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Departments of 1 Anesthesiology, Pharmacology, and 2 Toxicology, and 3 Division of Cardiovascular Diseases, Department of Medicine, Medical College of Wisconsin; 4 Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin 53226; and 5 Department of Anesthesiology, University of Graz, A-8036 Graz, Austria
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We tested the hypothesis that
hyperglycemia alters retrograde coronary collateral blood flow by a
nitric oxide-mediated mechanism in a canine Ameriod constrictor model
of enhanced collateral development. Administration of 15% dextrose to
increase blood glucose concentration to 400 or 600 mg/dl decreased
retrograde blood flow through the left anterior descending coronary
artery to 78 ± 9 and 82 ± 8% of baseline values,
respectively. In contrast, saline or L-arginine (400 mg · kg
1 · h1) had no
effect on retrograde flow. Coronary hypoperfusion and 1 h of
reperfusion decreased retrograde blood flow similarly in saline- or
L-arginine-treated dogs (76 ± 11 and 89 ± 4%
of baseline, respectively), but these decreases were more pronounced in
hyperglycemic dogs (47 ± 10%). L-Arginine prevented
decreases in retrograde coronary collateral blood flow during
hyperglycemia (100 ± 5 and 95 ± 6% of baseline at blood
glucose concentrations of 400 and 600 mg/dl, respectively) and after
coronary hypoperfusion and reperfusion (84 ± 14%). The results
suggest that hyperglycemia decreases retrograde coronary collateral
blood flow by adversely affecting nitric oxide availability.
collateral circulation; myocardial ischemia; reperfusion injury
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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HYPERGLYCEMIA may be an important contributor to and independent predictor of increases in short- and long-term cardiovascular mortality. A strong correlation between blood glucose concentrations at the time of hospital admission and long-term mortality was recently observed in a study of diabetic patients with acute myocardial infarction (28). A metaregression analysis of data published in 20 studies of more than 95,000 patients also demonstrated a relationship between fasting blood glucose concentration and the relative risk of sustaining a cardiovascular event (6). The mechanisms responsible for these increases in risk remain to be defined. Hyperglycemia impairs endothelium-dependent vasodilation in vitro (30) and coronary microvascular responses to myocardial ischemia in vivo (18). Human coronary vasculature may also demonstrate attenuated vasodilation during hyperglycemia (26). Coronary collateral perfusion is an important determinant of the extent of myocardial ischemic injury, but whether hyperglycemia affects collateral blood flow is unknown. We tested the hypothesis that hyperglycemia alters retrograde coronary collateral blood flow by a nitric oxide-dependent mechanism in a canine Ameriod constrictor model of enhanced coronary collateral development.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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All experimental procedures and protocols used in this investigation were reviewed and approved by the Institutional Animal Care and Use Committee of the Medical College of Wisconsin. All procedures conformed to the "Guiding Principles in the Care and Use of Animals" of the American Physiological Society and were performed in accordance with the Guide for the Care and Use of Laboratory Animals by the National Institutes of Health (Revised, 1996).
Implantation of Ameriod constrictors. Conditioned mongrel dogs were fasted overnight. Anesthesia was induced with intravenous propofol (5 mg/kg). After tracheal intubation, anesthesia was maintained with isoflurane (1.5 to 2%) in 100% oxygen using positive-pressure ventilation. A left thoracotomy was performed using sterile technique, and a segment (1.0-1.5 cm) of the left anterior descending (LAD) coronary artery immediately distal to the first diagonal branch was isolated. An Ameriod constrictor (Research Instruments and Manufacturing; Corvallis, OR) was placed around the vessel. The diameter of the internal lumen of the constrictor was 2.0-3.0 mm, and its size was chosen for a snug fit around the vessel without producing visible stenosis. The chest was closed in layers, and the pneumothorax was evacuated with a chest tube. Each dog received antibiotics [cefazolin (40 mg/kg) and gentamicin (4.5 mg/kg)] and analgesics [epidural morphine (0.2 mg/kg) and fentanyl (2 µg/kg)].
General preparation. Twelve weeks after implantation of Ameriod constrictors, dogs were anesthetized with pentobarbital sodium (15 mg/kg) and sodium barbital (200 mg/kg) and ventilated using positive pressure with oxygen-enriched air (fractional inspired oxygen concentration = 0.40) after tracheal intubation. A dual, micromanometer-tipped catheter was inserted into the aorta and left ventricle (LV) through the left carotid artery to measure arterial and LV pressures, respectively. Heparin-filled catheters were inserted into the right femoral vein and artery for administration of intravenous fluids and withdrawal of reference arterial blood samples used in the microsphere technique, respectively. The arterial catheter was advanced to the level of the descending thoracic aorta. A thoracotomy was performed in the left fifth intercostal space, the lung gently retracted, and the heart suspended in a pericardial cradle. A heparin-filled catheter was inserted in the left atrium for injection of radioactive microspheres. Descending thoracic aortic and inferior vena cava snares were placed to facilitate control of arterial pressure. Segments of the left circumflex coronary artery (LCCA; proximal to the first marginal branch) and LAD (distal to the Ameriod constrictor) were dissected free from surrounding myocardium. A transit time flow probe was positioned around the LCCA to measure coronary blood flow (ml/min). Each dog was anticoagulated with heparin (500 U/kg). Large-bore polyethylene cannulas attached to Silastic tubing were inserted in the right carotid artery and left jugular vein. The proximal LAD was ligated, a large-bore metal cannula positioned and secured in the distal arterial segment, and a carotid artery-to-LAD shunt established. Perfusion in the LAD was restored within 3 min after ligation. A segment of tubing perpendicular to the metal cannula was used to measure retrograde coronary flow and pressure during interruption of antegrade coronary flow through the carotid artery shunt to the LAD. Patency of the distal LAD perfusion cannula between measurements of retrograde blood flow was assessed. Reduced perfusion of collateral-dependent myocardium was achieved by diverting retrograde collateral blood flow to the left jugular vein. Hemodynamics were monitored continuously on a polygraph and digitized using a computer interfaced with an analog-to-digital converter.
Measurement of myocardial perfusion.
Carbonized plastic microspheres labeled with 141Ce,
103Ru, 51Cr, or 95Nb were used to
measure myocardial perfusion as previously described (20).
At the conclusion of each experiment, 10 ml of Patent blue dye were
injected into the LCCA simultaneously with saline infused intracoronary
into the LAD perfusion tubing at equal pressure to delineate the normal
and collateral-dependent regions, respectively. Transmural tissue
samples were selected from the collateral-dependent (distal to the
Ameriod constrictor) and normal (LCCA perfused) regions and subdivided
into subepicardial, midmyocardial, and subendocardial layers of
approximately equal thickness and weight. Tissue blood flow (in
ml · min1 · g1) was
calculated as
r · Cm · Cr1
where r is the rate of withdrawal of the reference
blood flow sample (ml/min), Cm is the activity [counts/min
(cpm)/g] of the myocardial tissue sample, and Cr is the
activity (cpm) of the reference blood flow sample. Transmural blood
flow was considered as the average of subepicardial, midmyocardial, and
subendocardial blood flows. Tissue blood flow to the
collateral-dependent myocardium is a measure of microvascular not total
collateral blood flow. Coronary perfusion pressure was determined as
the difference between end-diastolic arterial pressure and LV
end-diastolic pressure. Retrograde collateral conductance was
calculated as the ratio of retrograde blood flow to coronary perfusion pressure.
Experimental protocol. Hemodynamics were recorded, radioactive microspheres were injected, and LAD retrograde blood flow was measured 30 min after completion of the acute surgical preparation. Retrograde blood flow was assessed by collecting blood from the LAD cannula into a graduated cylinder for 90 s while the cannula tip was held at the level of the left atrium. Measurements were performed in triplicate and the results averaged. Microsphere injections were performed with the retrograde flow cannula open so that retrograde and LAD transmural (microvascular collateral) blood flow were measured simultaneously (15). Microvascular collateral flow was measured during baseline conditions, after 60 min of interventions, during prolonged diversion of retrograde flow (hypoperfusion), and 1 h after antegrade LAD flow was reestablished (reperfusion). Thus all determinations of microvascular collateral flow were made with the retrograde flow cannula open for either brief or prolonged periods of time.
The effects of acute hyperglycemia on coronary collateral blood flow before or after a 60-min period of coronary hypoperfusion were studied in four separate experimental groups (Fig. 1). Retrograde coronary collateral blood flow and pressure were measured under steady-state hemodynamic conditions after instrumentation during intravenous infusion of 0.9% saline (3 times at 30-min intervals), during 60 min of coronary hypoperfusion, and after 1 h of reperfusion. A second group of dogs received intravenous 15% dextrose in water to increase blood glucose concentrations to 200, 400, and 600 mg/dl (30 min at each concentration) before coronary hypoperfusion and reperfusion. Blood glucose concentration was maintained at 600 mg/dl during 60 min of coronary hypoperfusion and reperfusion. In two final groups of experiments, dogs received intravenous L-arginine (400 mg · kg1 · h1) in the
absence or presence of acute hyperglycemia with and without coronary
hypoperfusion and reperfusion. Arterial pressure was maintained
constant throughout experimentation by partial aortic or vena cava
constriction. Arterial blood gas tensions were maintained within a
physiological range by adjusting tidal volume and respiratory rate and
by administering sodium bicarbonate as necessary.
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Statistical analysis. Statistical analysis of data within and between groups was performed with multiple analysis of variance for repeated measures followed by application of Student-Newman-Keuls test. Changes within and between groups were considered statistically significant when P < 0.05. Data are expressed as means ± SE.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Forty-eight dogs were instrumented with Ameriod constrictors to obtain 43 successful experiments. The LAD cannulation was unsuccessful in five dogs.
Hemodynamics during control experiments.
Saline did not alter systemic hemodynamics, LCCA blood flow, or
retrograde collateral blood flow, conductance, and pressure (Table
1). Diversion of retrograde flow to
produce hypoperfusion of the collateral-dependent region did not affect
hemodynamics. A significant (P < 0.05) decrease in
retrograde collateral blood flow (76 ± 11% of baseline) was
observed after 1 h of reperfusion.
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Effects of hyperglycemia.
Hemodynamics were unchanged during administration of 15% dextrose
(Table 2). Dextrose decreased retrograde
collateral blood flow (Fig. 2),
retrograde conductance, and retrograde pressure (Table 2). Retrograde
flow (Fig. 3) and conductance were lower during coronary hypoperfusion (83 ± 9 and 77 ± 10% of
baseline, respectively) and reperfusion (47 ± 10 and 44 ± 10% of baseline, respectively) in hyperglycemic compared with
saline-treated dogs (107 ± 6 and 108 ± 8% of baseline
during hypoperfusion and 76 ± 11 and 81 ± 13% of baseline
during reperfusion, respectively).
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Effects of L-arginine.
L-Arginine did not alter systemic hemodynamics, LCCA blood
flow, or retrograde flow (Table 3).
Increases in retrograde blood flow (Fig. 3) and LCCA blood flow were
observed during hypoperfusion of the collateral-dependent region in
dogs receiving L-arginine. After reperfusion, retrograde
flow decreased to a similar extent in the presence of
L-arginine compared with dogs receiving saline.
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Effects of L-arginine during hyperglycemia.
L-Arginine decreased heart rate but did not alter mean
arterial pressure during graded increases in blood glucose
concentration (Table 4).
L-Arginine prevented decreases in retrograde collateral blood flow (Fig. 2), conductance, and pressure that occurred during dextrose-induced increases in blood glucose concentration. Retrograde collateral blood flow (84 ± 14% of baseline) and conductance
(91 ± 15% of baseline) were significantly greater 1 h after
reperfusion in dogs receiving dextrose in the presence compared with
the absence of L-arginine.
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Microvascular collateral and normal zone blood flow.
There were no differences in microvascular collateral blood flow among
groups (Table 5) under control
conditions, after 60 min of saline or dextrose administration, or
during prolonged diversion of retrograde flow (hypoperfusion).
Microvascular collateral flow increased after reperfusion in dogs
receiving dextrose and L-arginine compared with those
treated with L-arginine alone. Perfusion of
normal myocardium (Table 6) was
similar among groups under baseline conditions, after 60 min of saline
or dextrose administration, and after reperfusion. Transmural blood
flow to normal myocardium increased during hypoperfusion in dogs
receiving dextrose and L-arginine compared with those
treated with L-arginine alone.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Nitric oxide and coronary collaterals. Chronic imbalances of myocardial oxygen supply and demand produced by a coronary artery stenosis or occlusion stimulate growth of the coronary collateral circulation. This collateralization increases oxygen delivery to myocardium at risk for ischemic injury and may prevent infarction. The functional response of the coronary collateral circulation to various physiological and pharmacological stimuli may also be a critical factor that influences the extent of ischemic injury. Coronary collateral vessels respond to endothelium-dependent and -independent vasodilators in vitro (10) and in vivo (2). Nitric oxide has a tonic vasodilating effect on the coronary collateral circulation. Administration of a nitric oxide synthase (NOS) inhibitor increased coronary collateral resistance in models of enhanced collateral development produced by repetitive coronary artery occlusion or Ameriod constrictor implantation. This action was partially reversed by the nitric oxide precursor L-arginine (11). Nitric oxide contributes to maintenance of basal coronary blood flow (4, 25) and also maintains coronary collateral blood flow responsiveness during exercise (36). Moreover, nitric oxide may be a critically important regulator of coronary blood flow during myocardial ischemia and reperfusion (5, 8, 9). Inhibition of NOS blunts reactive hyperemia, increases the critical coronary perfusion pressure below which coronary flow becomes pressure dependent, and further reduces flow at pressures below the lower limit of autoregulation (32). These findings indicate that nitric oxide modulates coronary resistance adjustments required for the regulation of myocardial perfusion during and after ischemia. The availability of NOS substrate may influence this regulatory process. Endothelial dysfunction early (20 min) after coronary artery occlusion and reperfusion is reversible with the provision of excess substrate (L-arginine) for NOS (27). However, defects in L-arginine membrane transfer or the nitric oxide synthetic system may not be surmountable by excess L-arginine later during reperfusion (27).
Effects of acute hyperglycemia. The present results confirm and extend previous findings demonstrating a role of nitric oxide in the modulation of coronary collateral vasomotor tone. More importantly, we show that acute hyperglycemia alters the permissive action of nitric oxide on regulation of blood flow in the coronary collateral circulation. Retrograde collateral blood flow was reduced by hyperglycemia before and after hypoperfusion and reperfusion, and nitric oxide played an important role in this process. Mild hyperglycemia (200 mg/dl) alone had no effect on retrograde flow, but moderate (400 mg/dl) and profound (600 mg/dl) hyperglycemia produced similar reductions (~20%) in retrograde flow. Hyperglycemia also reduced retrograde collateral blood flow to <50% of baseline values after 1 h of reperfusion. Administration of L-arginine completely abolished these hyperglycemia-induced decreases in retrograde flow before, during, or after myocardial hypoperfusion but did not ameliorate the less pronounced reductions in retrograde flow during reperfusion observed in normoglycemic dogs. The results confirm that nitric oxide is at least partially responsible for the maintenance of blood flow through coronary collateral vessels. The results also indicate that hyperglycemia attenuates these nitric oxide-induced effects on collateral blood flow. Taken together, the data support the contention that hyperglycemia decreases retrograde collateral blood flow by interference with nitric oxide.
Coronary collateral blood flow was differentiated on the basis of collateral size because coronary vascular responses to pharmacological stimuli are heterogeneous in different-sized vessels (31). Retrograde coronary blood flow primarily reflects flow derived from epicardial collateral vessels with a small contribution from intramural collaterals. In contrast, microvascular collateral flow (measured with radioactive microspheres during retrograde flow collection) reflects continuing blood flow through microvascular intramural collaterals (7). Microvascular collateral flow accounts for ~50% of the total collateral blood flow (15). Total collateral blood flow available to perfuse dependent myocardium is the sum of retrograde flow derived from large interarterial collateral vessels and microvascular collateral blood flow. Hyperglycemia decreased interarterial (retrograde) collateral conductance but did not appreciably affect vasomotor tone of microvascular collaterals or resistance vessels in collaterally dependent myocardium, because ongoing tissue blood flow to this region remained essentially constant. These results suggest that hyperglycemia produces greater effects to alter vasomotor tone of large interarterial compared with microvascular collaterals and are consistent with findings that NOS inhibition decreases retrograde coronary collateral blood flow by ~30% (23). Decreases in retrograde collateral blood flow during hyperglycemia may also result from increases in vasomotor tone of epicardial coronary arteries, proximal to the origin of interarterial collateral vessels. The absence of changes in perfusion of normal myocardium during hyperglycemia, however, suggests that epicardial coronary arterial vasomotor activity was unaffected by hyperglycemia in the present investigation.Hyperglycemia and nitric oxide. Acute hyperglycemia has previously been demonstrated to impair responses to endothelium-dependent but not -independent vasodilators (3, 30, 37). Moderate hyperglycemia (270 mg/dl) reduced leg blood flow and increased platelet aggregation and blood viscosity in healthy volunteers. These detrimental effects were abolished by intravenous administration of L-arginine (12). Interestingly, administration of a NOS inhibitor produced very similar vascular abnormalities, indirectly suggesting hyperglycemia may act by decreasing nitric oxide availability (12). Substrate availability for NOS may become rate limiting during hyperglycemia because of impaired arginine uptake, increased utilization, or reduced enzyme affinity (16, 34). Hyperglycemia also increases superoxide anion formation (13, 29), and production of oxygen-derived free radicals inactivates nitric oxide (14). Ischemia and reperfusion are associated with disrupted architecture of the constitutively expressed NOS enzyme (17), an action that may result in enhanced production of superoxide anion and decreased nitric oxide formation (17). The present results suggest that hyperglycemia and L-arginine may exacerbate and ameliorate this response, respectively. L-Arginine prevented reduction in retrograde flow after coronary hypoperfusion and reperfusion in hyperglycemic dogs in the present investigation, findings that appear to be very similar to those observed during ischemia and reperfusion injury in skeletal muscle (17). L-Arginine treatment decreased superoxide anion production, increased nitric oxide accumulation, and prevented vasoconstriction in this previous study (17), but whether L-arginine produces such beneficial actions in myocardium is unknown.
Limitations. The results of the present investigation should be interpreted within the constraints of several potential limitations. Prostaglandins (1) and ATP-sensitive potassium (KATP) channels (24) have been implicated in the tonic vasodilation of coronary collateral vessels. We did not specifically evaluate the interactions between hyperglycemia and prostaglandins or KATP channels. However, elevated glucose concentrations have been previously shown to enhance the production of vasoconstrictor prostanoids (35). We recently demonstrated that hyperglycemia abolishes endogenous activation of KATP channels during ischemic preconditioning (21) and also impairs pharmacological activation of mitochondrial KATP channels by diazoxide (19). Whether hyperglycemia specifically impairs KATP channel-regulated coronary collateral vascular responsiveness in the presence or absence of coronary hypoperfusion remains to be determined. However, our findings indicate that hyperglycemia is not only deleterious for ischemic myocardium by inhibition of endogenous cardioprotective pathways. Hyperglycemia can also impact ischemic myocardium by reducing oxygen supply via collateral perfusion.
We have previously shown that acute administration of dextrose is also associated with hyperinsulinemia (22). Hyperinsulinemia may contribute to coronary vasospasm and sudden cardiac death in patients with coronary artery disease (33). Topical hyperglycemia in the absence of systemic hyperinsulinemia impaired nitric oxide-mediated vasodilation of rat arterioles (3), and the severity of hyperglycemia was directly related to myocardial infarct size independent of plasma insulin concentration in dogs (22). These findings suggest that hyperglycemia alone, and not concomitant hyperinsulinemia, is probably responsible for the impairment of nitric oxide-regulated coronary collateral blood flow observed in the present investigation. Nevertheless, a role for hyperinsulinemia alone in this process cannot be strictly excluded from the analysis. It also appears unlikely that hyperosmolality was responsible for decreases in retrograde blood flow observed during hyperglycemia. Incubation of endothelial cells with 33 mM (600 mg/dl) glucose increased superoxide anion production and decreased nitric oxide activity, in contrast to a similar hypertonic concentration of mannitol (44 mM) (13). In addition, increases in plasma osmolality produced by the nonmetabolizable sugar raffinose decreased myocardial infarct size in dogs (22), in contrast to increases in infarct size observed during dextrose-induced hyperosmolality. In summary, the present results demonstrate that hyperglycemia decreases retrograde coronary collateral blood flow and exacerbates myocardial hypoperfusion and reperfusion-induced collateral vascular dysfunction. Decreases in retrograde collateral blood flow observed during reperfusion were exaggerated by hyperglycemia and reversed by L-arginine. The results suggest that nitric oxide plays a role in maintaining interarterial coronary collateral blood flow. The results also demonstrate that hyperglycemia impairs the nitric oxide-mediated regulation of interarterial coronary collateral blood flow. Impairment of collateral blood flow regulation by hyperglycemia interfering with nitric oxide metabolism may represent a potential mechanism for increased cardiovascular risk during diabetes mellitus.| |
ACKNOWLEDGEMENTS |
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The authors thank David Schwabe for technical assistance and Mary Lorence-Hanke for preparation of the manuscript.
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FOOTNOTES |
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This work was supported in part by an American Heart Association Grant-in-Aid 97-50634 (to J. R. Kersten); American Diabetes Association Award (to J. R. Kersten), National Institutes of Health Grants HL-03690 (to J. R. Kersten), HL-63705 (to J. R. Kersten), AA-12331 (to P. S. Pagel), and HL-54280 (to D. C. Warltier); and Anesthesiology Research Training Grant GM-08377 (to D. C. Warltier).
Address for reprint requests and other correspondence: J. R. Kersten, Medical College of Wisconsin, Dept. of Anesthesiology, M4280, 8701 Watertown Plank Rd., Milwaukee, WI 53226 (E-mail: jkersten{at}mcw.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 27 April 2001; accepted in final form 24 July 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Significantly
(P < 0.05) different from saline alone;
§Significantly (P < 0.05) different from
L-Arg; ¶Significantly (P < 0.05)
different from Hyp + L-Arg.
