment
Figure 7 outlines the proposed molecular mechanisms involved in bradykinin pretreatment that lead to myocardial preconditioning. Downey and others [18, 19] have demonstrated that several mediators, including adenosine and bradykinin, trigger preconditioning in the rabbit heart by a receptor-mediated process. After the adenosine receptor is activated, an intracellular signal transduction cascade is initiated. In the rabbit, studies suggest that the initial step in the signal transduction cascade requires activation of the PKC family of serine-threonine kinases [13]. Discrete PKC isoforms translocate from the cytosol to the cell membrane after ischemic preconditioning, resulting in PKC activation [4]. Activated PKC in turn phosphorylates downstream substrate proteins that propagate the intracellular signal, resulting in enhanced resistance to myocardial ischemia.

View larger version (11K): [in this window] [in a new window]   Fig 7. Proposed molecular mechanisms involved in bradykinin pretreatment. Solid arrows refer to pathways requiring protein tyrosine kinase (TK) activation. Dashed arrows refer to alternative pathways involving protein kinase C (PKC). (Perpendicular lines = inhibition; MAP kinase = p38MAP kinase; KATP = ATP-sensitive potassium channel.)

Propagation of the signal beyond PKC and TK appears to involve activation of the discrete mitogen-activated protein kinase called p38MAP-kinase [22, 23]. Activated p38MAP kinase phosphorylates several substrates including transcription factors and other kinases that in turn phosphorylate the end-effectors of the preconditioning stimulus [23].

Limitations of study
To determine the molecular mechanism responsible for a physiologic response, one can use either a pharmacologic inhibitor of the pathway of interest, assay the activity of the stimulated enzyme itself or measure its end product. We utilized the pharmacologic inhibitor method because, it allowed us to measure in vivo changes in ventricular function. However, this method can be problematic if the inhibitor is nonspecific for the enzyme under evaluation. Genistein is the most specific inhibitor of TK that is widely available. Studies that will quantify TK activation after bradykinin pretreatment are ongoing in our laboratory.

Many pharmacologic agents that have been associated with induction of preconditioning, including adenosine and bradykinin, result in vasodilatation and an increase in coronary flow. This could lead one to the conclusion that the salutary effect of bradykinin pretreatment in the present study was due to the increase in coronary flow alone (the Gregg phenomenon). Other investigators have shown that administration of bradykinin in concentrations below that which cause vasodilatation still reduced infarct size and enzyme release in models of regional ischemia [13, 24].

Conclusions
Bradykinin pretreatment of the heart may be an important addition to our standard cardioplegic methods of myocardial protection. In addition, pharmacologic preconditioning may be an important new adjunct during minimally invasive revascularization of the heart because regional ischemia often cannot be avoided during those procedures. By identifying the molecular mechanisms responsible for preconditioning, more potent pharmacologic preconditioning agents will likely become available.

	Acknowledgments

 
This research project was supported in part by the Sklarow Foundation Trust and by the Children’s Heart Foundation.

	References

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This Article Abstract Full Text (PDF) 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): Eliot R. Rosenkranz Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Feng, J. Articles by Rosenkranz, E. R. Search for Related Content PubMed PubMed Citation Articles by Feng, J. Articles by Rosenkranz, E. R.