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1 Department of Medical Engineering and Systems Cardiology, Kawasaki Medical School, Okayama 701-0192; 2 Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8542; 3 Department of Nephrology, Saitama Medical School, Saitama 350-0495; 4 Department of Cardiovascular Physiology, Okayama University Graduate School of Medicine and Dentistry, Okayama 700-8558, Japan
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ABSTRACT |
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 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Time-sequential responses to endothelium-dependent and -independent vasodilators and angiotensin-converting enzyme (ACE) inhibitors were studied in the subendocardial arterioles (Endo) of canine renovascular hypertension (HT) compared with subepicardial arterioles (Epi; both <120 µm) by charge-coupled device intravital microscope. Vascular responses to acetylcholine, papaverine, and cilazaprilat were compared between normotensive (NT) and HT dogs [4 wk and 12 wk of HT (4wHT and 12wHT)]. The acetylcholine-induced vasodilation of Endo in both 4wHT and 12wHT was smaller than that of NT (both P < 0.01 vs. 4wHT and 12wHT), and that of Epi was smaller than that of NT only in 12wHT (P < 0.05). The papaverine-induced vasodilation of Endo, but not Epi, was impaired only in 12wHT (both P < 0.01 vs. NT and 4wHT). Vasodilation by cilazaprilat remained unchanged at 4wHT and 12wHT in both Epi and Endo. In conclusion, at the early stage, the endothelium-dependent response of Endo was impaired, whereas at the later stage, the endothelium-dependent and -independent responses of Endo and the endothelium-dependent response of Epi were impaired. However, the vasodilatory responses to the ACE inhibitor were maintained in both Endo and Epi of HT.
endothelium-dependent and -independent vasodilators; angiotensin-converting enzyme inhibitor
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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INCREASED VULNERABILITY of the hypertensive hypertrophied heart to ischemia is explained by a decreased coronary flow reserve (1). The subendocardium (Endo) is more prone to ischemia than the subepicardium (Epi) in the hypertrophic heart. Indeed, coronary subendocardial autoregulation was altered by hypertension (HT) (7, 13). Along with the microcirculatory dysfunction in HT, endothelial (25) and smooth muscle (12) dysfunctions develop with cardiac hypertrophy. However, there is no direct in vivo evaluation of the endothelium-dependent and -independent vasodilation in Endo in the time course of the HT.
Angiotensin-converting enzyme (ACE) activation contributes to development of vascular and myocardial changes in left ventricular (LV) hypertrophy. ACE inhibitors have been shown to prevent the development of HT and vascular hypertrophy and to improve the endothelium-dependent responses in the aorta (4). However, ACE inhibition-induced vasodilation in Endo arterioles has not been adequately defined in the in vivo hypertensive heart.
The purposes of this study were to clarify the following: 1) how and when transmural (Endo vs. Epi) difference of endothelium-dependent and -independent vasodilation with time-sequential changes appears in the renovascular hypertensive canine heart, and 2) whether the vascular responses to an ACE inhibitor are impaired in Endo. We evaluated the effects of endothelium-dependent and -independent vasodilators, and the action of ACE inhibitor on transmural arteriolar responses in the 4th- and 12th-wk renovascular HT by using our needle-lens probe intravital microscope.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animal preparation. This study conformed to the Guideline on Animal Experiments of Kawasaki Medical School, the Japanese Government Animal Protection and Management Law (No. 115) and the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publication No. 85-23, Revised 1996).
Mongrel dogs (10-25 kg) of either sex with HT (n = 20) and normotension (NT) under control conditions (n = 19) were anesthetized with ketamine (10 mg/kg im) and pentobarbital sodium (25 mg/kg iv). After intubation, each animal was ventilated with the use of a high-frequency jet ventilator (model VS600, IDC) with room air, supplemented with 100% oxygen. Aortic pressure (AoP) and LV pressure were measured with an 8-Fr pigtail double manometer catheter (model SPC-784A, Millar). The proximal portion of the left anterior descending coronary artery (LAD) was isolated and a transonic flow probe (model T206, Transonic Systems; Ithaca, NY) was placed around the vessel. The heart rate was kept constant at 100 beats/min during the experiment by right ventricular pacing after atrioventricular node blocking with 37% formaldehyde.Needle-probe intravital microscope. Details of the needle-probe intravital microscope have been previously described (29). Briefly, the needle probe (4.5 mm diameter) contains a gradient index lens surrounded by light guide fibers and a double-lumen sheath. A doughnut-shaped balloon on the tip avoids direct compression of the vessels by the needle tip. To obtain a clear image of the vessels, blood between the tip of the needle probe and the endocardium inside the doughnut was flushed away with a warm buffer solution injected through a microtube of the sheath.
Measurements of arteriolar diameters. The needle probe was introduced into the endocardium of LV through an incision in the left atrial appendage via the mitral valve. When a clear arteriolar image was obtained, the operator kept the probe position on the vessel manually. The vascular images at end diastole were taken with 30 pictures/s. The diameters of five scan lines neighboring each other and those for five consecutive heartbeats were ensemble averaged.
We also measured the end-diastolic diameter of Epi arterioles with the same instrument (8, 29), but separately from Endo measurements, because it was difficult to obtain access to Endo and Epi arterioles simultaneously.Preparation of renovascular hypertensive model. We used our earlier two-kidney and two-clip (2K2C) model (22). In brief, through a retroperitoneal incision, the kidney was exposed, and an electromagnetic flow probe was placed around the renal artery. Thereafter, an adjustable silver clip was placed around each renal artery. To induce moderate HT, the severity of renal artery stenosis was controlled to reduce renal blood flow of the ipsilateral kidney to 50% of the prestenotic level by monitoring renal blood flow with an electromagnetic flow probe. The dogs were kept for 4 wk (4wHT; n = 14) or for 12 wk (12wHT; n = 6).
Experimental protocol. After the surgical procedure and instrumentation, at least 30 min were allowed for stabilization by monitored hemodynamic variables. We did not resume the experiment until the recovery of baseline blood flow. We have chosen the vessels that did not have a baseline diameter change greater than ±5%. Injected volume of drug dissolved in saline (1 ml/min) did not change blood flow and arteriolar diameter.
First, to evaluate endothelium-dependent vasodilation, acetylcholine (1.0 µg/kg per min ic) was continuously infused into the diagonal branch of LAD with the use of a syringe pump (model STC 525, Terumo, Tokyo, Japan). The vascular responses of Epi arterioles in NT, 4wHT, and 12wHT were observed for 2 min with the LAD flow responses. Second, when coronary blood flow and blood pressure recovered to baseline 5-10 min later, to allow examination of endothelium-independent vasodilation in Epi, papaverine (1 mg bolus ic) was slowly infused into the diagonal branch, and the arteriolar responses were evaluated. Third, after reverting to the baseline as to the hemodynamics, acetylcholine was continuously infused again into the diagonal branch of LAD using a syringe pump. The vascular responses of Endo arterioles were observed for 2 min with the LAD flow responses (see Fig. 5B). Fourth, after recovering to the baseline level, papaverine was slowly infused again into the diagonal branch and Endo arteriolar responses in NT, 4wHT, and 12wHT were evaluated (see Fig. 5C). Fifth, when coronary blood flow and blood pressure recovered the baseline, the ACE inhibitor cilazaprilat (10.0 µg/kg per min ic) was continuously infused and Endo arteriolar responses were evaluated (see Fig. 5D). Finally, after reverting of the hemodynamics, the ACE inhibitor cilazaprilat was continuously infused again and Epi arteriolar responses were evaluated. All drugs were obtained from Sigma, except for cilazaprilat, which was purchased from Eisai (Tokyo, Japan).Statistical analysis. Data were reported as means ± SE. The difference in effects of acetylcholine, papaverine, and an ACE inhibitor on subendocardial arteriole versus subepicardial arteriole was tested by a multiple regression analysis with the use of a model, in which the change in diameter was set as a dependent variable (y) and vascular size as an explanatory variable (x), whereas the statuses of 4wHT and 12wHT were set as the dummy variables D1 and D2, respectively: y = a0 + a1x + a2D1 + a3D2, where a0-a3 are partial regression coefficients. Student's t-test was used for both paired and unpaired comparisons. The criterion for statistical significance was P < 0.05.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Hemodynamic parameters. The LV mass per body mass was 4.9 ± 0.3 g/kg in the NT group (n = 19), 6.6 ± 0.2 g/kg in 4wHT (n = 15, P < 0.01 vs. NT), and 6.6 ± 0.5 g/kg in 12wHT (n = 6, P < 0.05 vs. NT). LV wall thickness was 9 ± 1 mm in the NT group, 12 ± 1 mm in 4wHT (P < 0.01 vs. NT), and 14 ± 1 mm in 12wHT (P < 0.01 vs. NT). LV mass and wall thickness were not different between 4wHT and 12wHT. The systolic AoP (SBP: 4wHT, 145 ± 6 mmHg; 12wHT, 179 ± 12 mmHg) and diastolic AoP (DBP: 4wHT, 109 ± 5 mmHg; 12wHT, 137 ± 16 mmHg) of HT were higher than those of the NT group (SBP, 103 ± 4 mmHg, and DBP, 76 ± 4 mmHg, P < 0.05 and P < 0.01, vs. both hypertensive groups, respectively). SBP and DBP were different between 4wHT and 12wHT (both P < 0.05).
Table 1 lists the baseline hemodynamics after the dogs were stabilized with anesthesia and prepared for surgery. SBP and DBP were not significantly different between NT and both HT groups. LV end-diastolic pressure in HT slightly increased compared with NT. The LAD flow response during each intervention increased significantly from baseline values.
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Endothelium-dependent vasodilator response.
Figure 1A compares
endothelium-dependent vasodilation in Endo. There was a significant
difference between NT and 4wHT, and between NT and 12wHT (both
P < 0.01), but not between 4wHT and 12wHT. In Epi
(Fig. 1B), a significant difference was observed only
between NT and 12wHT (P < 0.05), but a decreasing
tendency without significance between NT and 4wHT (P = 0.07), probably due to wider scattering. Figure
2 is a comparison between Endo and Epi.
The vasodilation of Endo in 4wHT and 12wHT was smaller than that of Epi
(Fig. 2, B and C; P < 0.01), but
no significant difference in the NT group (Fig. 2A). As for
the vascular-size-dependent vasodilations, smaller vessels dilated more
in both Endo and Epi. Collectively, endothelium-dependent vascular
responses of arterioles were impaired in both 4wHT and 12wHT in Endo,
but only significant in 12wHT in Epi.
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Endothelium-independent vasodilator response.
Figure 3, A and B,
compares endothelium-independent vasodilation in the NT group with both
HT groups in Endo and Epi. There was no significant difference between
NT and 4wHT in both Endo and Epi, whereas the vasodilation in 12wHT was
impaired only in Endo (Fig. 3A, P < 0.01 vs. NT). Papaverine dilates both smaller and larger arterioles, but the
degree was greater in smaller vessels. Thus the endothelium-independent
vasodilation was impaired time sequentially only in Endo of 12wHT.
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Effects of ACE inhibitor.
Figure 4 shows effects of the ACE
inhibitor on arteriolar vasodilation. There was no significant
difference among three groups in both Endo and Epi, nor were there
transmural differences within each group. The vasodilation was also
greater in smaller arterioles.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The major findings from the present study were the following: 1) at 4wHT, the endothelium-dependent arteriolar response of Endo was impaired, but the endothelium-independent response was preserved; 2) at 12wHT, both the endothelium-dependent and -independent responses of Endo were impaired, but only the former was impaired in Epi; and 3) dilation after administration of the ACE inhibitor was not altered transmurally in the course of HT. Our results and discussion depend critically on several factors: 1) critique of experimental model and methodology; 2) impairment of coronary vasodilatory reserve of Endo with LV hypertrophy; 3) time course of impairment of endothelium-dependent and -independent vasodilator response; 4) the effect of the ACE inhibitor; and 5) clinical implications.
Critique of experimental model and methodology. We used Goldblatt HT dog model by application of 2K2C (22). In our renovascular model, development of 2K2C HT was associated with a marked increase in plasma renin activity, plasma angiotensin I, and plasma angiotensin II, followed by moderate increases during the maintenance of HT (22). We confirmed significant increases in SBP and DBP of both 4wHT and 12wHT. However, as for baseline hemodynamics during experiments, aortic pressure decreased in the hypertensive animals probably due to the anesthesia and surgical preparation. We focused our observation on the arterioles in both Endo and Epi with diameters of 45 ~ 120 µm because of the limitation of spatial resolution of our needle-probe videomicroscope. The vasodilation by acetylcholine and papaverine was attenuated in the course of our model hypertension, especially in Endo without any reduction in mean coronary flow. The discrepancy between the vessels and flow responses may be due to the greater involvement of metabolic autoregulation of the smaller arterioles below our spatial resolution and also due to transmural difference of vasodilation. Tomanek et al. (24) reported that the maximum flow by adenosine, which dilates preferentially smaller arterioles, was not different between control and 7-mo-old one-kidney, one-clip HT canine models, supporting our interpretation. In our experimental setup, the vascular diameter pulsation in Endo during a cardiac cycle was 21% in normal, 17% in 4wHT (P < 0.05 vs. control), and 15% in 12wHT (P < 0.05 vs. control). The decreased arteriolar diameter pulsation in Endo with HT may be mainly because the systolic blood pressure is reduced remarkably by the anesthesia and surgical preparation. The reduced compression may allow systolic myocardial inflow to some extent, contributing to discrepancy between the mean flow and diastolic vascular response. Because the systolic vascular compression in Endo must be much higher in conscious HT animals, their systolic myocardial inflow and mean coronary flow may be reduced with the decrease in diastolic vascular responses. On the other hand, abnormal flow responses of human coronary circulation to acetylcholine in patients with HT were well documented, probably due to the longer time course of HT in humans (26).
Acetylcholine and papaverine are well-established endothelium-dependent and -independent vasodilators. Microvascular responses were measured after an intracoronary administration (1.0 µg/kg) and bolus injection (1 mg), respectively, because we found that these procedures and doses produced transient maximal microvascular response to each agent without any systemic hemodynamics effects, as reported by Defily et al. (6). The intracoronary administration of cilazaprilat (10.0 µg/kg) increased coronary flow without any changes in the systemic hemodynamic as Kitakaze et al. (15) indicated. Kanatsuka et al. (14) reported that microvascular resistance in vessels (<150 µm) was twofold higher in HT cats compared with NT cats, whereas arterial resistance in vessels (>150 µm) was similar in HT and NT. Thus the present study focused on arterioles <120 µm. Another reason for the selection of arterioles (<120 µm) was practical difficulty in finding larger arterioles (>120 µm) in Endo. The methodological validity in the present study has been confirmed previously (8, 29). However, holding the needle probe on a fixed visual field of the endocardial surface for several minutes is usually technically difficult. Accordingly, we measured arteriolar diameters for ~2 min after vasodilator infusion to detect the maximal vasodilation, which had been validated by observation over longer periods. The spatial resolution of this system is ~5 µm for ×200 magnification (29). The maximum depth of field is ~250 µm.Impairment of coronary vasodilatory reserve of Endo with LV hypertrophy. Reduction in coronary flow reserve, especially in Endo is a possible mechanism for the impaired cardiac function in LV hypertrophy. Indeed, Vatner et al. (28) showed the importance of impaired coronary reserve in Endo as a mechanism for the diastolic dysfunction in a hypertrophied heart exposed to mechanical stresses. Harrison et al. (7) and Jeremy et al. (13) also indicated that HT and LV hypertrophy were associated with a profound impairment of the lower range of autoregulation in Endo. Hittinger et al. (10) and Bishop et al. (3) suggested that hemodynamic factors, i.e., compressive forces, were more important for reduced endocardial coronary reserve than structural alterations in LV hypertrophy caused by aortic stenosis. Thus the elevated LV end-diastolic pressure and wall stresses with increased systolic stresses, particularly in Endo, may cause abnormal endocardial coronary reserve.
By using our needle lens probe charge-coupled device videomicroscope, we found that Endo arterioles were more compressed at end systole compared with Epi under control conditions in pigs and dogs (8, 29). Compressive forces affect intramyocardial coronary circulation (1, 11). The increased systolic compression may be augmented in hypertensive hearts. Collectively, it is likely that coronary vasodilatory reserve of hypertensive hypertrophic hearts was more impaired in Endo than Epi.Time course of impairment of endothelium-dependent and -independent vasodilator response. It has been demonstrated that acetylcholine-induced relaxation is impaired in resistance arteries of experimental renovascular HT (17, 19) as well as other hypertensive models. Endothelium-dependent arteriolar response of Endo was already attenuated at 4wHT, whereas those of Epi were impaired at 12wHT (Fig. 2). The degree of the impairment is also greater in Endo than in Epi. It is known that nitric oxide (NO) release is inhibited in a pressure-dependent manner (9). In HT, systolic intramyocardial pressure should be increased with increasing LV pressure, and this trend is greater in Endo than in Epi, leading to higher intravascular pressure. Thus pressure-induced loss of NO release may be greater in Endo, reducing vascular dilation in Endo to which endothelium-derived NO significantly contributed (30).
The response to papaverine was impaired only in Endo of 12wHT. In moderate canine LV hypertrophy induced by renovascular HT for 6 wk and 7 mo, Tomanek et al. (23, 24) could not find any increase in the medial area of intramyocardial arteries nor any significant architectural difference. Thus in the renovascular hypertensive model, impaired endothelium-independent vascular responses in 12wHT may be the consequence of functional alterations in the microvascular smooth muscle. In addition, increased production and/or release of endothelium-dependent contractile factors (16, 18), such as angiotensin II, prostaglandin H2, thromboxane A2, and/or endothelin-1 with augmented sensitivity of vascular smooth muscles to vasoconstrictor stimuli in HT may lead to impaired vascular response.Effect of ACE inhibitor. Several studies (21, 31) have provided evidence for acute antihypertensive action of ACE inhibitors in different models of HT, which operates by dilating both canine coronary conductance and resistance arteries. In the present study, the vasodilation to the ACE inhibitor was unaltered, even in Endo in the course of HT (Figs. 4 and 5). What is the mechanism for unaltered vasodilation by the ACE inhibitor in the course of HT? To produce high blood pressure in dogs, we used our earlier 2K2C model. In this model, the elevation of blood pressure was associated with increases in plasma renin and angiotensin I and II, thus indicating activation of the renin-angiotensin system. Although the degree of angiotensin II increment became moderate during the maintenance of HT after initial remarkable augmentation, the vasodilatory response to the ACE inhibitor might be greater in the renovascular HT model. Thus an increased constrictor influence of angiotensin may override the papaverine-induced vasodilation. This may be a major reason for unaltered responses to the ACE inhibitors transmurally in the course of HT.
Kinin-NO-induced coronary vasodilation may be also related to the ACE inhibitor-induced vasodilation. Blockade of B2 kinin receptors has been shown to attenuate the hypotensive effect after a bolus injection of ACE inhibitor in two-kidney, one-clip hypertensive Wistar rats (2). Kitakaze et al. (15) demonstrated that an intracoronary infusion of cilazaprilat increased coronary flow in ischemic condition, especially in Endo with increase in bradykinin concentration and cGMP, suggesting that the kinin-NO effects are more prominent in Endo. The endothelial NO effect due to an ACE inhibitor might be partly modulated by vascular superoxide production. Angiotensin II has been shown to stimulate the NAD(P)H oxidase in smooth muscle cells, resulting in increased generation of superoxide that degrades NO (5). Actually, cilazaprilat prevented myocardial reactive oxygen species in Dahl salt-sensitive rats (27). However, because oxidative stress was not involved in the stage of compensatory hypertrophy (27), as in the present study, but was in the stage of heart failure, its contribution in our animal models is likely to be minor, if present at all.Clinical implications. This study discusses the results in which endothelium-dependent vasodilation was markedly impaired in the coronary microvessels of patients with HT and LV hypertrophy (25). The present study also indicated early (4th wk) impairment of endothelium-dependent vasodilation, but later (12th wk) involvement of endothelium-independent vasodilation, especially in Endo in the canine renovascular HT model. Thus the early control of HT may relieve the vascular dysfunction, especially endothelium-dependent impairment of vasodilation in Endo. ACE inhibitors may be one of the preferable treatments against renovascular HT to preserve both endothelium-dependent and -independent vasodilation. The homogenous myocardial blood flow distribution caused by ACE inhibitors (20) may be also beneficial to myocardial perfusion.
In conclusion, at 4wHT, the endothelium-dependent response of Endo was impaired. At 12wHT, both the endothelium-dependent and -independent responses of Endo were disturbed in the renovascular hypertensive hypertrophic canine model. These sequential changes may be related to the degree of decrease in coronary flow reserve of Endo in the course of LV hypertrophy. Larger impairment of coronary vascular response in Endo indicates the crucial role of higher hypertensive mechanical stress there. The vasodilatory responses to ACE inhibitor were preserved at 4wHT and 12wHT in both Endo and Epi. The mechanisms may be related to the effects of ACE inhibitors on angiotensin II and kinin-NO cascades.| |
ACKNOWLEDGEMENTS |
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We thank Prof. Takao Saruta for supervising this research.
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FOOTNOTES |
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This work was supported in part by Grants 12558114 and 14657178 from the Japanese Ministry of Education, Science, Sports, Culture, and Technology (Tokyo, Japan).
Address for reprint requests and other correspondence: T. Yada, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan (E-mail: yada{at}me.kawasaki-m.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.
First published January 9, 2003;10.1152/ajpheart.00819.2002
Received 13 September 2002; accepted in final form 2 January 2003.
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TOP
ABSTRACT
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METHODS
RESULTS
DISCUSSION
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