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Ann Thorac Surg 1998;66:1210-1215
© 1998 The Society of Thoracic Surgeons

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Original articles: cardiovascular

Heparin preserves nitric oxide activity in coronary endothelium during ischemia-reperfusion injury

^a Departments of Surgery, Physiology and Biophysics, and Anesthesiology, Georgetown University Medical Center, Washington, DC, USA
^b Division of Thoracic and Cardiovascular Surgery, Georgetown University Medical Center, Washington, DC, USA
^c University of Virginia Health Sciences Center, Charlottesville, Virginia USA

Address reprint requests to Dr Hannan, Department of Surgery, University of Virginia Health Sciences Center, Box 3501, Charlottesville, VA 22908
e-mail: (rhannan001{at}aol.com)

Presented at the Poster Session of the Thirty-fourth Annual Meeting of The Society of Thoracic Surgeons, New Orleans, LA, Jan 26–28, 1998.

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. Brief episodes of ischemia followed by reperfusion adversely affect endothelial vasomotor function. We hypothesized that heparin may impart a protective effect on the coronary endothelium during ischemia-reperfusion injury possibly via the nitric oxide pathway.

Methods. Eighteen anesthetized dogs were randomly assigned to one of two treatment groups: saline solution or bovine heparin (6.0 mg · kg intravenously). A flow probe and cannula were placed in the left anterior descending artery. Functional recovery of the coronary endothelium was assessed after 15 minutes of ischemia and during 120 minutes of reperfusion after acetylcholine and nitroprusside challenge. In a separate group (n = 10), nitric oxide activity was measured as nitrate/nitrite levels and cyclic guanosine monophosphate levels in the left anterior descending artery.

Results. Control dogs displayed a significant decrease in percent change of left anterior descending artery flow at 15, 30, and 60 minutes of reperfusion (67% ± 8%, 76% ± 11%, and 84% ± 8%) when compared with preischemic values (108 ± 6; p < 0.01). Heparinized dogs, however, showed preservation of coronary endothelial function after acetylcholine challenge throughout reperfusion. Heparin-treated dogs also displayed a significant increase in nitrate/nitrite levels during reperfusion (37.3 ± 4.1 µmol/L) when compared with the saline group (24.3 ± 0.8 µmol/L; p < 0.03). Left anterior descending artery levels of cyclic guanosine monophosphate were also significantly increased after heparin administration (3.0 ± 0.3 pmol/mg) when compared with ischemia-reperfusion alone (0.7 ± 0.1 pmol/mg; p < 0.03).

Conclusions. Heparin preserves the vasoregulatory function of the coronary endothelium during brief episodes of ischemia-reperfusion injury, in part, via the nitric oxide pathway. Administration of heparin may have important therapeutic implications in the prevention of coronary endothelial dysfunction associated with reperfusion injury.

	Introduction

Top Abstract Introduction Material and methods Results Comment References

 
Since the discovery that the endothelium regulates vascular reactivity by elaboration of endothelial-derived vasoactive mediators [1], the role of the coronary endothelium in pathophysiologic conditions such as ischemia-reperfusion injury has been extensively investigated. Recent studies have demonstrated that coronary endothelial function is significantly impaired after acute coronary occlusion and reperfusion [2]. Furthermore, the endothelial dysfunction associated with reperfusion injury is due, in part, to diminished production and release of vasoactive mediators, including nitric oxide [3]. Preserving the ability of the coronary endothelium to elaborate nitric oxide during ischemia-reperfusion injury may prevent some of the adverse consequences of reperfusion injury.

Heparin, which is widely used clinically as an anticoagulant, has been demonstrated to possess several physiologic properties in addition to its anticoagulant activity. Heparin has been shown to modulate the inflammatory response by inhibiting activation of polymorphonuclear leukocytes as well as components of the complement cascade [4, 5]. Recent studies have also linked heparin to the production and release of several endothelial vasoactive mediators including endothelin and nitric oxide [6, 7]. The protective effect of heparin in the setting of myocardial ischemia and reperfusion injury has also been recently reported [8].

The purpose of the present study was to investigate the role of heparin treatment in the modulation of coronary endothelial function during brief ischemia-reperfusion injury. Our hypothesis that heparin may modulate coronary endothelial function stems from our clinical observation that discontinuation or reversal of heparin in patients at risk for coronary vasospasm occasionally resulted in episodes of recurrent angina that were not associated with rethrombosis. We hypothesized that heparin may be interacting with the coronary endothelium and preserving function during pathophysiologic conditions such as reperfusion injury. We also hypothesized that the heparin-mediated effect may be secondary to modulation of the nitric oxide pathway. Therefore, the aims of the present study were to study coronary endothelial function in the setting of brief ischemia-reperfusion injury, elucidate the protective effect of heparin, and demonstrate the role of the nitric oxide pathway in the heparin-mediated effect on endothelial function.

	Material and methods

Top Abstract Introduction Material and methods Results Comment References

 
Animals
Male mongrel dogs (25 to 35 kg) were used in these studies. All experiments were approved by the Georgetown Animal Care and Use Committee and conformed to the guidelines of the "Guide for the Care and Use of Laboratory Animals" prepared by the National Institutes of Health (NIH publication 85-23, revised 1985).

Materials
Heparin (bovine lung), acetylcholine, sodium nitroprusside, aprotinin, ethylenediaminetetraacetic acid, sodium nitrite, and potassium nitrate were purchased from Sigma Chemical (St. Louis, MO). Cyclic guanosine monophosphate (cGMP) standard and anti-cGMP antibody were purchased from Calbiochem (San Diego, CA). Iodine-125–labeled succinyl cyclic guanosine 3'5' monophosphate tyrosyl methyl ester (specific gravity, 2,000 Ci/mmol) was purchased from New England Nuclear (Boston, MA).

Surgical preparation
Animals were fasted overnight before the operation, with water provided ad libitum. Anesthesia was induced with intravenous sodium thiopental (25 mg/kg) and after endotracheal intubation, the lungs were mechanically ventilated. Anesthesia was then maintained with halothane (1.5%) for the remainder of the experiment. Pancuronium bromide (0.1 mg/kg) was administered intravenously to produce complete muscle relaxation. Surgical preparation and collection of data were performed at an inspired oxygen fraction of 1.0 and a respiratory rate of 10 to 13 ventilations per minute. End-tidal halothane, CO₂, and arterial oxygen saturation were continuously monitored with a POET agent analyzer equipped with a pulse oxymeter (Criticare Systems, Waukesa, WI). End-tidal CO₂ levels were maintained between 33 and 37 mm Hg and end-tidal halothane concentration was maintained at 1.5% throughout the study. Body temperature was maintained in the normothermic range with a warming blanket.

A left thoracotomy was performed through the fifth intercostal space and the heart was suspended in a pericardial cradle. The left anterior descending artery (LAD) was then exposed and dissected free of the myocardium immediately distal to the first major diagonal branch. A 2.0-mm ultrasonic flow probe (Transonic Systems, Ithaca, NY) was positioned around the LAD distal to the first diagonal artery for the continuous monitoring of LAD flow with a Transonic T20 two-channel ultrasonic blood flow meter. A rubber vessel loop was then placed around the LAD proximal to the flow probe and the free ends were passed through a narrow silicone tube for use as a snare to occlude the LAD. A 24-gauge Teflon catheter (Desert Medical Inc, Sandy, UT) was inserted into the LAD via the first diagonal branch of the LAD with the catheter tip positioned at the level of the first diagonal branch. This catheter was used for the local infusion of acetylcholine and sodium nitroprusside, endothelial-dependent and independent vasodilators, respectively. A 20-gauge Teflon catheter was also inserted into the great cardiac vein for obtaining regional venous samples for the measurement of nitrate/nitrite, the metabolites of nitric oxide.

A polyvinyl chloride catheter (Desert Medical Inc) was placed in the right femoral artery. A high-fidelity pressure transducer (Millar Instruments, Inc, Houston, TX) was then placed through this catheter into the aortic arch for measurement of aortic pressure. A second transducer was placed in the left ventricle for the continuous monitoring of left ventricular pressure. After surgical instrumentation, all animals were allowed at least 15 minutes to stabilize.

Experimental protocols
In vivo studies
Eighteen animals were randomly assigned to one of two treatment groups: saline solution or bovine heparin. The treatment was administered after surgical instrumentation and before LAD occlusion. The dose of heparin was determined based on heparin dose-response curves performed for each individual animal with the Hepcon HMS microprocessor (Medtronic HemoTec, Inc, Englewood, CO). The optimum dose of heparin needed for anticoagulation was calculated for each individual dog based on the endogenous circulating level. Heparin was administered after surgical instrumentation, and the level was maintained throughout ischemia and reperfusion. Heparin levels were checked every 15 minutes with the Hepcon microprocessor, and an appropriate amount of heparin was infused as a bolus to maintain the optimum heparin level. The heparin level corresponded to an average activated clotting time greater than 500 seconds and a partial thromboplastin time greater than 100 seconds. The average dose of bovine heparin administered over the course of the protocol for all dogs was 6.0 mg/kg. Heparin was not reversed with protamine during the present study.

After treatment with either saline solution or bovine heparin, animals were subjected to 15 minutes of regional ischemia by LAD occlusion followed by 120 minutes of reperfusion. Cessation of LAD flow, wall motion changes, cyanosis of the anterior wall, and typical electrocardiographic changes immediately after LAD occlusion were used as indices of successful anterior wall ischemia. To ensure that no substantial collateral blood flow to the ischemic regions occurred during LAD occlusion, color-coded microspheres were injected before ischemia and during 10 minutes of ischemia, and regional myocardial blood flow was measured as described previously [9].

Coronary vasomotor function was assessed by infusing vasoactive drugs into the LAD over 60 seconds and measuring the subsequent vasodilatory response as an increase in LAD flow. The vasoactive drugs used were the endothelial-dependent agonist acetylcholine at a dose of 1.0 µg/min and the endothelial-independent agonist sodium nitroprusside at a dose of 10.0 µg/min. Each test was performed before ischemia and during reperfusion with the same dose of each drug. The doses of both drugs were based on dose-response experiments that yielded a submaximal vasodilatory response. These doses of drugs injected into the LAD over 60 seconds resulted in reproducible LAD flow increases without causing significant systemic hemodynamic changes [10].

The signals from the ultrasonic flow probes and pressure transducers were electronically processed via a calibration control unit (Millar Instruments, Inc), and a Gould transducer (model 13; Cleveland, OH). The analog signals were subsequently amplified and converted to digital signals at a sampling rate of 200 Hz. Analog signals were also displayed on an oscilloscope (model 5B10; Tektronic, Beaverton, OR) for signal verification throughout the experimental protocol. After the experiments, stored signals were digitized and the data were transferred for hemodynamic computations. Approximately ten heart beats were analyzed per intervention.

In vitro studies
In a separate group of experiments (n = 10), levels of the nitric oxide metabolites nitrate/nitrite and cGMP in the LAD were measured in saline placebo and bovine heparin-treated animals subjected to 15 minutes of ischemia followed by 15 minutes of reperfusion. Venous blood was collected from the great cardiac vein before ischemia and at 15 minutes of reperfusion, the time point of maximal coronary endothelial dysfunction in this model. Serum concentrations of nitrate and nitrite were determined by high performance liquid chromatography. At the end of the experimental protocol, the LAD was harvested from the ischemic region and processed for measurement of cGMP levels, the second messenger of nitric oxide. Levels of cGMP were measured with a standard radioimmunoassay technique as described by Cailla and associates [11].

Statistical analyses
Flow in the LAD, expressed as percent increase from baseline after acetylcholine and sodium nitroprusside challenge, was compared with preischemic values within each treatment group by analysis of variance with repeated measures. Nitric oxide metabolite levels and cGMP levels after reperfusion were compared with preischemic values with a two-tailed paired Student’s t test. Measurements are reported as mean values plus or minus the standard error of the mean.

	Results

Top Abstract Introduction Material and methods Results Comment References

 
Hemodynamic measurements and regional myocardial blood flow
Brief ischemia followed by 120 minutes of reperfusion had no significant effect on cardiac output, heart rate, mean arterial pressure, or left ventricular systolic or end-diastolic pressures. These hemodynamic measurements were also comparable in both treatment groups, indicating that heparin had no significant hemodynamic effect (Table 1). Regional myocardial blood flow also decreased equally in the ischemic region in both saline-treated (1.15 ± 0.03 to 0.34 ± 0.1 mL/min · g) and heparin-treated groups (1.16 ± 0.08 to 0.2 ± 0.04 mL/min · g; p < 0.01), indicating that there was no significant collateral flow to the ischemic region.

View larger version (20K): [in this window] [in a new window]   Fig 1. Left anterior descending artery (LAD) flow after challenge with the endothelial-dependent vasodilator acetylcholine (ACh) (A) or with the endothelial-independent vasodilator sodium nitroprusside (SNP) (B) after 15 minutes of ischemia followed by 120 minutes of reperfusion. The LAD flow is expressed as percent change from baseline after challenge with ACh or SNP. All animals (n = 18) received treatment before ischemia, and heparin levels (6.0 mg/kg) were maintained throughout the protocol. Data are expressed as means plus or minus the standard error of the mean. Asterisks indicate p less than 0.01 versus preischemic value within each group.

View larger version (16K): [in this window] [in a new window]   Fig 2. Nitric oxide activity in the coronary vasculature after ischemia-reperfusion injury in dogs treated with either saline solution or bovine heparin (6.0 mg/kg intravenously). Nitric oxide activity was measured as nitrate/nitrite levels from the great cardiac vein with high-performance liquid chromatography (A). Nitric oxide activity also was measured as cyclic guanosine monophosphate (cGMP) levels in the left anterior descending artery (LAD) by radioimmunoassay (B). All animals (n = 10) were subjected to 15 minutes of ischemia followed by 15 minutes of reperfusion. Data are expressed as means plus or minus the standard error of the mean. Asterisks indicate p less than 0.03 versus saline-treated dogs subjected to ischemia-reperfusion (IR) injury alone.

	Comment

Top Abstract Introduction Material and methods Results Comment References

Since the discovery of endothelium-dependent vasodilation by Furchgott and Zawadzki in 1980 [1], the endothelium has been recognized as a critical functional unit involved in the modulation of the underlying vascular smooth muscle. Since this original report, several physical and chemical stimuli have been identified that cause endothelial-dependent vasodilation. In response to these stimuli, the coronary endothelium releases several vasoactive substances that cause either vasodilation or vasoconstriction of the underlying smooth muscle. This vasodilatory response requires the presence of an intact and functional endothelium [1, 12]. During pathophysiologic conditions such as ischemia-reperfusion injury, the endothelium becomes dysfunctional and vasomodulation of the underlying smooth is perturbed [13]. Brief episodes of ischemia (10 to 20 minutes) followed by reperfusion induce an "endothelial stunning" characterized by impairment of endothelium-dependent vasodilation without evidence of endothelial damage [10]. These results were confirmed in the present study, in which brief episodes of ischemia-reperfusion injury resulted in coronary endothelial dysfunction manifested by a diminished response to the endothelial-dependent agonist acetylcholine during early reperfusion. Endothelial-dependent vasodilation subsequently recovered after 120 minutes of reperfusion, signifying that the endothelium was "stunned" and not permanently damaged.

One postulated mechanism to explain the impaired vasodilatory response observed after ischemia-reperfusion is based on the observation that mechanical removal or destruction of the endothelium of a coronary artery enhances vasoconstrictive responses to several vasoactive stimuli [14]. Acute coronary occlusion followed by reperfusion causes a type of "functional" damage to the coronary endothelium that augments contractile reactivity and impairs endothelium-dependent relaxation [2]. This functional derangement may stem from an imbalance in the vasoactive mediators produced and released from the endothelium during ischemia-reperfusion injury. Recent studies have shown that the local production and release of endothelial-derived vasoconstrictive substances such as endothelial-derived contracting factor and endothelin-1 are augmented after brief episodes of ischemia-reperfusion injury [15]. Furthermore, production of endothelial-derived relaxing factor (nitric oxide) is compromised after ischemia-reperfusion injury [3, 16]. Nitric oxide has several protective properties to the coronary vasculature including vasodilation, free radical scavenger, inhibition of platelet aggregation, and neutrophil adherence. Therefore, diminished nitric oxide activity during reperfusion injury may predispose the coronary vessel to further injury and dysfunction.

Heparin has been demonstrated to possess several properties specific to the endothelium in addition to its anticoagulant activity. Heparin is a potent antiinflammatory agent through its ability to inhibit neutrophils and complement activation [4, 5]. Heparin also releases superoxide dismutase from the endothelium, which may serve to protect the endothelium from free radicals, which are prevalent during reperfusion injury [17]. Heparin has also recently been shown to modulate the release of several endothelial-derived vasoactive mediators, including endothelin and nitric oxide. Endothelin, a potent endothelial-derived vasoconstrictor peptide, is released from the endothelium after short-term coronary artery occlusion [15]. Heparin inhibits endothelin synthesis and release by endothelial cells [6]. Recent studies also demonstrate that heparin modulates the production of nitric oxide in cultured endothelial cells [7]. These potential mechanisms may explain the recent findings that heparin administration is protective in the setting of mechanical as well as ischemia-reperfusion injury [18, 19]. Sternbergh and associates [19] have recently demonstrated that heparin prevents postischemic endothelial cell dysfunction in an isolated rat hindlimb model of reperfusion injury. The exact mechanism of how heparin protects in the setting of ischemia-reperfusion and the role that endothelial-derived vasoactive mediators play have not been clearly addressed to this point.

The present data clearly demonstrate that the preischemic administration of bovine heparin preserves nitric oxide-mediated, endothelial-dependent vasodilation in the setting of coronary arterial occlusion and reperfusion. Furthermore, we have demonstrated that one possible mechanism of the heparin-mediated effect is via the modulation of nitric oxide. Administration of bovine heparin increased nitric oxide production during reperfusion injury as evidenced by increased nitrate/nitrite levels and cGMP levels in the LAD. These results are consistent with previous studies, which have shown that nitric oxide replacement therapy, in the form of L-arginine, the precursor of nitric oxide, improves endothelial function during reperfusion injury [20]. The role that heparin plays in the modulation of endothelin-1 during reperfusion injury is another possible pathway that needs further study.

Preserving the normal homeostasis of the endothelium and maintaining the balance between the vasoactive mediators released by the endothelium remains critical for the prevention of endothelial dysfunction during ischemia-reperfusion injury. Administration of heparin and other heparinoids in the setting of ischemia-reperfusion may preserve the balance of endothelial-derived vasoactive mediators, thus preventing sequelae such as vasospasm, rethrombosis, and recurrent angina.

	References

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