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J Thorac Cardiovasc Surg 1995;110:1047-1053
© 1995 Mosby, Inc.

CARDIOPULMONARY BYPASS, MYOCARDIAL MANAGEMENT, AND SUPPORT TECHNIQUES

CONSTITUTIVE NITRIC OXIDE RELEASE IS IMPAIRED AFTER ISCHEMIA AND REPERFUSION

Farmington, Conn., and Springfield, Mass.

Supported by grants HL 22559-14 and HL 34360-07 from the National Institutes of Health.

Received for publication Dec. 14, 1994. Accepted for publication March 24, 1995. Address for reprints: Daniel T. Engelman, MD, 7 Lincoln Ave., West Hartford, CT 06117.

Abstract

Myocardial ischemia and reperfusion may result in endothelial dysfunction and reduced release of nitric oxide. With the use of an amperometric sensor, the first direct measurements of constitutive nitric oxide release from a beating heart were measured from the coronary effluent of isolated working rat hearts subjected to ischemia and reperfusion. Rats, six to eight per group, were randomly studied as follows: control (no pretreatment) and pretreatment with the nitric oxide donor L–arginine (3 mmol/L), its enantiomer D–arginine (3 mmol/L), nitric oxide inhibitor N–nitro–L–arginine methyl ester (100µmol/L), and combined N–nitro–L–arginine methyl ester/L–arginine. Isolated hearts were pretreated for 10 minutes before 30 minutes of global ischemia and 30 minutes of reperfusion. A nonischemic control group (n = 4) was continuously perfused with oxygenated unsupplemented buffer. After ischemia/reperfusion, hearts supplemented with L–arginine recovered significantly (p <0.05) increased developed pressure, first derivative of the aortic pressure (dP/dt_max), and aortic flow compared with all other hearts that underwent ischemia/reperfusion. In addition, nitric oxide release was significantly (p <0.05) increased during reperfusion in the L–arginine group. During reperfusion, the recovery of aortic flow correlated with nitric oxide release (r = 0.81, p <0.0001). We conclude that after ischemia/reperfusion, endothelial dysfunction results in decreased nitric oxide release, which can be ameliorated with L–arginine pretreatment. The direct cytoprotective properties of nitric oxide may contribute to improved functional recovery in hearts pretreated with L–arginine. Augmentation of the L–arginine/nitric oxide pathway may provide a new approach for improved recovery after cardiovascular operations. (J THORAC CARDIOVASC SURG 1995;110:1047-53)

Endothelium–derived relaxing factor is a naturally occurring, continuously released, vasoactive agent that controls coronary vascular tone. ¹ Endothelium–derived relaxing factor, synonymous with nitric oxide (NO), is synthesized by the vascular endothelium through the conversion of L–arginine to L–citrulline by the enzyme NO synthase. ^2,3 Endothelial cells produce NO in response to a wide range of agonists, including norepinephrine, adenosine diphosphate, calcium ionophore, acetylcholine, and bradykinin. ⁴ NO synthesis can be inhibited by the selective inhibitor N–nitro–L–arginine methyl ester (L–NAME). ⁵ Indirect methods for monitoring NO generation, with the use of isolated coronary arteries and veins, have documented impaired endothelium–dependent vasorelaxation (a measure of NO synthesis) after myocardial ischemia and reperfusion. ^6,7 Further, reduced vasorelaxation can be attenuated, and myocardial injury thereby reduced, with supplemental L–arginine. ^8,9 However, in these models, the presence of NO has only been inferred on the basis of the physiologic effects of NO generation/inhibition, and misleading information may therefore be provided. ¹⁰

With the use of a porphyrinic sensor, it has recently beendemonstrated by direct measurements that the stimulated release of NO is impaired after myocardial ischemia associated with heterotopic rat heart transplantation. ¹¹ Because of the ubiquitous nature of NO, to our knowledge, the direct measurement of continuous basal NO release from beating hearts has not previously been reported. In this experiment an amperometric probe was used to monitor continuous constitutive NO release from a working heart. We hypothesized that after global ischemia and reperfusion, coronary vascular endothelial cell dysfunction would result in reduced constitutive NO release, and that this could be ameliorated by the administration of L–arginine before ischemia. We further examined the ability of L–arginine to preserve myocardial function after ischemia and reperfusion.

MATERIALS AND METHODS

Perfusion technique
Male Sprague–Dawley rats weighing 320 to 360 gm were anesthetized with an intraperitoneal injection of sodium pentobarbital (Nembutal 80 mg/kg) and with heparin (500 IU/kg) intravenously. All animals received humane care in compliance 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" prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH Publication No. 86-23, revised 1985). After thoracotomy, the hearts were excised and placed in ice–cold perfusion buffer. The aorta was then cannulated and the hearts were perfused by the Langendorff method at a constant perfusion pressure of 100 cm of water. ¹²

The perfusion medium consisted of a modified Krebs–Henseleit bicarbonate buffer (KHB) (millimolar concentration: NaCl 118, NaHCO₃ 24, KCl 4.7, KH₂PO₄ 1.2, MgSO₄ 1.2, CaCl₂ 1.7, and glucose 10) gassed with 95% O₂/5% CO₂ with a pH of 7.4 at 37° C. This solution was filtered through a 5 µm filter to remove any particulate contaminants. The pulmonary vein was then cannulated and the Langendorff perfusion discontinued. The preparation was then converted to the working heart mode, which is a preparation of the left side of the heart in which oxygenated KHB at 37° C enters the cannulated pulmonary vein and left atrium at a filling pressure of 17 cm H₂O. The perfusion fluid then passes to the left ventricle, from which it is ejected spontaneously through the aortic cannula against a pressure of 100 cm H₂O. Thus in this mode contractility and amounts of aortic and coronary flow could be measured. ¹³

Experimental design
The experimental protocol is shown in Fig. 1. All hearts were on the perfusion apparatus for a total of 75 minutes. After conversion to the working heart mode, the hearts (n = 36) were perfused for 5 minutes with KHB. Baseline contractile function was then measured. The nonischemic control group (NCON; n = 4) then had continuous Langendorff perfusion for 50 minutes followed by a 20-minute period of working perfusion. The other groups had Langendorff perfusion for 10 minutes with untreated KHB (ischemic control group), KHB supplemented with L–arginine 3 mmol/L (Sigma Chemical Co., St. Louis, Mo.), its enantiomer, D–arginine 3 mmol/L (Sigma), L–NAME 100 µm/L (Sigma), or L–NAME 100 µm/L plus L–arginine 3 mmol/L. Normothermic global ischemia was then instituted by clamping the aortic and atrial cannulas. The animals were randomly assigned into groups as follows: ischemic control (CON; n = 8), L–arginine plus ischemia (L–ARG; n = 6), D–arginine plus ischemia (D–ARG; n = 6), L–NAME plus ischemia (L–NAME; n = 6), and L–NAME/L–arginine plus ischemia (L–ARG/L–NAME; n = 6). After 30 minutes of global ischemia, hearts were reperfused with oxygenated KHB at 37° C via the Langendorff method for 10 minutes, then converted to the working mode for 20 minutes. Contractile function values were obtained after 10 and 20 minutes of working heart reperfusion.

View larger version (19K): [in this window] [in a new window]   Fig. 1. Schemata of experimental protocol for nonischemic control hearts (NCON), ischemic control hearts (CON), and experimental hearts pretreated with L-arginine, D-arginine, and L-NAME. Myocardial function (dP/dtmax,developed pressure, aortic flow, coronary flow, and heart rate) were measured at baseline and at 20 and 30 minutes of reperfusion. NO levels were measured during working perfusion (W-P) at baseline and during 10 to 30 minutes of reperfusion. L-P, Langendorff perfusion.

2NaNO₂ + 2KI + 2H₂SO₄ + 2K₂SO₄2NO

+ I₂ + 2H₂O + 3K₂SO₄ + Na₂SO₄

A typical calibration curve is seen in Fig. 2. NO calibration was always linear (r 0.99). After heart isolation and initiation of working perfusion, the NO probe was placed into the right atrial chamber to continuously measure NO in the coronary effluent. NO was measured only while the hearts were in the working mode (before and after ischemia) to eliminate potential flow differences between working and Langendorff perfusion.

View larger version (26K): [in this window] [in a new window]   Fig. 2. Representative relationship between NO concentration and output current of electrode (linear regression analysis).

Statistical analysis
The values for myocardial function and NO release are expressed as the mean plus or minus the standard error of the mean. A two–way analysis of variance (Scheffe's) was first done to test for any differences between groups. If differences were established, the values were compared by a Student's t test for paired data. Significance was considered at a p value <0.05. Spearman's correlation coefficient was used to correlate NO release with the percent recovery of aortic flow.

RESULTS

Myocardial function
For the combined groups, baseline dP/dt_max, was 3099.8 ± 65.4 mm Hg/sec, baseline developed pressure was 72.5 ± 0.9 mm Hg, baseline aortic flow rate was 44.5 ± 0.8 ml/min, and baseline coronary flow rate was 25.2 ± 0.5 ml/min. There were no significant differences between groups for any of these baseline values. The effect of ischemia and reperfusion on myocardial contractile function measured at the end of 30 minutes of reperfusion is shown in Table I. There was no significant difference between 20 and 30 minutes of reperfusion for any of the hemodynamic variables in any group; data are therefore presented only for the 30-minute reperfusion measurement. After 30 minutes of global ischemia and 30 minutes of reperfusion, the recovery of dP/dt_max, developed pressure, and aortic flow was significantly increased in the L–ARG group compared with respective values in all other groups. The developed pressure in the L–NAME group was significantly decreased compared with that in all other groups. The addition of L–arginine to L–NAME produced an increased aortic flow rate compared with that in the L–NAME group; however, the rate remained significantly below that in the L–ARG group. The coronary flow rate was significantly decreased in the L–NAME group compared with that in the L–ARG group. The nonischemic control hearts had a slight insignificant decrease from baseline values. Baseline heart rate was 313.0 ± 0.5 beats/min. There was no difference in heart rate between any of the groups, at any point. Therefore ventricular pacing was not necessary for measurements of ventricular contractility.

View this table: [in this window] [in a new window]   Table I. Hemodynamic data* and NO release after 30 minutes of reperfusion

View larger version (36K): [in this window] [in a new window]   Fig. 3. Time course of NO release during working reperfusion (n = 6 to 8 per group). Data are given as mean change from baseline values plus or minus standard error of mean.*p < 0.05 versus all other groups; #p < 0.05 versus D-ARG, CON, and L-NAME groups.

View larger version (24K): [in this window] [in a new window]   Fig. 4. Relationship between recovery of aortic flow and change in NO release from baseline values in combined group of all hearts that underwent ischemia/reperfusion (linear regression analysis).

Researchers have been limited in their investigation of NO, because of its scant release and rapid breakdown/consumption in biologic systems. ¹⁵ In this study, for the first time, we have directly measured continuous constitutive or basal NO release from a working heart with the use of an extremely sensitive and specific NO probe. ¹⁴ Free NO has a half–life of 3 to 5 seconds in physiologic salt solution, which makes its direct measurement difficult. ⁴ We placed our NO probe into the right atrial chamber of beating hearts to measure newly generated NO from the coronary sinus. We have demonstrated that during ischemia/reperfusion, constitutive NO release and myocardial contractility are decreased proportionally and do not return to baseline levels after 30 minutes of reperfusion.

Ambient L–arginine levels have been shown to regulate NO synthesis/release. ¹⁴ Therefore, in the CON group, reduced intracellular L–arginine content after ischemia/reperfusion may be responsible for reduced NO release. Other possibilities include impaired endothelial membrane receptors, decreased L–arginine utilization, reduced NO synthase activity, reduced transport/release, or increased binding/degradation of NO. ¹⁶ Specifically, it has been suggested that the NO pathway fails after ischemia/reperfusion because of increased binding and breakdown by superoxide anion ^11,17 and high shear stress and pressure on the coronary endothelium during reperfusion of ischemic myocardium. ¹⁸

It is logical to assume that ischemia/reperfusion adversely affects both endothelial cells and cardiac musculature. However, it is unclear whether decreased NO release is partially responsible for decreased myocardial function in this setting. In this study, we demonstrated that the degree of postischemic contractile dysfunction correlated with the degree of endothelial dysfunction. We have shown that L–arginine pretreatment resulted in significantly increased constitutive NO synthesis/release (to baseline levels) and improved functional recovery after ischemia/reperfusion. This response was both specific and stereoselective, inasmuch as D–arginine administration did not prevent the reduction in NO release or improve myocardial function on reperfusion.

The maintenance of constitutive NO release appears to be important in the recovery of function after an ischemic injury. Others have similarly demonstrated reduced infarct size ^8,19 and decreased contractile dysfunction ²⁰ by supplementing NO release after ischemia/reperfusion. We have shown that endogenous NO production can be readily augmented by providing excess L–arginine substrate before ischemia without being limited by impaired substrate uptake, synthesis, or release. It is important to note that exogenous NO donors were not necessary to maintain adequate NO release. Furthermore, the NO synthase enzyme appears to be relatively resistant to the deleterious effects of ischemia/reperfusion in this setting.

We have confirmed the ability of L–NAME, an L–arginine analog, to block NO synthase, as evidenced by reduced NO release in the L–ARG/L–NAME group compared with that in the L–ARG group. The fact that L–NAME pretreatment alone did not further reduce NO release compared with control values suggests that endothelial function is already at nadir levels. The antagonism of L–NAME can reportedly be overcome by exogenous L–arginine. ²¹ This may explain the significantly increased NO release (especially in early reperfusion) seen in the L–ARG/L–NAME group compared with that in the L–NAME group. In addition, contractility was also slightly improved in the L–ARG/L–NAME group (as evidenced by significantly increased aortic flow) compared with that in the L–NAME group. This would suggest that our dosage of L–arginine was able to partially overcome the antagonistic effect of L–NAME.

The mechanism by which L–arginine pretreatment improved functional recovery after ischemia/reperfusion is not clear. Coronary vasodilation was not a major component in this protection, because coronary flow was not significantly increased in hearts pretreated with L–arginine versus control hearts and collateral flow is not significant in the rat heart model. The systemic effects of L–arginine were also not a factor, inasmuch as the experiment was done on isolated hearts. Others have shown that NO may be cardioprotective by inhibiting neutrophil aggregation and adherence. ²² This is clearly not a factor in the crystalloid–perfused rat heart model.

Recent evidence has suggested that NO may directly protect against cellular damage from reactive oxygen species generated during ischemia/reperfusion by blocking the formation of hydroxyl radicals and terminating free radical chain reactions within the lipid membrane. ²³ Further, it has been shown that nitroxides maybe cytoprotective through the neutralization of oxygen–derived free radicals. ^24,25 By binding and eliminating these toxic metabolites, NO may reduce lipid peroxidation and retard the damaging effects of reperfusion injury. This may explain why others have noted that the coronary vascular endothelium exhibits little damage immediately after ischemia, but that tremendous dysfunction appears after only 2.5 minutes of reperfusion. ^26,27

Not all studies have concluded that NO supplementation is cardioprotective. Others have shown that NO augmentation may increase and NO synthase blockers may decrease postischemic injury. It has been suggested that increased peroxynitrite and hydroxyl radical formation may be cytotoxic. ^28,29 However, these results may be model dependent, with the predominance of data supporting the protective effects of NO supplementation.

The ability to protect endothelial function before an ischemic insult may have direct clinical applicability. In our model, the maintenance of NO release at baseline levels after reperfusion was associated with significantly improved functional recovery. Similar findings might be expected in human subjects. It has recently been demonstrated in human beings that L–arginine supplementation inhibits platelet aggregation, ³⁰ reduces neutrophil superoxide anion release, ³¹ and normalizes coronary endothelial dysfunction. ³² This may be especially important after cardiac operations, because NO release has been found to be decreased in patients with coronary atherosclerosis ³³ and diabetes. ³⁴ L–arginine supplementation to cardioplegic solutions may preserve endothelial function during reperfusion. In addition to its cytoprotective actions, enhanced NO release after cardiac operations may improve collateral circulation and reduce postoperative graft vasospasm ³⁵ and thrombosis. ²⁶

In conclusion, the continuous monitoring of constitutive NO release from working hearts has demonstrated that after ischemia/reperfusion NO release is significantly decreased. Further, this decrease was prevented by L–arginine pretreatment, which resulted in improved myocardial function on reperfusion. Although the exact mechanism or mechanisms for this protection remain unclear, NO appears to be an important component in the recovery of myocardium from an ischemic insult.

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