AT1 Receptor Antagonist Treatment Caused Persistent Arterial Functional Changes in Young Spontaneously Hypertensive Rats
Abstract The effects of chronic treatment with an AT1 receptor antagonist (L-158,809) on hypertension development and cardiovascular changes were studied in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). L-158,809 treatment (0.6 mg/kg PO) was initiated at 3 weeks of age and lasted 12 weeks, to 15 weeks of age. The treatment prevented hypertension development in the SHR (systolic blood pressure, BP, of 136±1 mm Hg compared with 198±3 mm Hg in control SHR), and lowered the BP of WKY (99±2 vs 128±1 mm Hg in control WKY). Treatment significantly reduced the heart weight in SHR and WKY. Ten weeks after treatment withdrawal (25 weeks of age), BP had increased in SHR and WKY to 172±8 and 117±3 mm Hg, respectively. Body weight and kidney weight were not affected by the treatment. Mesenteric arteries from treated SHR were less responsive than control SHR arteries to periarterial nerve stimulations at transmural pressures higher than 80 mm Hg (15 and 25 weeks). Control WKY arteries were less responsive than control SHR arteries at almost all transmural pressures tested (15 weeks) and to pressures greater than 80 mm Hg (25 weeks). Pretreatment of arteries with 10−8 mol/L angiotensin II enhanced their response to nerve stimulation in vessels from control SHR and WKY (25 weeks) but not from treatment-withdrawn SHR and WKY. Treatment did not alter arterial reactivity in response to norepinephrine. Alteration in arterial structure due to L-158,809 treatment was found only when measured at a transmural pressure of 100 mm Hg. In conclusion, L-158,809 was effective in preventing hypertension during the treatment period, in reducing hypertension severity during the withdrawal period, and in persistently decreasing the reactivity of the arteries.
The renin-angiotensin system is believed to be important in the development of hypertension in SHR,1 2 a hypothesis supported by chronic studies using both angiotensin-converting enzyme inhibitors and AT1 receptor antagonists. Chronic angiotensin-converting enzyme inhibitor treatment permanently reduced the BP in the SHR and prevented the development of cardiac hypertrophy and medial vessel wall thickening, both of which are normally associated with hypertension development in SHR.3 4 Previous chronic treatment studies of young SHR with the AT1 antagonists losartan or D 8731 showed significant BP reduction,1 2 which was maintained on withdrawal of the treatment.2 Although the importance of arterial structural changes to the development of hypertension has been suggested many times,5 6 some studies have not found a good correlation between the BP-lowering effects of the AT1 antagonist treatment and its effects on vascular structure.1 2 However, these studies did not investigate the effect of the AT1 antagonist treatment on vascular reactivity or the relationship between structure and reactivity.
The aim of this study was to assess the effects of chronic blockade of AT1 receptors on the development of hypertension, vascular and cardiac structure, and vascular reactivity, with treatment initiated in young SHR and WKY. We hypothesized that if angiotensin II is a major factor in the development of hypertension, early blockade of the AT1 receptors would result in the permanent attenuation of hypertension, possibly through its effects on the these cardiovascular parameters. The AT1 antagonist that we have used in this study (L-158,809) is 30 times more potent than losartan (PO dosing) in rats.7 We have shown previously that L-158,809 treatment of adult SHR at a dose of 0.6 mg/kg maximally lowered the SHR BP, an effect that was partially persistent on withdrawal of the L-158,809.8
All chemical compounds were obtained from Sigma Chemical Company unless otherwise indicated.
Forty each of male SHR and WKY were obtained from the McMaster University colonies that originated from the Charles River strains. Through inbreeding we have maintained the SHR colony since 1976 and the WKY colony since 1983. After weaning, the rats were kept under a 12-hour light/dark cycle. Food and water were constantly accessible. Daily L-158,809 treatment of SHR and WKY began at 3 weeks of age. Treatment was given by gavage for 12 weeks until the animals reached 15 weeks of age. At 15 weeks of age, half of the animals in the SHR and WKY control and SHR and WKY treated groups were killed and used for experiments. The other half were monitored for a further 10-week treatment withdrawal period. The care of these animals was in accordance with the guidelines of the Canadian Council on Animal Care.
Treatment with the AT1 receptor antagonist L-158,809 (tetrazolic acid monohydrate, Merck Research Laboratories) was carried out at a dose of 0.6 mg · kg−1 · d−1. L-158,809 was dissolved in a saturated NaHCO3 solution and then diluted with 0.5% methyl cellulose. The control groups received the vehicle alone at 0.2 mL/100 g body wt/d. Body weight was measured daily for the calculation of the treatment dose.
Systolic BP was measured weekly by the tail-cuff compression method (model PE300, Narco Bio-Systems) for the duration of the treatment and withdrawal periods.
Preparation of Animals and Sampling of the Tissues
The rats were anaesthetized with sodium pentobarbital (45 mg/kg IP) (MTC Pharmaceuticals). The kidneys and heart were removed and weighed. To obtain the dry weight, the left kidney was dried in a 40°C oven, then reweighed.
Reactivity experiments were carried out using the pressure myograph system previously described by Smeda,9 similar to that used by Osol and Halpern.10 This system allowed the measurement of the lumen alterations of the large mesenteric artery (first branch from the superior mesenteric artery), in response to pressure changes, chemical stimulations, or electrical stimulations (via two electrodes surrounding the artery, connected to a stimulator, model S48, Grass Medical Instruments). The artery was viewed through a microscope (model M3C, Leica), observed as a transparent image with the lumen visible. Alterations in lumen diameter were recorded via a video camera connected to a video recorder. The images were measured when played back on a television monitor.
Arterial reactivity was measured in response to a 20-Hz stimulation at a 10-second train of monophasic 0.85-ms pulses at 150 mV, with 20 mm Hg incremental steps of TMP from 20 to 140 mm Hg. Then, reactivity was measured in response to increasing stimulation frequencies (2 to 20 Hz) with a constant TMP of 100 mm Hg. The response of the arteries to a 20-Hz stimulation at 60 mm Hg TMP in the presence or absence of 10−8 mol/L angiotensin II was also measured. On separate arteries, concentration-response curves to NE were constructed in the presence of propranolol (3 μmol/L) and desipramine (1 μmol/L) to block β-adrenoceptor–induced stimulations and neuronal reuptake of NE, respectively. Response to 100 mmol/L KCl was used as 100%, and the response to NE was normalized to KCl response.
Morphometric measurements on large mesenteric (first-order) arteries were made using two techniques.1 Wall thickness and lumen diameters were measured during the reactivity experiments at TMPs of 20 and 100 mm Hg. When this technique was used, it was impossible to define the boundary between the media and adventitia layers due to limited resolution, so that wall thickness was measured.2 Wall, media, and lumen cross-sectional areas (CSA) and SMC layers were measured from the tracings of perfusion-fixed, maximally dilated arteries, as described previously.11 These arteries were fixed under low pressure (≈20 mm Hg) and flow (1 mL/min per 100 g body wt) conditions, and prepared for light microscopy as previously reported.11 CSA measurements were made by tracing the image of the cross section on a digitizing board (GraphicMaster, Labtronics). Lumen diameter and media thickness were calculated from the CSA using the equation area=πr2.
Values are expressed as mean±SEM. Statistical analysis was performed using the SigmaStat program (Jandel Scientific). For multiple comparisons of three or more groups of data, one-way ANOVA and the Student-Neuman-Keuls multiple comparisons test were used. For repeated multiple comparisons, a two-way ANOVA with repeated measures was used. Two-tailed Student’s t tests were used to compare two individual groups. Results were considered significant at P<.05.
After 12 weeks of treatment (age 15 weeks), systolic BP of treated SHR was 136±1 mm Hg (Fig 1A⇓), significantly less than that of the age-matched control SHR (198±3 mm Hg). In treated WKY, BP (99±2 mm Hg) was significantly lower than in control WKY (128±1 mm Hg). Ten weeks after withdrawal of the treatment (age 25 weeks), BP of treatment-withdrawn SHR had gradually increased to 172±7 mm Hg, still significantly less than age-matched control SHR BP (208±2 mm Hg). BP of the WKY treatment-withdrawn group increased immediately, then stabilized around 117±2 mm Hg, significantly less than the control WKY BP (125±2 mm Hg).
The body weights of SHR and WKY were similar at the beginning of the treatment. Both treated and control SHR showed faster growth than WKY, so that overall the body weights of both SHR groups were higher than those of the WKY groups (Fig 1B⇑). Treatment with L-158,809 did not affect the body weight of SHR or WKY. However, treatment significantly lowered the heart weight of SHR and WKY as compared with control SHR and WKY (Table 1⇓). After treatment withdrawal there were no differences in the heart weights between the control and treated SHR or WKY. L-158,809 treatment or treatment-withdrawal did not affect the wet weight or the dry weight of the kidneys in either SHR or WKY (data not shown). There was no difference in wet-to-dry weight ratio of the kidneys among the treated and control SHR and WKY, indicating that there was no tissue edema (Table 1⇓).
At a TMP of 100 mm Hg, lumen diameter was similar among the arteries from treated and control SHR and WKY at 15 or 25 weeks of age, except in arteries from treatment withdrawn SHR, which had a larger lumen at 25 weeks than the treated SHR at 15 weeks (Table 2⇓). Wall thickness and w/l ratio values were higher in control SHR than the other three groups after the treatment period (15 weeks of age). Unlike the SHR, in WKY L-158,809 treatment did not affect the lumen, wall thickness, or w/l ratio.
After the withdrawal period, control SHR arteries still had thicker walls than control and treatment-withdrawn WKY arteries but not treatment-withdrawn SHR, because of the increase in the wall thickness in these SHR at 25 weeks as compared with 15 weeks (Table 2⇑). Nevertheless, for the w/l ratio, the control SHR ratio remained higher than the treatment-withdrawn SHR ratio because of an increase in the lumen size from 15 to 25 weeks. Control SHR w/l ratio was also higher than both WKY groups’ ratios. A positive correlation was found between wall thickness and BP (r=.9787, P<.0001), and w/l and BP (r=.9423, P=.0005) among the 8 groups of rats (Fig 2⇓).
Values from morphometric measurements of the perfusion-fixed arteries under maximal relaxation again showed no significant difference in lumen size between control and treated SHR at 15 or 25 weeks of age (Table 3⇓). Lumen size of the treated WKY at both 15 and 25 weeks was significantly larger than the age-matched control WKY. Control SHR medial layer CSA was larger than control WKY at 15 and 25 weeks. Treatment did not alter the medial layer CSA of SHR or WKY, at 15 or at 25 weeks of age. Media-to-lumen ratios (m/l) were significantly higher in control SHR as compared with the age-matched WKY, at both 15 and 25 weeks. Treatment of SHR or WKY did not affect the m/l ratio at 15 weeks of age. However, at 25 weeks of age, the m/l ratio was smaller in treatment-withdrawn SHR and WKY than in the control animals. A positive correlation existed between medial CSA and BP (r=.7494, P<.03) and between m/l ratio and BP (r=.9047, P=.002) among the 8 groups of rats.
When calculated as linear dimensions, the lumen diameter of the control SHR was similar to that of control WKY at 15 and 25 weeks of age (Table 3⇑). Treatment did not affect the SHR lumen diameter but affected the lumen diameter in treated WKY at 15 and 25 weeks. Wall thickness and w/l ratio were higher in control SHR than in control WKY at 15 and 25 weeks. Neither the treatment nor the treatment withdrawal altered the wall thickness or w/l ratio of SHR; however, w/l ratio was decreased in the treatment-withdrawn WKY compared with control WKY.
The number of SMC layers was always higher in the SHR than WKY arteries at 15 and 25 weeks of age. Treatment with L-158,809 did not affect the number of SMC layers in the arteries from SHR or WKY. There was an age-related increase in the number of SMC layers in the WKY in both control and treatment-withdrawn WKY.
In comparison to the linear dimensions calculated for arteries measured after perfusion fixation, the linear dimensions measured during reactivity experiments (20 mm Hg TMP), showed no differences among the lumen diameters of the 8 groups (Table 3⇑). The vessel wall from control SHR was thicker than that from control WKY at 15 and 25 weeks. Values for w/l ratio were smaller in WKY than in SHR in both age groups. Treatment did not alter the wall thickness or w/l ratio of arteries from SHR or WKY at 15 and 25 weeks.
In response to a 20-Hz stimulation, mesenteric arteries from 15-week-old control SHR showed significantly greater contraction than treated SHR arteries at TMPs greater than 80 mm Hg, and they also generated more contraction than WKY arteries at almost all TMPs tested (Fig 3A⇓). After the treatment withdrawal period, arteries from the 25-week-old control SHR still contracted more than those from treatment-withdrawn SHR at TMPs greater than 80 mm Hg, and more than WKY at TMPs greater than 60 mm Hg (Fig 3B⇓). When the resultant lumen diameters were compared, lumen diameters of control SHR arteries were smaller than those of WKY at pressures greater than 20 mm Hg at 15 and 25 weeks; smaller than those of treated SHR at pressures greater than 60 mm Hg at 15 weeks (Fig 4A⇓), and smaller than those of treated SHR at pressures greater than 80 mm Hg at 25 weeks (Fig 4B⇓).
At a TMP of 100 mm Hg, mesenteric arteries from SHR and WKY showed a linear contractile response to increasing frequencies of electrical stimulation (Fig 5⇓). At 15 weeks and 25 weeks, control SHR arteries contracted more than treated SHR arteries at frequencies greater than 8 Hz. WKY arteries contracted less than control SHR arteries at frequencies greater than 8 Hz at 15 weeks (Fig 5A⇓) and at all frequencies at 25 weeks (Fig 5B⇓). All of these stimulated contractions could be blocked by tetrodotoxin.
The arteries from control and treated SHR and WKY showed similar NE concentration dose-response curves at 15 weeks (Fig 6A⇓) and 25 weeks (Fig 6B⇓). The calculated EC50 values at 15 weeks were similar in the control and treated SHR (4.9±0.9×10−5 and 5.5±3.5×10−5 mol/L, respectively) and WKY (1.1±1.0×10−4 and 7.7±6.7×10−5 mol/L). At 25 weeks, EC50 values were similar between control and treated SHR (2.1±0.5×10−5 and 1.7±0.6×10−5 mol/L, respectively) and between control and treated WKY (2.7±1.1×10−5 and 1.4±0.3×10−5 mol/L, respectively). There was no difference between control and treated SHR or WKY at 15 or 25 weeks.
After the treatment-withdrawal period, contractility of the mesenteric arteries from the 25-week-old control SHR and WKY in response to a 20-Hz stimulation was significantly enhanced in the presence of angiotensin II (Fig 7⇓). This potentiation effect of angiotensin II was not found in arteries from treated SHR and WKY.
The major findings of this study are that (1) chronic treatment of young SHR and WKY with L-158,809 resulted in lower BP levels in both animal strains and that up to 10 weeks after the withdrawal of the treatment, BP levels were maintained lower than levels in age-matched control animals; (2) maintenance of permanent BP change was associated with persistent functional changes in the SHR arteries but not in the WKY arteries; and (3) measurable changes in arterial structure were dependent on the measurement techniques.
Treatment Effects on BP Level
The level of BP control in the SHR obtained with L-158,809 treatment in this study was similar to the level observed with losartan treatment in young animals2 (31% and 32% reduction in BP, respectively) and was better than L-158,809 treatment initiated in adult SHR with established hypertension (24% reduction).8 However, the level of BP reduction after withdrawal of the treatment was similar (17% to 18%, 10 to 17 weeks after treatment withdrawal), regardless of whether treatment was initiated in young (see Reference 22 and this study) or adult SHR.8 These results indicate that better BP control can be achieved during the treatment period with an AT1-receptor antagonist when treatment is initiated in young SHR before the development of hypertension, but early treatment is not more beneficial than treatment of adult SHR with regard to the persistence of BP reduction after treatment withdrawal.
The fact that the BP of both SHR and WKY was lowered by the L-158,809 treatment highlights the involvement of the AT1 receptors in normal BP regulation in these animals. Because of this, and because early AT1-antagonist treatment did not permanently prevent the development of hypertension, the action of angiotensin II on AT1 receptors is not likely the primary initiator of hypertension development in SHR. Nevertheless, treatment with L-158,809 did attenuate the level of BP rise after withdrawal of the treatment in SHR, suggesting that persistent changes in BP homeostasis were induced by the treatment in these rats. Our results indicate that some of these changes are related to the changes in the arteries as discussed below.
Treatment Effects on Arterial Structure and Function
Prehypertensive SHR (3 to 4 weeks of age) have an increased arterial media mass and an increased number of SMC layers when compared with WKY arteries, but BP is similar to that in age-matched WKY.12 13 These changes contribute to the ability of these arteries to produce more contraction when challenged with agonists and electrical field stimulation, and also to withstand a higher TMP than arteries from WKY.13 As these changes occur before the increase in BP in SHR, it can be concluded that increased BP level is not a mechanism contributing to these artery structural changes. Vascular dimensions measured in perfusion-fixed arteries at maximal relaxation showed that the SHR arteries had a thicker wall and a higher m/l ratio than the WKY arteries, as was expected. However, treatment with L-158,809 did not alter these parameters or the number of SMC layers, indicating that activation of the AT1 receptor is also not an important mechanism contributing to these artery structural changes, as blockade of the receptor did not reverse these changes. However, the fact that the structure of the arteries did not change with treatment does not mean that the arteries were not affected by the treatment. For this reason, it is important to consider the functional reactivity of these arteries in order to understand the significance of the changes that did occur in these arteries with L-158,809 treatment. We therefore also studied these arteries in vitro to look at the vascular dimensions under pressure and also the contractile responses of these arteries. Measurements made using the pressurized myograph system showed again that under low TMP conditions (20 mm Hg) no structural differences were observed between the arteries from treated and those from control animals, similar to what was observed with the in situ measurement method. However, in vascular measurements made at 100 mm Hg TMP, the w/l ratio was reduced in the treated SHR as compared with control SHR, indicating that L-158,809 treatment had indeed caused some alterations of the SHR arteries. This was a persistent change as it was also observed 10 weeks after treatment withdrawal.
The wall thickness and w/l ratio both correlated positively and significantly with the BP levels after the treatment and withdrawal periods, which is consistent with previous observations made after chronic losartan treatment of young SHR.2 However, the change in structure observed with this technique was due to functional changes of the arteries, as the arteries from treated SHR tended to yield to higher pressures than control SHR. Part of this change may have been due to the preservation of endothelial cell function in the treated SHR so that the endothelial cells released endothelium-derived relaxing factor when stimulated by high pressure, therefore causing relaxation. This hypothesis is consistent with the recent finding that 12 weeks of treatment with losartan enhanced endothelium-dependent relaxation and abolished acetylcholine-induced endothelium-dependent contraction of small arteries from SHR.14
The functional correlate of the reduction in the w/l ratio due to treatment with L-158,809 in the SHR and WKY arteries is in the reactivity responses of these arteries. Electrical stimulation at higher TMP caused arteries from control SHR to contract more than those from treated SHR. The greater level of contraction corresponded to a significantly smaller lumen size in the control SHR arteries. This response was also observed after the treatment-withdrawal period, indicating the persistence of this treatment effect and suggesting that a persistent reactivity change in the arteries had been invoked by the L-158,809 treatment. Such an effect was not seen in response to stimulation by NE, suggesting a presynaptic site for this reactivity change. We believe that these presynaptic changes are related to the functional maturation of the innervation of these arteries as discussed below.
We have shown recently that in neonatal SHR arteries there is a delay in the maturation between the interaction of sympathetic innervation and vascular smooth muscle when compared with WKY arteries.13 At 3 weeks of age, nerve-evoked vascular response in the SHR was minimal or absent as compared with age-matched WKY, despite the presence of a hypertrophied medial wall.13 It is therefore possible that treatment of young SHR with L-158,809 may have prolonged this delay in the maturation of nerve-muscle interaction, which resulted in a reduced nerve-stimulated response. Support for this hypothesis also stems from the fact that persistent changes in WKY arterial reactivity did not occur with L-158,809 treatment, presumably due to the more advanced maturation of the nerve-muscle interaction in WKY arteries, which existed at the initiation of treatment. Likewise, adult SHR also did not show altered arterial reactivity in response to L-158,809 treatment,8 indicating that treatment must be initiated during the development of nerve-muscle interactions in order to induce changes in the arterial reactivity.
Another effect on arterial function induced by AT1-receptor antagonist treatment was the permanent inhibition of the potentiating effects of angiotensin II on sympathetic nerve function. The potentiating effect of angiotensin II on vascular functions is well documented.15 16 17 It is postulated that angiotensin II acts presynaptically to enhance NE release.15 18 19 We have reported previously that treatment of adult SHR with L-158,809 for 12 weeks abolished the potentiating effects of angiotensin II to nerve-stimulated responses.8 In this study we have extended this observation by finding that the interference with the potentiating effect of angiotensin II on nerve-stimulated response due to treatment with L-158,809 was persistent, because the effect was still present in treated SHR and WKY 10 weeks after withdrawal of the treatment. The cause of this treatment effect is unknown. It is possible that chronic inhibition of AT1 receptors at the presynaptic site has contributed to this persistent effect.
Treatment Effects on the Heart
In this study we found that treatment of young SHR with L-158,809 reduced the weight of the heart but not the body weight. The regression of left ventricular hypertrophy with antihypertensive therapy is well documented.2 3 20 Chronic treatment of young SHR with losartan was reported to cause a reduction in body weight,2 although treatment with D 8731 did not.1 Losartan may have nonspecific effects in addition to AT1 blockade that caused this alteration in body weight.
Consideration of the Methods
In this study vascular dimensions were measured using two different techniques, which yielded different results. Vessels fixed in situ by perfusion fixation experienced a low perfusion pressure (15 to 24 mm Hg) and are fixed in a maximally relaxed condition.11 12 Under these conditions, vascular wall dimensions represent the basal, unstimulated state of the vessels. Results obtained using this technique have consistently shown structural changes in the large mesenteric arteries of various animal models of human essential hypertension, typified by an increase in the medial wall area and m/l ratio. In some models such as SHR, an increased number of SMC layers is also observed.6 In this study we found that L-158,809 treatment did not affect the CSA, medial thickness, or the number of SMC layers in the SHR when measured at maximal dilation, indicating that the treatment had minimal effect on the structure of the vessel wall. This is consistent with the vascular dimensions measured using the functional technique at a TMP of 20 mm Hg. However, as this low TMP level is nonphysiological, it is not possible to use these morphological results to predict the reactivity of these vessels under physiological situations. Our functional experiment results indeed showed that at a low TMP (20 mm Hg), there were no differences in arterial reactivity between treated and control SHR in response to electrical stimulation. At higher TMP levels, the contractile response of the arteries from treated SHR was less than control SHR, suggesting functional alteration of the treated SHR arteries. Likewise, the vascular wall dimensions measured at a higher TMP (100 mm Hg) showed significant differences between the control and treated SHR arteries in both wall thickness and w/l ratio.
Although the observed changes are indicative of the functional manifestation of the arterial changes, there may be an inherent distortion of vascular dimensions because of the technique. In vessels fixed in situ by perfusion fixation, no change in the axial or radial dimensions of the arteries was observed (Dickhout and Lee, unpublished results, 1997). In contrast, in vessels pressurized using the blind-sac preparation, there is always a change in the axial length of the vessels with pressurization, affecting the arterial wall thickness.21 Since arteries from treated SHR yielded more under pressure, which translates to a reduced ability to contract against higher pressure when stimulated, it is likely that the difference in wall thickness between arteries from control and treated SHR measured at 100 mm Hg was due to the relative increases in axial length of the arteries in response to pressure. It is clear that each measurement method provides a different type of information about these arteries and that each method has its inherent merits and pitfalls. Therefore, it is important to take these factors into consideration when relating findings on structural changes to artery function.
In conclusion, we have shown that treatment with the AT1 receptor antagonist L-158,809 prevented hypertension during the treatment period and reduced the severity of hypertension development after withdrawal of the treatment. However, the effect of such a treatment is likely due to the blockade of a major BP regulator (ie, angiotensin II) and not due to the blockade of an early hypertension initiator. The antihypertensive effect of chronic AT1-receptor blockade was associated with a persistent decrease in the reactivity of the SHR arteries, which may have contributed to the persistently lower BP levels on withdrawal of the treatment.
Selected Abbreviations and Acronyms
|AT1||=||angiotensin type 1|
|SHR||=||spontaneously hypertensive rats|
|SMC||=||smooth muscle cell|
This study was supported by the Heart and Stroke Foundation of Ontario. We thank Merck Research Laboratories for the supply of L-158,809. Leesa Gillies was a recipient of a Graduate Student Fellowship provided jointly by the Canadian Hypertension Society, Pfizer Canada, and the Medical Research Council of Canada.
- Received April 8, 1997.
- Revision received May 5, 1997.
- Accepted June 18, 1997.
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