| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medicine, Fukuoka 815-8552, Japan
 |
ABSTRACT |
|---|
 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Recent evidence suggests that increased inactivation of endothelium-derived nitric oxide (NO) by oxygen free radical (OFR) formation is involved in the pathogenesis of endothelial dysfunction in heart failure (HF). However, it is unclear whether increased OFR limits coronary flow reserve in HF. To test this hypothesis, we examined the effects of antioxidant therapy on coronary flow reserve in a canine model of tachycardia-induced HF. The flow reserve (percent increase in coronary blood flow) to adenosine or to 20-s ischemia was less and OFR formation (electron-spin resonance spectroscopy) in myocardial tissues was greater in HF dogs than in controls. Immunohistochemical staining of 4-hydroxy-2-nonenal, an OFR-induced lipid peroxide, was detected in coronary microvessels of HF dogs. Intracoronary infusion of a cell-permeable OFR scavenger, tiron, suppressed OFR formation and improved the vasodilating capacity to adenosine or brief ischemia in HF dogs but not in controls. A NO synthesis inhibitor, NG-monomethyl-L-arginine (L-NMMA), diminished the beneficial effects of tiron in HF dogs. Vasodilation to sodium nitroprusside was similar between control and HF dogs, and no change in its response was noted with tiron or tiron + L-NMMA in either group. In summary, antioxidant treatment with tiron improved coronary flow reserve by increasing NO bioactivity in HF dogs. Thus increased OFR formation may impair coronary flow reserve in HF by reducing NO bioactivity.
oxygen free radicals; endothelium-derived factors
| |
INTRODUCTION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
MAXIMAL CORONARY VASODILATING CAPACITY (coronary flow reserve) in response to a brief period of ischemia (reactive hyperemia) and pharmacological vasodilator, such as adenosine, is attenuated in an animal model of heart failure (HF) (28). Limited vasodilator capacity to dipyridamole has also been demonstrated in patients with HF. Although the vasodilator response to a brief period of ischemia must be more complex than the response with drugs like adenosine and dipyridamole, prior studies (5, 13, 24-26) imply impaired coronary flow reserve in both animal and human models of HF. Elevated filling pressure, increased heart rate (HR), and decreased coronary perfusion pressure have been attributed to the impairment of coronary vasodilating capacity. However, intrinsic microvascular dysfunction may also contribute to such abnormal vasodilating capacity in HF, because abnormal coronary blood flow (CBF) responses to pacing tachycardia (metabolic coronary vasodilation) and to dipyridamole infusion (pharmacological coronary flow reserve) occur in patients with cardiomyopathy before development of overt HF (24). Recent clinical and experimental studies (6, 17, 19, 31, 34) have documented impaired endothelium-dependent/nitric oxide (NO)-mediated relaxation of coronary and peripheral arteries in HF. There is growing evidence that HF is associated with increased oxygen free radicals (OFR) (3, 4, 22). Recently, our laboratory (2, 11) reported increased formation of OFR from vascular and myocardial tissues of tachycardia-induced HF dogs. Moreover, we and others have shown that endothelium-dependent coronary and peripheral vasodilation evoked by acetylcholine is attenuated in human and animal models of HF, which was restored by antioxidant therapy with vitamin C (10) or with the cell-permeable OFR scavenger sodium dihydroxybenzene disulfonate (tiron) (2). OFR, especially superoxide anion, reacts with NO to form peroxynitrite, which in turn inactivates NO. Overall, enhanced inactivation of NO by OFR may be involved in endothelial dysfunction in HF. However, it is still not known whether such OFR-induced reduction in NO bioavailability limits coronary flow reserve (maximal vasodilating capacity to adenosine or brief ischemia) in HF. Accordingly, the aim of the present study was to test the hypothesis that increased inactivation of endothelium-derived NO by OFR is involved in the mechanism of impaired coronary flow reserve in a canine model of tachycardia-induced HF.
| |
METHODS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Induction of Pacing-Induced HF
This study was approved by the Committee on the Ethics of Animal Experiments, Faculty of Medicine, Kyushu University, and was conducted according to the Guidelines for Animal Experiments of the Faculty of Medicine, Kyushu University, and Law (No. 105) and Notification (No. 6) of the Japanese Government. A part of this study was performed in the Kyushu University Station for Collaborative Research.Experiments were performed in adult mongrel dogs (16-25 kg body wt). Under general anesthesia and fluoroscopic guidance, a bipolar pacing lead (1452T/58, Pacesetter) was introduced into the right external jugular vein and advanced to the apical area of the right ventricle. The dogs were then allowed to recover from the surgery.
HF was induced by rapid ventricular pacing at 240 beats/min for 4 wk (2, 11). Ventricular pacing was performed continuously by connecting the lead to an external pulse generator (Nihon-Kohden; Tokyo, Japan). Control dogs were treated in identical manner as HF dogs without pacing.
On the day of the final study, all dogs underwent echocardiographic
examinations in the conscious condition in sinus rhythm after 15 min of
the stabilization period. Echocardiographic images were obtained with
an ultrasonograph (SSH-160A, Toshiba Medical; Tokyo, Japan). Left
ventricular (LV) short-axis (cross sectional) views were recorded at
the papillary muscle level, and the internal LV dimensions and the
thickness of the lateral wall of the LV were measured. The LV ejection
fraction (in percent) was then calculated with the use of the following
formula: 100 × {[(LV end-diastolic
dimension)3 
(LV end-systolic
dimension3)]/(LV end-diastolic dimension)3}.
Surgical Preparation and Measurements
After echocardiographic examination, the animals were sedated with intravenous diazepam (10 mg), intubated after intravenous administration of pentobarbital sodium (25 mg/kg), and ventilated with a respirator. Dogs were then anesthetized with intravenous infusion of
-chloralose (3.75 mg/min). A thoracotomy was performed in the left fourth intercostal space, and the heart was suspended in a
pericardial cradle. A heating pad was used to maintain the rectal
temperature of animals within the range of 36.0-37.0°C.
A 7-Fr catheter was inserted into the aortic arch through the left carotid artery for measurement of aortic pressure (AoP), and a 7-Fr catheter-tipped pressure transducer was inserted into the LV cavity through the left atrium for the measurement of LV pressure (LVP).
AoP was measured using a strain-gauge transducer (TP-400T, Nihon-Kohden). A cardiotachometer triggered by AoP pulses was used to monitor HR. LVP was measured with a catheter-tipped transducer (PC-350, Millar Instruments; Houston, TX), and the positive first derivative of LVP (LV dP/dt) was obtained by electronic differentiation. A transit-time flow probe was placed at the midportion of the left anterior descending (LAD) coronary artery (16), and CBF was measured with an ultrasonic flowmeter (T201, Transonic Systems; Ithaca, NY). Peak responses of CBF to drugs were used for analysis. All variables were continuously monitored and recorded using a polygraph system (RM-6000, Nihon-Kohden).
Heparin-filled tubing (2-Fr size) was inserted into the LAD immediately distal to the flow probe for drug infusion. A 3-Fr catheter was inserted into the great cardiac vein and was advanced into the anterior interventricular vein for venous blood sampling. The hemoglobin content in each venous blood sample was also measured.
Myocardial oxygen consumption (MVO2) was
calculated from the following formula: MVO2 (in
ml/min) = CBF (in ml/min) × 0.0136 × Hb (in g/dl) × [SaO2 (in percent) SvO2
(in percent)]/100, where Hb is hemoglobin content and
SaO2 and SvO2 represent oxygen saturation of the coronary arterial and venous blood, respectively.
Drugs
Tiron was dissolved in normal saline and neutralized by addition of equimolar NaOH. Indomethacin was diluted with sodium carbonate. Adenosine, sodium nitroprusside (SNP), and NG-monomethyl-L-arginine (L-NMMA) were dissolved in normal saline. All drugs were obtained from Sigma (St. Louis, MO).Experimental Protocols
After the surgical preparation was completed, indomethacin (5 mg/kg) was administered intravenously to block the cyclooxygenase pathway. The animals were studied 30 min after the administration of indomethacin, when all of the hemodynamic parameters had stabilized.Protocol 1: effects of tiron and tiron + L-NMMA
on CBF response to adenosine, reactive hyperemia, and SNP.
Six control dogs and nine HF dogs were used. Adenosine at graded doses
(3, 10, and 30 µM) was infused into the LAD for 1 min while CBF at
the LAD, AoP, LVP, LV dP/dt, and HR were monitored continuously and recorded. Adenosine at the dose of 30 µM/min was
chosen because this dose induced maximal coronary vasodilation (percent
increase in CBF by nearly 400%) in both control and HF dogs without
affecting other hemodynamic variables. The percentage of coronary
vasodilation by adenosine at 30 µM/min was comparable with that by
brief coronary occlusion (Fig. 1 and
Table 1). After all of the variables
returned to baseline, reactive hyperemia was produced by LAD occlusion
just proximal to the flow probe for 20 s and complete reperfusion.
After 5 min, all of the variables returned to baseline, and the
endothelium-independent vasodilator SNP (30 µg/min) was then
administered. After return to baseline, tiron was infused at 7 mmol/l
per CBF (in ml/min) into the LAD (2). This dose of tiron
was selected because this dose scavenged OFR in both intracellular and
extracellular environment in vitro (20, 23). Ten minutes
after the beginning of tiron infusion, the infusions of adenosine and
SNP and reactive hyperemia were repeated during tiron infusion. After
the subsequent return to baseline, tiron + the NO synthase
inhibitor L-NMMA (1 mg/kg) were infused into the LAD. We
recently showed that L-NMMA at this dose significantly
inhibited the CBF response to acetylcholine (3 µg/min ic) in both
control and HF dogs (P < 0.01) without affecting other hemodynamic variables or myocardial metabolism (2).
Adenosine and SNP injection and reactive hyperemia were repeated.
|
|
Protocol 2: reproducibility of vasodilatory response to adenosine, reactive hyperemia, and SNP. Five control and five HF dogs were used. The vasodilatory responses to adenosine, reactive hyperemia, and SNP were repeated three times at 30-min intervals without any treatment.
Protocol 3: measurement of OFR formation in myocardial tissues.
Ten control dogs with (n = 5) or without
(n = 5) intracoronary administration of tiron (7 mmol · l
1 · min1) for 10 min and 10 HF dogs with (n = 5) or without
(n = 5) intracoronary tiron were used. To confirm OFR
formation, electron-spin resonance (ESR) spectroscopy was used
(11). ESR measurements were performed at room temperature
using an X-band (9.45 GHz) ESR spectrometer (JES-RE-1X, Jeol).
Freeze-clamped myocardial samples weighing 100 mg each were excised
from the LV free wall and homogenized in 50 mmol/l sodium phosphate
buffer containing protease inhibitors. The homogenates were immediately
reacted with 4-hydroxy-2,2,6,6-tetramethyl-peperidine-N-oxyl (0.1 mmol/l), and the ESR spectra were recorded. We
(11) previously reported that the increase in the ESR
signal decay in HF dogs was scavenged by tiron or catalase, indicating
that superoxide is produced in myocardium from HF dogs.
Protocol 4: immunohistochemistry of 4-hydroxy-2-nonenal-modified protein. To assess the cellular localization of lipid peroxidation by histochemical analysis, sections of LV myocardium were immunolabeled with an antibody raised against 4-hydroxy-2-nonenal (HNE)-modified protein, an aldehydic byproduct of lipid peroxidation (32, 38). Paraffin-embedded tissue sections (5 µm thick) were deparaffinized with xylene, refixed with Bouin's solution for 20 min, immersed in PBS, and incubated with 0.3% H2O2 in methanol for 30 min. The sections were further incubated with polyclonal antiserum raised against a HNE-modified histidyl peptide (Gly3-His-Gly3; 4 or 8 µg/ml, NN2050-70, Funakoshi). After the sections were rinsed with 0.01 mol/l PBS, they were incubated with biotin-labeled goat anti-rabbit IgG antiserum (1:100 dilution; DAKO A/S) for 60 min and then with avidin-biotin complex (1:100 dilution; Vectastain ABC kit) for 60 min. After the sections were rinsed, they were finally incubated with 0.02% 3,3-diaminobenzidine and 0.03% H2O2 in deionized water for 6-9 min. As a negative control, sections were incubated with normal rabbit serum as well.
Statistical Analysis
Data are presented as means ± SE. Differences between two experiments were compared using Student's t-tests. Differences among three or experiments were determined using two-way analysis of variance and a Bonferroni's multiple comparison test. A P value of 0.05 or less was considered statistically significant.| |
RESULTS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Echocardiographic examination revealed that long-term pacing
tachycardia caused a significant decrease in LV ejection fraction (71 ± 2% and 32 ± 3%, respectively, in control and HF
dogs) and an increase in LV end-diastolic dimensions (33 ± 1 and
45 ± 1 mm, respectively, in control and HF dogs). Hemodynamic
parameters, which were measured under anesthesia, are shown in Table
2. Mean AoP and LV dP/dt were
less and LV end-diastolic pressure (LVEDP) was greater in HF dogs than
in controls (P < 0.01). There was no significant
difference between the two groups in CBF and HR.
|
Protocol 1: Effects of Tiron and Tiron + L-NMMA on CBF Response to Adenosine, Reactive Hyperemia, and SNP
In control and HF dogs, treatment with tiron did not affect basal CBF, other hemodynamic parameters, or myocardial metabolic states (Table 2). The increase in CBF evoked by adenosine at 30 µM/min was significantly impaired in HF dogs compared with controls (Fig. 1). Treatment with tiron significantly enhanced the adenosine-induced increase in CBF in HF dogs but not in controls (Fig. 1). Peak reactive hyperemia after 20-s ischemia was also significantly impaired in HF dogs compared with controls. Tiron treatment significantly enhanced the peak reactive hyperemia in HF dogs but not in controls (Table 1). The repayment (area of reactive hyperemia after reperfusion)-to-debt (area of debt during LAD occlusion) ratio was similar between the two groups. Tiron treatment had no effects on the repayment-to-debt ratio in both groups (Table 1). After treatment with tiron, the increase in CBF by adenosine at 30 µM/min and peak reactive hyperemia did not significantly differ between the two groups (Fig. 1 and Table 1). Treatment with tiron + L-NMMA abolished the beneficial effect of tiron in adenosine-induced increases in CBF and peak reactive hyperemia in HF groups. SNP-induced increases in CBF were similar between the two groups and no changes in its response were noted with tiron or tiron + L-NMMA treatment (Table 1).Protocol 2: Time Control Study
Changes in CBF in response to adenosine, reactive hyperemia, and SNP were not significantly different among the first, second, and third experiments (Table 3).
|
Protocol 3: OFR Formation in Myocardial Tissue
In dogs without in vivo tiron treatment, OFR formation was significantly greater in HF dogs compared with controls. In dogs with in vivo tiron treatment, OFR formation did not differ between the two groups (Fig. 2). These results indicate that OFR formation is enhanced in HF dogs and in vivo tiron treatment can effectively scavenge OFR.
|
Protocol 4: Immunohistochemical Detection of Lipid Peroxidation
Immunohistochemical analysis of HNE-modified protein was performed in five control and five HF dogs. Lipid peroxides were positively stained in many coronary microvessels (small arteries, arterioles, and venules) in all five HF dogs without in vivo treatment with tiron (Fig. 3). Large epicardial arteries and myocardial myocytes were weakly stained in HF dogs. In contrast, no labeling was observed in coronary vessels or myocardium in control dogs. No immunoactivity was noted when the antibody against HNE-modified protein was replaced with nonimmune IgG (negative control).
|
| |
DISCUSSION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
The major finding of the present study was that antioxidant therapy with tiron improved coronary flow reserve evoked by adenosine or brief ischemia in dogs with pacing-induced HF. In contrast, tiron did not affect coronary flow reserve in healthy control dogs. Furthermore, after treatment with tiron + L-NMMA, the beneficial effects of tiron on coronary flow reserve were not noted. These findings suggest that antioxidant therapy with tiron increased the bioavailability of endothelium-derived NO and thereby improved the coronary flow reserve in HF dogs.
We and other investigators (2, 3, 11, 22) have reported an increase in OFR formation in cardiovascular tissue from animals and humans with HF. In the present study, OFR formation was increased in myocardial tissues of HF dogs compared with controls. In addition, immunohistochemical staining of HNE-modified protein indicated increased OFR levels, especially in the endothelium of coronary vessels. In vivo treatment with tiron did not affect the level of OFR formation in control dogs but did reduce it in HF dogs, suggesting that tiron indeed acted as the antioxidant in our dogs with HF. Because OFR inactivates NO (19), the bioactivity of endothelium-derived NO would be impaired in HF, which in turn decreases endothelium-dependent vasodilation (2, 3, 31, 34). Therefore, our present observations extend our previous observations (2) and suggest that an increased inactivation of NO was involved in the impaired coronary flow reserve in the animal model of HF. It is unlikely that tiron increased the vasodilatory capacity of smooth muscle cells in coronary vessels, because tiron or tiron + L-NMMA treatment did not affect the SNP-induced dilation in both control and HF dogs.
We considered the possibility that the beneficial effect of tiron on coronary flow reserve was attributable to changes in the severity of HF or in hemodynamic parameters. It has been suggested that the increase in extravascular compressive force such as elevated LVEDP may be major mechanism of reduced coronary flow reserve in HF (7, 13, 26, 28). Shannon et al. (28) reported that acute reduction in LVEDP resulted in partial improvement of subendocardial coronary flow reserve in response to adenosine in a dog model of pacing-induced HF. In contrast, others (18, 24, 25) argued that the increased LVEDP may not totally explain the mechanism of reduced coronary flow reserve in HF by demonstrating that coronary flow reserve is reduced in animal and patients with HF in the absence of increased LVEDP. In the present study, treatment with tiron had no effect on hemodynamic parameters and myocardial metabolic state (Table 2). Thus, although we did not examined the pressure-flow relationship over a range of perfusion pressure during coronary vasodilation, our present results suggest that the beneficial effects of tiron seen in HF dogs are not attributable solely to changes in hemodynamic parameters. This study suggests that reduced bioavailability of NO by increased OFR may be a major cause of reduced coronary flow reserve in HF. Because we did not measure the perfusion area distal to the flow probe, we cannot demonstrate CBF per gram of myocardium in the present study. However, we previously measured CBF/myocardial weight and reported that CBF per unit of myocardial mass was less in HF dogs compared with control dogs (37). Regarding LV weight, our laboratory (12) previously reported that the weight of the myocardium per body weight did not differ between control and HF dogs.
The coronary vasodilatation evoked by adenosine has been shown to be attenuated after inhibition of NO synthesis (15, 29, 36) or after endothelial removal (8, 27), suggesting that adenosine-induced coronary vasodilation is mediated in part by endothelium-derived NO. Adenosine may cause coronary vasodilatation by a combination of direct receptor-mediated relaxation of vascular smooth muscles, receptor-mediated release of NO from the endothelium, and secondary flow-mediated release of NO from the endothelium (9, 14, 21, 30). Reduced bioavailability of NO thereby impairs adenosine-induced coronary vasodilation, as seen in the HF dogs in the present study. We show herein reduced peak flow in HF dogs, whereas the repayment-to-debt ratio did not significantly differ between control and HF dogs. Because peak reactive hyperemia was not inhibited by a NO synthesis inhibitor in healthy normal dogs (1, 35), improvement of peak reactive hyperemia by tiron treatment cannot be explained by a mere increase in NO bioactivity. However, in the presence of adenosine receptor blockade, additional treatment with a NO synthesis inhibitor has been shown to reduce peak reactive hyperemia in healthy normal dogs (35). Therefore, the decrease in bioactive NO from the endothelium may decrease peak reactive hyperemia in HF dogs. In preliminary studies, we examined several durations of brief coronary artery occlusion (5, 10, 20, and 60 s) in control and HF dogs and found that a 20-s occlusion of the coronary artery was sufficient to achieve the maximal reactive hyperemic response in both control and HF dogs (data not shown). We then examined the effects of tiron on reactive hyperemia in response to the 20-s coronary occlusion in control and HF dogs. Thus we do not know whether or not the same conclusion can be drawn when different occlusion durations are used.
There are at least three limitations in the present study. First, coronary flow reserve and other hemodynamic parameters were measured under anesthesia. In physiological conscious conditions, resting HR must be higher in HF dogs due to increased chronotropic drive. However, this was not the case in the present study. Furthermore, increased resting HR in control dogs might drive up the basal myocardial oxygen demand, which in turn decreased coronary flow reserve. Therefore, some of the differences in coronary flow reserve might have been masked. Second, multiple interventions, such as the adenosine infusion, were not randomized. Because reproducibility of vasodilatory response was presented, it is unlikely that the observed effects of tiron and tiron + L-NMMA treatment are time-dependent nonspecific effects. Third, although we have shown here that tiron suppressed increased OFR formation in HF dogs, we cannot exclude a possibility that tiron might affect coronary flow reserve through a currently unrecognized mechanism.
In conclusion, the present study demonstrated that the antioxidant treatment with tiron is capable of improving abnormal coronary flow reserve in response to adenosine and brief ischemia in a dog model of pacing-induced HF. Our present observations suggest that increased oxidative stress in the coronary vascular bed in HF not only impairs bioactive NO and causes endothelial dysfunction but also impairs coronary flow reserve. Reduced coronary flow reserve in patients with HF has been reported to be associated with myocardial ischemia (33), suggesting that a reduced coronary flow reserve in HF may initiate myocardial hypoperfusion and thus lead to the progression of HF. If antioxidant therapy proves to ameliorate reduced perfusion of vital organs such as the heart, brain, and kidney in HF, increased OFR may be a new therapeutic target for HF.
| |
FOOTNOTES |
|---|
Address for reprint requests and other correspondence: K. Egashira, Dept. of Cardiovascular Medicine, Kyushu Univ. Graduate School of Medicine, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8552, Japan (E-mail: egashira{at}cardiol.med.kyushu-u.ac.jp).
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 17 April 2001; accepted in final form 13 August 2001.
| |
REFERENCES |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
1.
Altman, JD,
Kinn J,
Duncker DJ,
and
Bache RJ.
Effect of inhibition of nitric oxide formation on coronary blood flow during exercise in the dog.
Cardiovasc Res
28:
119-24,
1994
2.
Arimura, K,
Egashira K,
Nakamura R,
Ide T,
Tsutsui H,
Shimokawa H,
and
Takeshita A.
Increased inactivation of nitric oxide is involved in coronary vascular endothelial dysfunction in tachycardia-induced heart failure.
Am J Physiol Heart Circ Physiol
280:
H68-H75,
2001
3.
Bauersachs, J,
Bouloumie A,
Fraccarollo D,
Hu K,
Busse R,
and
Ertl G.
Endothelial dysfunction in chronic myocardial infarction despite increased vascular endothelial nitric oxide synthase and soluble guanylate cyclase expression: role of enhanced vascular superoxide production.
Circulation
100:
292-298,
1999
4.
Belch, JJ,
Bridges AB,
Scott N,
and
Chopra M.
Oxygen free radicals and congestive heart failure.
Br Heart J
65:
245-248,
1991
5.
Cannon, RO, 3rd,
Cunnion RE,
Parrillo JE,
Palmeri ST,
Tucker EE,
Schenke WH,
and
Epstein SE.
Dynamic limitation of coronary vasodilator reserve in patients with dilated cardiomyopathy and chest pain.
J Am Coll Cardiol
10:
1190-200,
1987[Abstract].
6.
Drexler, H.
Endothelial dysfunction: clinical implications.
Prog Cardiovasc Dis
39:
287-324,
1997[ISI][Medline].
7.
Ellis, AK,
and
Klocke FJ.
Effects of preload on the transmural distribution of perfusion and pressure-flow relationships in the canine coronary vascular bed.
Circ Res
46:
68-77,
1980
8.
Headrick, JP,
and
Berne RM.
Endothelium-dependent and -independent relaxations to adenosine in guinea pig aorta.
Am J Physiol Heart Circ Physiol
259:
H62-H67,
1990
9.
Hein, TW,
and
Kuo L.
cAMP-independent dilation of coronary arterioles to adenosine: role of nitric oxide, G proteins, and K(ATP) channels.
Circ Res
85:
634-42,
1999
10.
Hornig, B,
Arakawa N,
Kohler C,
and
Drexler H.
Vitamin C improves endothelial function of conduit arteries in patients with chronic heart failure.
Circulation
97:
363-368,
1998
11.
Ide, T,
Tsutsui H,
Kinugawa S,
Suematsu N,
Hayashidani S,
Ichikawa K,
Utsumi H,
Machida Y,
Egashira K,
and
Takeshita A.
Direct evidence for increased hydroxyl radicals originating from superoxide in the failing myocardium.
Circ Res
86:
152-157,
2000
12.
Igarashi-Saito, K,
Tsutsui H,
Yamamoto S,
Takahashi M,
Kinugawa S,
Tagawa H,
Usui M,
Yamamoto M,
Egashira K,
and
Takeshita A.
Role of SR Ca2+-ATPase in contractile dysfunction of myocytes in tachycardia-induced heart failure.
Am J Physiol Heart Circ Physiol
275:
H31-H40,
1998
13.
Inoue, T,
Sakai Y,
Morooka S,
Hayashi T,
Takayanagi K,
Yamaguchi H,
Kakoi H,
and
Takabatake Y.
Vasodilatory capacity of coronary resistance vessels in dilated cardiomyopathy.
Am Heart J
127:
376-381,
1994[ISI][Medline].
14.
Ishibashi, Y,
Duncker DJ,
Zhang J,
and
Bache RJ.
ATP-sensitive K+ channels, adenosine, and nitric oxide-mediated mechanisms account for coronary vasodilation during exercise.
Circ Res
82:
346-359,
1998
15.
Jones, CJ,
Kuo L,
Davis MJ,
DeFily DV,
and
Chilian WM.
Role of nitric oxide in the coronary microvascular responses to adenosine and increased metabolic demand.
Circulation
91:
1807-1813,
1995
16.
Katsuda, Y,
Egashira K,
Ueno H,
Akatsuka Y,
Narishige T,
Arai Y,
Takayanagi T,
Shimokawa H,
and
Takeshita A.
Glibenclamide, a selective inhibitor of ATP-sensitive K+ channels, attenuates metabolic coronary vasodilatation induced by pacing tachycardia in dogs.
Circulation
92:
511-517,
1995
17.
Katz, SD.
Mechanisms and implications of endothelial dysfunction in congestive heart failure.
Curr Opin Cardiol
12:
259-264,
1997[ISI][Medline].
18.
Knecht, M,
Burkhoff D,
Yi GH,
Popilskis S,
Homma S,
Packer M,
and
Wang J.
Coronary endothelial dysfunction precedes heart failure and reduction of coronary reserve in awake dogs.
J Mol Cell Cardiol
29:
217-227,
1997[ISI][Medline].
19.
Kojda, G,
and
Harrison D.
Interactions between NO and reactive oxygen species: pathophysiological importance in atherosclerosis, hypertension, diabetes and heart failure.
Cardiovasc Res
43:
562-571,
1999[ISI][Medline].
20.
Krishna, CM,
Liebmann JE,
Kaufman D,
DeGraff W,
Hahn SM,
McMurry T,
Mitchell JB,
and
Russo A.
The catecholic metal sequestering agent 1,2-dihydroxybenzene-3,5-disulfonate confers protection against oxidative cell damage.
Arch Biochem Biophys
294:
98-106,
1992[ISI][Medline].
21.
Liao, JC,
and
Kuo L.
Interaction between adenosine and flow-induced dilation in coronary microvascular network.
Am J Physiol Heart Circ Physiol
272:
H1571-H1581,
1997
22.
Mallat, Z,
Philip I,
Lebret M,
Chatel D,
Maclouf J,
and
Tedgui A.
Elevated levels of 8-iso-prostaglandin F2
in pericardial fluid of patients with heart failure: a potential role for in vivo oxidant stress in ventricular dilatation and progression to heart failure.
Circulation
97:
1536-1539,
1998
23.
Munzel, T,
Sayegh H,
Freeman BA,
Tarpey MM,
and
Harrison DG.
Evidence for enhanced vascular superoxide anion production in nitrate tolerance. A novel mechanism underlying tolerance and cross-tolerance.
J Clin Invest
95:
187-194,
1995.
24.
Neglia, D,
Parodi O,
Gallopin M,
Sambuceti G,
Giorgetti A,
Pratali L,
Salvadori P,
Michelassi C,
Lunardi M,
Pelosi G,
Marzilli M,
and
L'Abbate A.
Myocardial blood flow response to pacing tachycardia and to dipyridamole infusion in patients with dilated cardiomyopathy without overt heart failure. A quantitative assessment by positron emission tomography.
Circulation
92:
796-804,
1995
25.
Nitenberg, A,
Foult JM,
Blanchet F,
and
Zouioueche S.
Multifactorial determinants of reduced coronary flow reserve after dipyridamole in dilated cardiomyopathy.
Am J Cardiol
55:
748-754,
1985[ISI][Medline].
26.
Opherk, D,
Schwarz F,
Mall G,
Manthey J,
Baller D,
and
Kubler W.
Coronary dilatory capacity in idiopathic dilated cardiomyopathy: analysis of 16 patients.
Am J Cardiol
51:
1657-1662,
1983[ISI][Medline].
27.
Rubanyi, G,
and
Vanhoutte PM.
Endothelium-removal decreases relaxations of canine coronary arteries caused by beta-adrenergic agonists and adenosine.
J Cardiovasc Pharmacol
7:
139-144,
1985[ISI][Medline].
28.
Shannon, RP,
Komamura K,
Shen YT,
Bishop SP,
and
Vatner SF.
Impaired regional subendocardial coronary flow reserve in conscious dogs with pacing-induced heart failure.
Am J Physiol Heart Circ Physiol
265:
H801-H809,
1993
29.
Smits, P,
Williams SB,
Lipson DE,
Banitt P,
Rongen GA,
and
Creager MA.
Endothelial release of nitric oxide contributes to the vasodilator effect of adenosine in humans.
Circulation
92:
2135-2141,
1995
30.
Stepp, DW,
Nishikawa Y,
and
Chilian WM.
Regulation of shear stress in the canine coronary microcirculation.
Circulation
100:
1555-1561,
1999
31.
Treasure, CB,
Vita JA,
Cox DA,
Fish RD,
Gordon JB,
Mudge GH,
Colucci WS,
Sutton MG,
Selwyn AP,
Alexander RW,
and
Ganz P.
Endothelium-dependent dilation of the coronary microvasculature is impaired in dilated cardiomyopathy.
Circulation
81:
772-779,
1990
32.
Uchida, K,
Itakura K,
Kawakishi S,
Hiai H,
Toyokuni S,
and
Stadtman ER.
Characterization of epitopes recognized by 4-hydroxy-2-nonenal-specific antibodies.
Arch Biochem Biophys
324:
241-248,
1995[ISI][Medline].
33.
Van den Heuvel, AF,
van Veldhuisen DJ,
van der Wall EE,
Blanksma PK,
Siebelink HM,
Vaalburg WM,
van Gilst WH,
and
Crijns HJ.
Regional myocardial blood flow reserve impairment and metabolic changes suggesting myocardial ischemia in patients with idiopathic dilated cardiomyopathy.
J Am Coll Cardiol
35:
19-28,
2000
34.
Wang, J,
Seyedi N,
Xu XB,
Wolin MS,
and
Hintze TH.
Defective endothelium-mediated control of coronary circulation in conscious dogs after heart failure.
Am J Physiol Heart Circ Physiol
266:
H670-H680,
1994
35.
Yada, T,
Hiramatsu O,
Kimura A,
Tachibana H,
Chiba Y,
Lu S,
Goto M,
Ogasawara Y,
Tsujioka K,
and
Kajiya F.
Direct in vivo observation of subendocardial arteriolar response during reactive hyperemia.
Circ Res
77:
622-631,
1995
36.
Yada, T,
Hiramatsu O,
Tachibana H,
Toyota E,
and
Kajiya F.
Role of NO and K
37.
Yamamoto, M,
Egashira K,
Arimura K,
Tada H,
Shimokawa H,
and
Takeshita A.
Coronary vascular K
38.
Yoritaka, A,
Hattori N,
Uchida K,
Tanaka M,
Stadtman ER,
and
Mizuno Y.
Immunohistochemical detection of 4-hydroxynonenal protein adducts in Parkinson disease.
Proc Natl Acad Sci USA
93:
2696-2701,
1996
This article has been cited by other articles:
|
|
 |
|
  S. Iida, Y. Chu, J. Francis, R. M. Weiss, C. A. Gunnett, F. M. Faraci, and D. D. Heistad Gene transfer of extracellular superoxide dismutase improves endothelial function in rats with heart failure Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H525 - H532. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Oishi, Y. Nishimura, K.-i. Imasaka, N. Kajihara, S. Morita, M. Masuda, and H. Yasui Impairment of coronary flow reserve and left ventricular function in the brain-dead canine heart Eur. J. Cardiothorac. Surg., September 1, 2003; 24(3): 404 - 410. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
P < 0.01 vs. after tiron treatment;
P < 0.05 vs. corresponding control dogs. NS, not
significant.
