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Ann Thorac Surg 2000;70:2119-2124
© 2000 The Society of Thoracic Surgeons

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Original article: cardiovascular

Bradykinin protects the rabbit heart after cardioplegic ischemia via NO-dependent pathways

^a Division of Cardiothoracic Surgery, Daughtry Family Department of Surgery, University of Miami School of Medicine, Miami, Florida, USA

Accepted for publication May 7, 2000.

Address reprint requests to Dr Rosenkranz, Division of Cardiothoracic Surgery, Jackson Memorial Hospital, PO Box 016960 (R-114), Miami, FL 33101
e-mail: erosenkr{at}med.miami.edu

Presented at the Seventy-fourth Annual Meeting of the American Heart Association, Atlanta, GA, November 7–9, 1999.

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. Depressed myocardial performance is an important clinical problem after open heart surgery. We hypothesized pretreating with bradykinin would pharmacologically precondition the heart and improve postischemic performance, and induce myocardial preconditioning by activating nitric oxide synthase.

Methods. Thirty-three rabbit hearts underwent retrograde perfusion with Krebs-Henseleit buffer (KHB) followed by 50 minutes 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 µMol/L bradykinin-enriched KHB and cardioplegic arrest with 0.1 µMol/L bradykinin-enriched StTCP. Six other hearts received 0.1 µMol/L HOE 140, a selective B2 receptor antagonist, added to both the 0.1 µMol/L bradykinin-enriched KHB and 0.1 µMol/L bradykinin-enriched StTCP solutions. Finally, six other hearts received 100 µMol/L of N--nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase, added to both the 0.1 µMol/L bradykinin-enriched KHB and 0.1 µMol/L bradykinin-enriched StTCP solutions.

Results. Bradykinin pretreatment significantly improved postischemic performance and coronary flow (CF) compared with control (LVDP: 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). Both HOE 140 and L-NAME abolished bradykinin-induced protection, resulting in recovery equivalent to untreated controls.

Conclusions. Bradykinin pretreatment improves recovery of ventricular and coronary vascular function via nitric oxide-dependent mechanisms. Pharmacologic preconditioning by bradykinin pretreatment may be an important new strategy for improving myocardial protection during heart surgery.

	Introduction

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Postreperfusion depression of myocardial performance remains an important cause of postoperative morbidity and mortality after open heart operations that require a period of elective cardioplegic arrest. 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. Although the molecular mechanisms responsible for ischemic preconditioning are incompletely understood, induction of the preconditioned state by pharmacologic agents may be an important strategy for reducing myocardial dysfunction after cardioplegic arrest. Several mediators released from the ischemic myocardium during ischemia and reperfusion, including adenosine [2] and bradykinin [3, 4], can induce the preconditioned state when given exogenously before a period of prolonged ischemia.

The mechanism by which bradykinin protects the heart from ischemia is controversial. Studies from our laboratory [5] have shown that pretreating the heart with bradykinin before a period of cardioplegic ischemic arrest induced pharmacologic preconditioning and improved postreperfusion myocardial function via molecular pathways that required the activation of both tyrosine kinase and protein kinase C. Bradykinin B2 receptor activation in vascular endothelial cells and in myocytes also results in nitric oxide (NO) generation due to activation of the endothelial and inducible isoforms of nitric oxide synthase (NOS), respectively [6]. NO generated during ischemic preconditioning has been shown to reduce the incidence of ischemia and reperfusion-associated arrhythmias [7] and is associated with triggering the induction of the late form of ischemic preconditioning [8] via molecular pathways that involve activation of specific protein kinase C (PKC) isoforms [9]. This study tests the hypotheses that bradykinin pretreatment of the heart activates the bradykinin B2 receptor and induces the preconditioned state of the rabbit heart via molecular pathways that involve generation of NO, which can be prevented by pretreatment with an inhibitor of NOS. This may be the triggering mechanism for the subsequent activation of PKC and tyrosine kinase, resulting in myocardial preconditioning after bradykinin pretreatment.

	Material and methods

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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 (Radnotti Glass Technology, Inc, Monrovia, CA). The heart was retrogradely perfused at 75 mm Hg with a modified Krebs-Henseleit buffer (KHB) with the following composition (mMol/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-µ 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 (CF, 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 LV end diastolic pressure (LVEDP) of 10 mm Hg during measurement of baseline LV performance. This same balloon volume was used for subsequent measurements of LV performance after reperfusion. LV performance was assessed by measurement of LV developed pressure (LVDP, mm Hg) and LV end-diastolic pressure (LVEDP, mm Hg). The maximum positive and negative first derivatives of LVDP (+dP/dt_max and -dP/dt_max, mm Hg/s) were calculated as indices of ventricular contractility and compliance, respectively. Analog pressure data from the LV balloon was 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 LV performance. Hearts failing to generate a LVDP >80 mm Hg, or a CF >25 mL/min during the stabilization phase of the experiment were excluded from further study.

View larger version (26K): [in this window] [in a new window]   Fig 1. Protocol. All hearts received a 20-minute period of pretreatment before 50 minutes of normothermic cardioplegic arrest. After 60 minutes of reperfusion, recovery of LV performance and CF was recorded. See Material and Methods for details. (STCP = St. Thomas’ cardioplegia solution.)

All hearts then underwent 50 minutes of cardioplegic arrest induced with a single dose of St. Thomas’ cardioplegia solution of the following composition (mMol/L): NaCl 110, KCl 16, MgCl₂ 16, CaCl₂ 1.5, NaHCO₃ 10, and glucose 10. The cardioplegia solution was then gassed with 95% O₂ and 5% CO₂, and the pH was adjusted to pH 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. Control hearts received unmodified cardioplegia solution. Bradykinin-pretreated hearts received 0.1 µMol/L bradykinin-enriched cardioplegia solution. Bradykinin + HOE 140-pretreated hearts received 0.1 µMol/L bradykinin-enriched cardioplegia solution, which also contained 0.1 µMol/L HOE 140. Finally, bradykinin + L-NAME-pretreated hearts received 0.1 µMol/L bradykinin-enriched cardioplegia solution, which also contained 100 µMol/L L-NAME. At the conclusion of the 50-minute ischemia period, all hearts were reperfused with 37°C 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 Co (St. Louis, MO). HOE 140 and L-NAME were purchased from Research Biochemicals Inc. (Natick, MA). Bradykinin, HOE 140, and L-NAME were dissolved in distilled water and were diluted to their final concentration in KHB or St. Thomas’ cardioplegia solution.

Statistical analysis
Data are presented as mean ± standard error of the mean. One-way analysis of variance (ANOVA) was used for repeated measures and was 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 before ischemia. A p value of less than 0.05 was considered statistically significant.

	Results

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Preischemic cardiac function
There were no significant differences in baseline LV performance between any of the groups. In BK-pretreated hearts, the 10-minute infusion of bradykinin resulted in a significant increase in CF and slight increase in LVDP (Figs 2, 3). In BK + HOE-pretreated hearts, the 10-minute infusion of HOE 140 completely prevented the bradykinin-induced increase in LVDP and CF. In BK + L-NAME-pretreated hearts, 10 minutes of administration of L-NAME alone both reduced basal CF (from 42.5 ± 3.3 to 35 ± 4.7 mL/min, p < 0.05) and prevented the bradykinin-induced increase in CF and LVDP (Figs 2, 3).

View larger version (23K): [in this window] [in a new window]   Fig 2. LV developed pressure. Bradykinin-treated hearts had significantly better recovery of LVDP during reperfusion compared with control hearts. Pretreatment with HOE 140 or L-NAME blocked the beneficial effect of BK pretreatment.

View larger version (23K): [in this window] [in a new window]   Fig 3. CF. Pretreatment with bradykinin caused a slight increase in CF before ischemia. During reperfusion, BK hearts had significantly higher CF than control hearts. Pretreatment with HOE 140 or L-NAME blocked the beneficial effect of BK pretreatment.

View larger version (34K): [in this window] [in a new window]   Fig 4. LV contractility. Bradykinin-treated hearts had significantly better recovery of contractility than control hearts. Pretreatment with HOE 140 or L-NAME blocked the benefit of bradykinin pretreatment.

View larger version (25K): [in this window] [in a new window]   Fig 5. LV end diastolic pressure. Although LVEDP rose in all hearts during ischemia, bradykinin-treated hearts had significantly lower LVEDP at the end of reperfusion compared with control hearts. Pretreatment with HOE 140 or L-NAME blocked the beneficial effect of BK pretreatment.

View larger version (38K): [in this window] [in a new window]   Fig 6. LV compliance. Bradykinin-treated hearts had significantly better recovery of compliance than control hearts. Pretreatment with HOE 140 or L-NAME blocked the benefit of bradykinin pretreatment.

Postischemic recovery of vascular function
Figure 3 shows the recovery of CF after 60 minutes of reperfusion in the four 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 greater in bradykinin-pretreated hearts compared with control hearts. Pretreatment with HOE 140 or L-NAME 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 BK + HOE, BK + L-NAME and control hearts.

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
The results of this study demonstrate that pretreating the heart with bradykinin before 50 minutes of cardioplegic ischemia with bradykinin-enriched cardioplegia solution significantly improved the recovery of postischemic ventricular function compared with that seen in untreated control hearts. The benefits of bradykinin pretreatment were completely prevented by the coadministration of HOE 140, indicating that bradykinin-induced protection was mediated by the bradykinin B2 receptor. Finally, our results demonstrate that bradykinin triggered preconditioning via molecular pathways that require generation of NO by activation of NOS. When hearts were pretreated with an inhibitor of NOS, L-NAME, the benefit of bradykinin pretreatment was lost.

Cardioprotective effects of bradykinin
Previous studies from our laboratory and by others [3–6] have demonstrated that the administration of bradykinin before regional or global ischemia improved postischemic recovery of systolic and diastolic ventricular function, reduced myocardial enzyme leakage [5], attenuated the severity of reperfusion arrhythmias [6], and limited infarct size [10]. These benefits of bradykinin pretreatment in animals mimic those associated with ischemic preconditioning against infarction, and bradykinin is among the mediators responsible for inducing ischemic preconditioning in the rat, rabbit, dog, and pig [3, 4, 7, 11]. Recent clinical studies have shown that bradykinin improves ischemia tolerance in patients undergoing angioplasty [12] and is the probable mediator responsible for the reduction in infarct size and mortality in patients with myocardial ischemia who are treated with ACE inhibitors [13–15]. The results of the present study extend these observations by demonstrating that bradykinin pharmacologic preconditioning combined with hyperkalemic cardioplegia is a new strategy to reduce postischemic myocardial dysfunction after open heart surgical procedures.

Proposed molecular mechanisms of bradykinin preconditioning
In the myocyte, bradykinin occupancy of the B2 receptor results in G-protein-linked activation of phospholipase C, generation of diacylglycerol, and activation of PKC. Previous studies from our laboratory have demonstrated that the subsequent molecular steps in the signal transduction pathways resulting in the preconditioned state after bradykinin pretreatment also require activation of tyrosine kinase (TK) and the ATP-sensitive potassium channel [5, 16]. These same molecular pathways have also been shown to be activated in models of early and late ischemic preconditioning [9, 17].

In vascular endothelial cells and myocytes, bradykinin activates constitutive (endothelial) NO synthase (eNOS), resulting in generation [15, 18]. In an elegant series of studies using a model of late ischemic preconditioning, Bolli and associates [8, 9, 19, 20] suggested that NO is a required mediator of ischemic preconditioning and is responsible for activating the more distal signal transduction pathways leading to the preconditioned state. Bolli [8], Jones [21], and Takano [19] and associates demonstrated that the initial ischemic preconditioning stimulus results in release of NO via activation of eNOS. NO reacts with reactive oxygen species, such as oxygen radical, formed during reperfusion of ischemic myocardium, which then combine to generate peroxynitrite. Pretreatment of the heart with NOS inhibitors or oxygen radical scavengers blocked early and late preconditioning. Subsequent studies by Ping and associates [9] and Bolli and associates [22] have shown that NO, reactive oxygen species, and peroxynitrite induce the translocation and activation of PKC, which we have also found to play a critical role in the preconditioning signal transduction pathway [23]. The protective effects of late preconditioning are then amplified by activation of the TK-dependent signal cascade, which results in activation of iNOS gene product as evidenced by an increase in iNOS mRNA [21, 24].

The results of the present study demonstrate that the beneficial effects of bradykinin pretreatment of the heart before a prolonged period of global ischemia are also mediated via NO, presumably produced by activation of eNOS. In previous studies, we demonstrated that bradykinin’s protective effects are also dependent upon the activation of both PKC and TK [5]. As shown in Figure 7, we believe that bradykinin pretreatment results in activation of eNOS and generation of NO. NO then may act as second messenger between the vascular endothelium and the myocyte, resulting in activation of the PKC- and TK-dependent signal transduction pathway leading to the preconditioned state. Coadministration of L-NAME blocked NO generation, which prevented activation of the proposed protective mechanisms.

View larger version (24K): [in this window] [in a new window]   Fig 7. Proposed molecular mechanisms. BK activates eNOS via the bradykinin B2 receptor, resulting in the production of NO. NO then activates the signal transduction cascade, leading to early and late preconditioning by forming reactive oxygen species (ROS). ROS activate discrete PKC isoforms, leading to opening of the ATP-sensitive potassium (KATP) channel and induction of the early preconditioned state. Simultaneously, inducible NOS (iNOS) is activated and iNOS mRNA transcripts are produced by the activation of nuclear factors such as NFB, resulting in "amplification" of the signal transduction cascade, leading to the late preconditioned state. HOE 140 can block these signal transduction pathways by preventing the activation of the bradykinin B2 receptor. L-NAME can block these pathways by preventing activation of both eNOS and iNOS.

Conclusions
This study demonstrates that bradykinin pretreatment before prolonged surgical ischemia improves ventricular functional and vascular recovery via molecular pathways that require NOS activation. Further animal and clinical studies will be required to determine the appropriate dosage and clinical safety of bradykinin pretreatment. However, the dosage used in the present study (approximately 5 µg/min) was similar to that used clinically by Leesar [12] in angioplasty patients (2.5 µg/min). Pharmacologic preconditioning of the heart by bradykinin pretreatment may become an important addition to our current methods of myocardial protection with potassium cardioplegia and may be an important adjunct during minimally invasive revascularization of the heart because regional ischemia often cannot be avoided during these procedures.

	Acknowledgments

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

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

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments 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.