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Ann Thorac Surg 2005;79:911-916
© 2005 The Society of Thoracic Surgeons

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Original article: Cardiovascular

Bradykinin Preconditioning Preserves Coronary Microvascular Reactivity During Cardioplegia–Reperfusion

Division of Cardiothoracic Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts

Accepted for publication September 2, 2004.

^* Address reprint requests to Dr Sellke, Division of Cardiothoracic Surgery, BIDMC, LMOB 2A, 110 Francis Street, Boston, MA 02215 (E-mail: fsellke{at}caregroup.harvard.edu).

	Abstract

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
BACKGROUND: Alterations of microvascular reactivity reduce myocardial perfusion after ischemic cardioplegia. We hypothesized that bradykinin preconditioning (BKPC) would preserve endothelium-dependent microvascular responses and improve myocardial function after cardioplegic ischemia–reperfusion.

METHODS: Rabbit hearts were perfused with Krebs-Henseleit buffer (KHB). The hearts were arrested for 60 minutes with moderately cold (25°C) crystalloid cardioplegia (MCCP, n = 8) or with cold (0° to 4°C) crystalloid cardioplegia (CCCP) (n = 6). The BKPC hearts received a 10-minute coronary infusion of 10^–8 M BK-enriched KHB, followed by a 5-minute recovery period, and then were arrested for 60 minutes with MCCP (BKPC + MCCP, n = 8) or with CCCP (BKPC + CCCP, n = 6). The hearts were reperfused for 30 minutes with KHB. Six control hearts were perfused with KHB for 90 minutes without cardioplegia-ischemia. Left ventricle performance was measured, and in vitro relaxation responses of precontracted coronary arterioles (internal diameter, 80 to 150 µm) were obtained in a pressurized no-flow state.

RESULTS: Ischemic arrest with MCCP or CCCP markedly reduced endothelium-dependent relaxation to adenosine 5'-diphosphate, substance P, and calcium ionophore (A23187). Both MCCP and CCCP significantly enhanced contractile responses to U46619 (10^–7 M), a thromboxane A₂ analogue, compared with control (p < 0.05). In contrast, BKPC significantly improved the recovery of endothelium-dependent relaxation to adenosine 5'-diphosphate, substance P, and A23187 compared with MCCP or CCCP, respectively. BKPC reduced the contractile responses to U46619 compared with MCCP or CCCP. BKPC also improved postischemic performance compared with MCCP or CCCP alone (p < 0.05).

CONCLUSIONS: BKPC preserves endothelium-dependent microvascular responses and prevents the hypercontractility to U46619. These effects may provide increased coronary perfusion and prevent arteriolar spasm after open heart surgery. They suggest that BK preconditions the coronary microvasculature during cardiovascular surgery.

	Introduction

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Ischemic preconditioning (IPC) has been defined as an adaptive mechanism induced by a brief period of nonlethal ischemia–reperfusion (IR) increasing the heart's resistance to a subsequent ischemia [1]. The protective effects of IPC have been demonstrated in all animal species including humans, resulting in the endogenous form of protection against infarct size, cardiac dysfunction, and arrhythmias [1–5]. We, and others, have found that IPC protects coronary microvessels against endothelial dysfunction and preserves normal microvascular regulation [6–8].

Although the molecular mechanisms responsible for IPC are incompletely understood, the induction of the preconditioned state by pharmacologic agents may be an important strategy for reducing myocardial dysfunction after cardioplegic arrest [9–11]. Several triggers or mediators released from the ischemic heart during IR, including adenosine, bradykinin (BK), and nitric oxide (NO), can induce the preconditioned state when given exogenously before a period of prolonged ischemia [3, 4, 12–15].

Recent investigations have shown that BK pretreatment improves recovery of left ventricular (LV) function after normothermic ischemia and reperfusion [16–18]. These observations suggest that pharmacologic BKPC may be an important new strategy for improving myocardial protection during heart surgery. The present study tested the hypotheses that pharmacologic BKPC would also preserve microvascular responses and improve endothelial function after a period of cardioplegic ischemia in an isolated rabbit heart preparation.

	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 (National Institutes of Health publication No.5377-3 1996). The Institutional Animal Care and Use Committee of Beth Israel Deaconess Medical Center and Harvard Medical Area Standing Committee approved the protocols used in this study.

New Zealand white rabbits (1.5 to 2.5 kg) were used in this study (Millbrook Farm, Amherst, MA). Rabbits were anesthetized with ketamine (35 mg/kg) and xylazine (2.5 mg/kg, intramuscularly) and anticoagulated with heparin (2000 U/kg, intravenously). The heart was rapidly exposed, the aorta was cannulated, and the heart was retrogradely perfused in situ to avoid ischemia.

The heart was excised and mounted in an organ chamber on a Langendorff perfusion system. The heart was retrogradely perfused at 70 mm Hg with a modified Krebs-Henseleit buffer (KHB) composed of 118 mmol/L NaCl , 25 mmol/L NaHCO₃, 1.2 mmol/L KHPO₄, 4.7 mmol/L KCl, 1.2 mmol/L MgSO₄, 1.8 mmol/L CaCl₂, and 11.0 mmol/L 11.0 glucose. 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). The right ventricular myocardial temperature was measured with a thermistor needle probe (Mallinckrodt, Inc, St. Louis, MO) and was maintained at 37°C during the periods of KHB perfusion and reperfusion by regulation of the organ chamber temperature. Our Langendorff apparatus permits instantaneous change of the perfusion fluids from standard KHB to one containing different pharmacologic substances or cardioplegia solution by adjusting an inlet valve to the aortic perfusion cannula.

Measurements
Isovolumetric measurement of LV performance was made using a compliant latex balloon connected to a pressure transducer that was inserted in the 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 5 mm Hg during the measurement of the 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 systolic pressure (LVSP) and LVEDP. LV developed pressure (LVDP) = LVSP – LVEDP. Positive and negative first derivatives of LVSP (+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 amplified and converted to a digital signal for on-line data recording and computation (Gould-PONEMAN, Gould, Valley View, OH). Continuous pressure measurements were sampled at specific time points in each experiment. Coronary flow (mL/min) was measured by the timed collection of effluent from the right ventricle exiting the heart from the severed pulmonary artery. Hearts that failed to generate a LVDP greater than 80 mm Hg or a coronary flow of less than 25 mL/min during the stabilization phase of the experiment were excluded from further study.

Experimental Protocols
After 30 minutes of equilibration, the hearts were divided into three groups. Six hearts (control group) were further buffer-perfused for 60 minutes without cardioplegic ischemia. In crystalloid cardioplegia (CCP) groups, the hearts were arrested for 60 minutes with moderately cold (25°C) CP (MCCP, n = 8) or with cold (0° to 4°C) CP (CCCP, n = 6). MCCP or CCP was reinfused every 20 minutes during 60 minutes of hypothermic ischemia. In BKPC groups, eight hearts received a 10-minute coronary infusion of 10^–8 M BK-enriched KHB, followed by a 5-minute recovery period and then were arrested for 60 minutes with MCCP (BKPC + MCCP, n = 8) or CCCP (BKPC + CCCP, n = 6). The hearts from MCCP, CCCP, BKPC + MCCP, and BKPC + CCCP groups were reperfused for 30 minutes with KHB. The composition of the crystalloid cardioplegic solution was 121 mmol/L NaCl, 25 mmol/L KCl, 12 mmol/L NaHCO₃, and 11.1 mmol/L glucose. The pH was 7.6, and the partial pressure of oxygen range was 180 to 300 mm Hg.

After 60 minutes of cardioplegia arrest, the hearts were reperfused for 30 minutes with KHB. In all groups, the hearts were excised and one piece of LV tissue was immersed in cold KHB buffer for in vitro microvessel study.

In Vitro Coronary Microvessel Studies
Coronary artery microvessels (80 to 150 µm in internal diameter) from the LV free wall were dissected under a x10 to 60 magnification microscope (Olympus Optical, Tokyo, Japan). Microvessels were placed in a microvessel chamber, cannulated with dual glass micropipettes (40 to 80 µm in diameter), and secured with 10-0 nylon monofilament sutures (Ethicon, Inc, Somerville, NJ). Oxygenated (95% oxygen and 5% carbon dioxide) KHB warmed to 37°C was continuously circulated through the microvessel chamber and a 100-mL reservoir.

The vessels were pressurized to 40 mm Hg in a no-flow state by using a burette manometer filled with KHB. With an inverted microscope (x40 to 200 magnification, Olympus CK2, Olympus Optical) connected to a video camera, the vessel image was projected onto a television monitor. An electronic dimension analyzer (Living System Instrumentation, Burlington, VT) was used to measure the internal lumen diameter and wall thickness. Vessels were allowed to bathe in the organ chamber for at least 30 minutes before a pharmacologic intervention.

Microvessel Study Protocols
After equilibration in the organ chamber, the coronary microvessels were constricted with U46619 (1 µmol/L) by 30% to 50% of the baseline diameter. Once the steady-state tone was reached, the dose responses to sodium nitroprusside (SNP) (1 nmol/L to 100 µmol/L), adenosine 5'-diphosphate (ADP) (1 nmol/L to 100 µmol/L), substance P (1 pmol/L to 100 µmol/L), or calcium ionophore (A23187) (1 nmol/L to 100 µmol/L) were ascertained extra-luminally. Drugs were administered in a random order except for A23187, which was always tested last. The dose response to substance P was examined only once in each vessel to avoid tachyphylaxis. One to four interventions were performed on each vessel. The vessels were washed 3 times with KHB and allowed to equilibrate in drug-free buffer for 15 to 30 minutes between interventions.

Drugs
U46619, SNP, ADP, substance P, and A23187 were obtained from Sigma Chemical (St. Louis, MO). SNP, ADP, and substance P were dissolved in ultra-pure distilled water and prepared on the day of the study. U46619 was dissolved in ethanol to make a stock solution. A23187 was dissolved in dimethylsulfoxide to make a stock solution. All stock solutions were stored at –20°C. All dilutions were prepared daily.

Data Analysis
Data are presented as the mean and standard of deviation (mean ± SD) or the standard error of the mean (mean ± SEM). The relaxation responses were expressed as the percentage of relaxation of the U46619-preconstricted diameter of the microvessels. The dose–response curves of all experimental groups were compared using two-way analysis of variance with a repeated-measures design, followed by the Student-Newman-Keuls test (SigmaStat, Systat Software, Inc, Point Richmond, CA). Statistical significance was taken at a p value of less than 0.05. The paired Student t test was used to compare changes in hemodynamic variables after reperfusion between groups.

	Results

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Hemodynamics
The baseline LV performance before ischemia did not differ significantly among any of the groups. Ten minutes of BK 10^–8 M infusion induced a slight but not significant increase in coronary flow (37 ± 7 mL/min in BKPC + MCCP group vs 35 ± 5 mL/min of baseline, 38 ± 9 mL/min in BKPC + CCCP group vs 36 ± 5 mL/min of baseline). LVDP and ±dP/dt_max were not changed during BK coronary infusion. In the moderate cold (25°C) groups, there were no significant differences in the recoveries of LVDP and +dP/dt_max between BKPC + MCCP and MCCP hearts (Table 1). There were significant differences in the recoveries of –dP/dt_max (p < 0.05) and coronary flow (p < 0.05) (Table 1) between BKPC and MCCP hearts. In cold (0° to 4°C) groups, BKPC significantly improved the recoveries of LVDP (p < 0.05), +dP/dt_max (p < 0.01), –dP/dt_max (p < 0.01), and coronary flow (p < 0.05) compared with CCCP alone (Table 1).

The percentage of contraction after the application of U46619 was 35% ± 6% in the control group, 41% ± 4% in the MCCP group, 37% ± 5% in BKPC + MCCP group, 44% ± 6% in CCCP group, and 38% ± 4% in BKPC + CCCP group. The mean concentrations required to obtain these percentages of contractions were 5 x 10^–6 mol/L in the control group, 1 x 10^–6 mol/L in the MCCP group, 3 x 10^–6 mol/L in the BKPC + MCCP group, 1 x 10^–6 mol/L in the CCCP group, and 3 x 10^–6 mol/L in the BKPC + CCCP group.

Endothelium-Independent and Endothelium-Dependent Relaxation
The endothelium-independent relaxation of coronary microvessels to SNP were similar among groups (Fig 1).

View larger version (17K): [in this window] [in a new window]   Fig 1. Response to sodium nitroprusside (SNP) in vitro of rabbit coronary microvessels from control hearts (n = 6, •) and hearts after 60 minutes of ischemic arrest using moderately cold (25°C) crystalloid cardioplegia (MCCP, n = 8, ) or cold (0° to 4°C) crystalloid cardioplegia (CCCP, n = 6, ), and bradykinin preconditioning (BKPC) with MCCP (BKPC + MCCP, n = 8, ) or CCCP (BKPC + CCCP, n = 6, *) followed by 30 minutes of reperfusion. The range bars represent mean ± SEM.

View larger version (17K): [in this window] [in a new window]   Fig 2. Response to adenosine 5'-diphosphate (ADP) in vitro of rabbit coronary microvessels from control hearts (n = 6, •) and hearts after 60 minutes of ischemic arrest using moderately cold (25°C) crystalloid cardioplegia (MCCP, n = 8, ) or cold (0° to 4°C) crystalloid cardioplegia (CCCP, n = 6, ), and bradykinin preconditioning (BKPC) with MCCP (BKPC + MCCP, n = 8, ) or CCCP (BKPC + CCCP, n = 6, *), followed by 30 minutes of reperfusion (*p < 0.05, BKPC + MCCP vs MCCP, or p < 0.05, BKPC + CCCP vs CCCP). The range bars represent mean ± SEM.

In contrast, BKPC significantly reduced the contractile responses to U46619 (14% ± 3% vs 28% ± 4% of contraction, p < 0.05). BKPC also reduced the contractile responses to U46619 compared with MCCP (14% ± 3% of BKPC + MCCP vs 28% ± 4% of MCCP; or 15% ± 2% in BKPC + CCCP vs 30% ± 4%, p < 0.05, respectively).

	Comment

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
BK is locally formed in the heart and elevated following IR, and the administration of exogenous BK exerts protective effects [12, 19]. Angiotensin-converting enzyme (ACE) inhibitors, which inhibit the degradation of BK, protect ischemic heart, and BK receptor antagonists reverse their beneficial effects [19–20]. BK has been considered as one of mediators for IPC [12–14, 21–22]. Previous studies have showed that pretreating the heart with BK before warm crystalloid cardioplegic ischemia significantly improves postischemic ventricular function [16–17].

The present study used a pharmacologic PC regimen with 10 minutes of 10^–8 M of BK infusion and 5 minutes of KHB before cold crystalloid cardioplegic ischemia and indicates that BK preconditions the rabbit heart against postischemic LV dysfunction. Although our results show that BKPC did not improve the recovery of LV contractility in the moderately hypothermic condition, it enhanced the recovery of LV compliance and vascular function.

Leesar and colleagues have shown that BK induces PC in patients undergoing coronary angioplasty 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 [15]. A recent clinical study has also indicated that an exogenous BK infusion immediately before the initiation of cardiopulmonary bypass limits myocardial injury in patients undergoing coronary artery bypass grafting [23].

It has been reported that BK between 10^–12 to 10^–6 M has beneficial effects in the ischemic myocardium [12–17]. In previous studies, 10^–7 M of BK was used in a warm ischemia model [16–17]. In the present study, 10^–8 M of BK, a moderate concentration, was used under a hypothermic ischemic preparation and this dosage is close to that used clinically in patients undergoing coronary angioplasty and coronary artery bypass grafting [15, 23].

The microcirculation is particularly vulnerable to the pathologic effects of IR [24]. Endothelial integrity is very important for adequate vasomotor reactivity of the coronary microcirculation, which is essential for appropriate perfusion–reperfusion of the myocardium [25]. Although many studies have shown that classic IPC protects myocardial cells, a number of recent studies have extended these observations to coronary microvascular endothelium. Defily and Chilian reported IPC reduces the endothelial dysfunction of coronary arterioles after IR in the intact beating heart [7]. Richard and colleagues claimed that IPC protects against endothelial dysfunction of small coronary artery induced by IR in the rat [8].

The results of our previous studies also found that IPC preserves endothelium-dependent relaxation of coronary arterioles and preserves ß-adrenergic signal transduction in swine coronary smooth muscle [6]. The major new finding in the present study is that BKPC mimics IPC, protects against coronary arteriolar vasoregulatory dysfunction, and may prevent vasospasm from IR injury. The improved microvascular regulation by BKPC may speculatively contribute to its increased coronary perfusion and LV performance.

Many laboratories have extensively investigated the molecular mechanism of BK-induced myocardial PC [4, 12–14, 16–18]. Feng and colleagues have proposed that BK pretreatment activates endothelial NO synthase and generates NO [16, 17], which then may act as second messenger between the vascular endothelium and the myocyte, resulting in the activation of protein kinase C [14, 18, 26], tyrosine kinase [16], phosphatidylinositol 3-kinase [16], and the opening of the K_ATP channel [27]. This cascade induces the heart in preconditioned state.

Oldenburg and colleagues recently claimed that in isolated rabbit cardiomyocyte, BK preconditions through receptor-mediated production of NO [28]. NO within the myocardial cell stimulates guanylyl cyclase, which leads to an increased level of cyclic guanosine monophosphate that in turn activates protein kinase G. The activated protein kinase G opens the mitochondrial K_ATP channel. Subsequent release of mitochondrial reactive oxygen species triggers cardioprotection. Thus, it can be speculated that BK-induced microvascular PC is possibly through the similar molecular pathways as BK-induced myocardial PC.

The vascular endothelium also plays a key role in the control of both leukocyte and platelet function. It has been reported that BK reduces IR-induced tissue injury by preventing leukocyte recruitment and preserving microvascular barrier function in the rat mesentery [29]. Furthermore, Shigematsu and colleagues indicate that BK pharmacologically preconditions single mesenteric postcapillary venules to resist IR-induced leukocyte recruitment and microvascular barrier dysfunction by a mechanism that involves B₂ receptor-dependent activation of nonconventional protein kinase C isotypes and subsequent formation of NO [30].

In conclusion, BKPC may be an important addition to our standard cardioplegic methods of microvascular protection. BKPC may provide increased coronary perfusion, prevent arteriolar spasm, and protect against increased endothelial dysfunction after open-heart surgery. In addition, pharmacologic PC of coronary microvasculature may be an important new adjunct during minimally invasive revascularization of the heart because microvascular dysfunction often cannot be avoided during those procedures.

View larger version (18K): [in this window] [in a new window]   Fig 3. Response to calcium ionophore (A23187) in vitro of rabbit coronary microvessels from control hearts (n = 6, •) and hearts after 60 minutes of ischemic arrest using moderately cold (25°C) crystalloid cardioplegia (MCCP, n = 8, ) or cold (0° to 4°C) crystalloid cardioplegia (CCCP, n = 6, ), and bradykinin preconditioning (BKPC) with MCCP (BKPC + MCCP, n = 8, ) or CCCP (BKPC+ CCCP, n = 6, *), followed by 30 minutes of reperfusion (*p < 0.05, BKPC + MCCP vs MCCP, or p < 0.05, BKPC + CCCP vs CCCP). The range bars represent mean ± SEM.

View larger version (20K): [in this window] [in a new window]   Fig 4. Response to substance P in vitro of rabbit coronary microvessels from control hearts (n = 6, •) and hearts after 60 minutes of ischemic arrest using moderately cold (25°C) crystalloid cardioplegia (MCCP, n = 8, ) or cold (0° to 4°C) crystalloid cardioplegia (CCCP, n = 6, ), and bradykinin preconditioning (BKPC) with MCCP (BKPC + MCCP, n = 8, ) or CCCP (BKPC + CCCP, n = 6, *), followed by 30 minutes of reperfusion (*p < 0.05, BKPC + MCCP vs MCCP, or p < 0.05, BKPC + CCCP vs CCCP). The range bars represent mean ± SEM.

	Acknowledgments

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	References

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