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Research Center for Endocrinology and Metabolism (Å.T., K.S., O.G.P.I., J.-O.J., C.O., J.I.), Department of Internal Medicine, Wallenberg Laboratory (E.B., R.M.), and Department of Clinical Physiology (K.C., G.B.), Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden; Department of Physiology (I.A., S.F., G.B.), University of Göteborg, S-405 30 Göteborg, Sweden; Department of Physiology and Pharmacology (O.S.), University of Southern Denmark, DK-5000 Odense C, Denmark; and Fraser Laboratories (J.-L.L.), Royal Victoria Hospital, McGill University, Montréal, Québec H3A 1A1, Canada
Address all correspondence and requests for reprints to: Åsa Tivesten, M.D., Research Center for Endocrinology and Metabolism, Gröna Stråket 8, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden. E-mail: asa.tivesten{at}medic.gu.se.
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Abstract |
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Introduction |
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Both IGF-I and the IGF-I receptor are expressed in the heart and the vasculature (1), indicating that IGF-I may exert its effects in an autocrine/paracrine manner. However, IGF-I is also present in the circulation and may thus act in an endocrine fashion. Although the impact of IGF-I on the cardiovascular system has been extensively studied, the relative importance of local and endocrine IGF-I remains unclear.
Liver-derived IGF-I holds a unique position, because hepatocytes produce IGF-I but have no detectable IGF-I receptor expression. The development of transgenic mice with a liver-specific, inducible knockout of the IGF-I gene using the Cre-LoxP conditional knockout system (LI-IGF-I-/- mice) has made it possible to investigate the physiological role of liver-derived IGF-I. LI-IGF-I-/- mice have a lifelong 75–80% reduction of serum IGF-I levels and increased GH secretion (9, 10, 11). These mice have normal early postnatal growth (10); however, metabolic abnormalities, such as high insulin levels and reduced fat mass, are observed (9). In the present study, we used LI-IGF-I-/- mice to examine the role of circulating, liver-derived IGF-I in cardiovascular physiology.
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Materials and Methods |
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Study design
Basal tail-cuff systolic BP was assessed in both male and female LI-IGF-I-/- and control mice at 4 months of age. Because the difference in systolic BP was larger in females, females were chosen for further mechanistic evaluation in a second part of the study. Between 5 and 6 months of age echocardiography, urine collection and acute studies with nitric oxide (NO)-synthase inhibitor and 
1-adrenergic antagonist were performed. At the end of the study (7 months of age), the female mice were anesthetized with a combination of fentanyl and fluanisone (0.55 and 17.5 mg/kg; Hypnorm, Janssen Pharmaceuticals, Beerse, Belgium) and midazolam (8.75 mg/kg; Dormicum, Hoffman-La-Roche Inc., Basel, Switzerland) and were killed by rapid excision of the heart. The internal organs were weighed and snap-frozen in liquid nitrogen, and the mesenteric bed was removed for subsequent assessment of mesenteric vascular function. Separate cohorts of animals were used for the determinations of plasma nitrate (female LI-IGF-I-/- and control mice, 5 months of age), plasma renin (female LI-IGF-I-/- and control mice, 15 months of age), BP in the study with octreotide (female LI-IGF-I-/- and control mice, 6 months of age), and norepinephrine (NE) in cardiac tissue (male and female LI-IGF-I-/- and control mice, 2 months of age).
Systolic BP and heart rate measurements
Systolic BP and heart rate were measured using a computerized noninvasive tail-cuff system (RTBP Monitor; Harvard Apparatus, Inc., South Natick, MA). Unanesthetized animals were kept in a restrainer, with a standardized acclimatization time of 10 min and gentle heating of the tail before the recordings. For basal systolic BP, measurements were performed at three different time points, with at least three recordings for each time point. Final systolic BP was obtained by averaging the mean values from the different time points.
Echocardiography
Mice were anesthetized with a combination of fentanyl and fluanisone and midazolam, as described above. The anterior chest was shaved, and electrocardiographic leads were placed on the extremities. A warming pad was used to maintain the body temperature. Cardiac ultrasound studies were performed, using a commercially available Vingmed Ultrasonograph (GE, West Milwaukee, WI), by methods previously validated (14). A 10-MHz linear transducer was used to obtain two-dimensional parasternal short-axis imaging close to the papillary muscles. This served as a guide for M-mode tracing. For pulsed-wave Doppler (5 MHz) recordings, the minimum sample size was used to record the velocities in the left ventricular (LV) outflow tract and the mitral inflow. From the parasternal view, the main pulmonary artery was visualized, its diameter was measured, and pulmonary artery flow was recorded. All tracings were recorded at a sweep rate of 200 mm/sec and stored on magnetic optical discs for off-line measurements. After the basal echocardiographic examination, the mice were reexamined, 4 min after an ip injection of isoprenaline (0.15 mg/kg; APL Umeå, Umeå, Sweden).
Off-line measurements were blind-coded and performed using an image analysis system (Echo Pac 5.4; Vingmed). M-mode measurements of LV internal diameters and posterior wall thickness in diastole and systole were made using the leading edge convention of the American Society of Echocardiography. The onset of the QRS complex defined end-diastole, and end-systole was taken at the peak inward motion of the anterior wall. At least four beats were averaged for each measurement. LV fractional shortening was calculated as follows: (LV internal diameter in diastole - LV internal diameter in systole)/LV internal diameter in diastole x 100%. Relative wall thickness was calculated as (2 x posterior wall thickness)/LV internal diameter in diastole. Velocity of circumferential shortening (Vcf) was calculated as fractional shortening/ejection time, where ejection time was measured from the LV outflow tract velocity. Stroke volume was calculated as the product of the velocity time integral in the pulmonary artery and the corresponding pulmonary artery area. Multiplying stroke volume with heart rate yielded cardiac output.
Effects of N[
]-nitro-L-arginine methylester hydrochloride (L-NAME), prazosin hydrochloride, and octreotide on BP
Systolic BP and heart rate measurements were also performed at baseline and 30 and 60 min after a single ip injection of the NO-synthase inhibitor L-NAME, 1 mg/kg; Sigma-Aldrich Corp. Sweden AB). Systolic BP was also registered at baseline and 30 min after a single ip injection of the 1-adrenergic antagonist prazosin hydrochloride (1 mg/kg; Sigma-Aldrich Corp. Sweden AB). The selection of appropriate doses of L-NAME and prazosin hydrochloride, as well as time intervals, were based on results in pilot experiments (data not shown). In a separate experiment, systolic BP was measured in LI-IGF-I-/- and control mice after 4 d of treatment with vehicle and subsequently after 4 d of treatment with the somatostatin analog octreotide (Sandostatin; Novartis Sweden AB, Täby, Sweden), 2.5 mg/kg·d, administered sc twice daily.
Mesenteric vascular function
Segments of small resistance arteries were taken from the mesenteric bed and mounted in a Multimyograph 610M (Danish Myo Technology, Aarhus, Denmark). The isometric wall tension was recorded at well-defined internal circumferences. The solutions used were equilibrated with 5% CO2, and bath temperatures were maintained at 37 C. Concentration-response curves were obtained for NE (L-arterenol, Sigma-Aldrich Corp. Sweden AB; range, 0.08–10 µM) and for KCl (range, 11–125 mM). Acetylcholine (ACh; range, 10-9–4 x 10-6 M) and sodium-nitroprusside (SNP) (range, 10-10–4 x 10-6 M) were cumulatively administered to precontracted vessels (NE, 75–100% of maximal wall tension). A second concentration-response curve for ACh was performed in the presence of the NO-synthase inhibitor N[]-nitro-L-arginine (L-NNA, 100 µM, Sigma-Aldrich Corp. Sweden AB).
Measurements of nitrate in plasma and creatinine in serum and urine
Plasma nitrate levels were determined as previously described (15). Urine was collected from LI-IGF-I-/- and control mice placed in metabolic cages during 24 h, with free access to tap water and food pellets. Creatinine in serum and urine was determined by a colorimetric method (Sigma-Aldrich Corp. Sweden AB), and the 24-h excretion of creatinine in urine was calculated.
Plasma renin measurements
Nine microliters of fresh plasma from tail blood was diluted to 50 µl and frozen for later assay. Five microliters of each sample were incubated in serial dilutions for 24 h with angiotensin I antibody and purified renin substrate (1200 ng angiotensin I/ml), after which an RIA was performed. Renin values were expressed in Goldblatt units and were standardized with renin standards (Medical Research Council Reagent no. 65/119) obtained from the National Institute for Biological Standards and Control (Potters Bar, Hertsfordshire, UK).
Determination of tissue NE
Tissue NE was purified and concentrated by extraction with acid-washed aluminum oxide, as previously described, with some modifications (16). One hundred milligrams of frozen cardiac tissue was homogenized as previously described; 50 µl -methyl DOPA (2 µg/ml) was used in all samples as an internal standard. Two series of four different concentrations, between 6.25 and 50 ng/ml of external standard solutions, were prepared for calibration of a linear standard curve. The samples were then kept at -20 C and thawed just before analysis. Twenty microliters of the extracted samples were injected into the HPLC-EC system composed of the High Precision Pump (Gynotek GmbH, München, Germany) and electrochemical detector (The Decade; ANTEC Leyden, Leiden, The Netherlands), with a separation C18(2) column (Luna, VA 150/4.6 Nucleosil 100-5SA, Phenomenex Inc., Torrance, CA). The current signal was monitored using a software Chromeleon version 4.32 (Dionex-softron GmbH, Germering, Germany).
Real-time PCR analysis
Total RNA from liver, aorta, and heart was extracted by TriReagent (Sigma, St. Louis, MO). The PCR analysis was performed using the ABI Prism 7700 Sequence Detection System (PE Applied Biosystems, Stockholm, Sweden) using an FAM-labeled probe specific for the IGF-I, endothelial NO-synthase (eNOS), or endothelin-1 (ET-1) transcript (PE Applied Biosystems; Table 1
). Predesigned primers and a VIC-labeled probe for 18S rRNA were included in the reactions as an internal standard. The cDNA was amplified at the following conditions: 1 cycle at 50 C for 2 min and 95 C for 10 min, followed by 40 cycles at 95 C for 15 sec and 60 C for 1 min. The mRNA amount of each gene was calculated using the standard curve method (multiplex reaction, following the instructions in User Bulletin no. 2, PE Applied Biosystems) and adjusted for the expression of 18S rRNA.
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Results |
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After induction of Cre-expression, serum IGF-I levels were reduced by 81% in males [LI-IGF-I-/-, 77 ± 5 ng/ml (n = 9); controls, 394 ± 16 ng/ml (n = 16), P < 0.0001] and by 77% in females [LI-IGF-I-/-, 84 ± 3 ng/ml (n = 9); controls, 372 ± 21 ng/ml (n = 8), P < 0.001]. Real-time PCR measurements demonstrated that this reduction in serum IGF-I levels was associated with a 96% decrease in IGF-I mRNA levels in liver, whereas IGF-I mRNA levels in heart were unchanged. However, local IGF-I mRNA was increased by 240% in aorta of LI-IGF-I -/-, compared with control mice (Table 2).
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). The difference (BP in LI-IGF-I-/- mice minus mean value of male/female controls) was larger in female than in male LI-IGF-I-/- mice (P = 0.041). There was no significant difference in basal heart rate in conscious animals of either sex [female LI-IGF-I-/-, 691 ± 13 vs. female controls, 705 ± 8 beats/min (bpm); male LI-IGF-I-/-, 700 ± 15 vs. male controls, 716 ± 14 bpm]. A similar increase in systolic BP was seen in LI-IGF-I-/- mice at 3 and 6 months of age (data not shown).
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, stroke volume and cardiac output, with and without correction for BW, were significantly decreased in LI-IGF-I-/- mice. Heart rate, fractional shortening, and Vcf were similar in the two groups (Table 3). There was no change in early (E-wave) and late (A-wave) diastolic transmitral velocity or E/A ratio, indicating preserved diastolic function in LI-IGF-I-/- mice (Table 3). The posterior and relative wall thicknesses were increased in LI-IGF-I-/- mice (Fig. 2B), but there was no difference in LV chamber diameter in systole or diastole (Table 3).
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Increased pressor response to NO-synthase inhibition in LI-IGF-I-/- mice
To examine the possible mechanisms for the increased systolic BP in LI-IGF-I-/- mice, systolic BP was measured before and after administration of the NO-synthase inhibitor L-NAME. Thirty minutes after injection of L-NAME, systolic BP increased more in LI-IGF-I-/- mice than in controls (Fig. 3A). The increase in BP was associated with a pronounced decrease in heart rate in LI-IGF-I-/- mice (Fig. 3B). Treatment with the 1-adrenergic antagonist prazosin hydrochloride acutely decreased systolic BP similarly in both groups (16 ± 6 mm Hg in LI-IGF-I-/- mice and 17 ± 7 mm Hg in controls) but did not change heart rate (data not shown). After 4 d of treatment with vehicle, there was a significant mean difference in systolic BP between LI-IGF-I-/- and control mice (mean difference, 15 mm Hg, P = 0.02), whereas after 4 d of treatment with octreotide, the mean difference between the groups disappeared [<1 mm Hg, not significant (NS)]. However, because the study design does not permit comparisons between vehicle and octreotide treatment within one group and because octreotide has many effects besides reducing GH levels, it is difficult to draw, from these data, conclusions regarding the contribution of GH to the increase of BP in LI-IGF-I-/- mice.
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), suggesting increased NO production in LI-IGF-I-/- mice.
Impaired relaxation to ACh in mesenteric resistance vessels of LI-IGF-I -/- mice
To investigate whether the increased BP in LI-IGF-I-/- mice was associated with vascular dysfunction, vascular responses of mesenteric resistance vessels were examined in a small vessel myograph. We found no significant difference in maximal response or sensitivity to NE or KCl (Table 4). However, sensitivity to ACh-induced vasorelaxation was reduced in LI-IGF-I-/- mice, compared with control mice (Fig. 4A, Table 4). After pretreatment with the NO-synthase inhibitor L-NNA, there was no longer a significant change in sensitivity to ACh (Fig. 4B, Table 4). This probably was attributable to the fact that, after L-NNA, the highest doses of ACh induced a paradoxical decrease in the relative relaxation in LI-IGF-I-/- mice and thus a decrease in the maximal relaxation. Such paradoxical effects of high doses of ACh have been shown before in hypertensive models (17). LI-IGF-I-/- and control mice showed similar vasorelaxation in response to the NO-donor SNP (Table 4), indicating preserved endothelium-independent relaxation in LI-IGF-I-/- mice.
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), whereas eNOS mRNA levels were unchanged (Fig. 4D).
Plasma renin, serum, and urinary creatinine
There was no difference in plasma renin concentration between LI-IGF-I-/- and control mice (LI-IGF-I-/-, 5.42 ± 1.05, n = 10 vs. controls, 6.15 ± 1.90 mGoldblatt U/ml, n = 8). Release of creatinine in urine was similar in LI-IGF-I-/- and control mice (data not shown). At 7 months of age, there was no significant difference in serum creatinine (LI-IGF-I-/-, 0.33 ± 0.06, n = 9 vs. controls, 0.27 ± 0.05 mg/dl, n = 7).
Cardiac NE content
As an indication of possible changes in sympathetic activity, myocardial stores of NE were assessed. However, we found no difference in cardiac NE content between LI-IGF-I-/- and control mice (female LI-IGF-I-/-, 5.1 ± 0.3 vs. female controls, 5.1 ± 0.2; male LI-IGF-I-/-, 4.7 ± 0.2 vs. male controls, 4.6 ± 0.2 nmol/g tissue).
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Discussion |
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IGF-I and BP
It is well known that both acute and chronic administration of IGF-I reduces BP and total peripheral resistance (4, 5). However, it is unclear whether IGF-I plays a physiological role in BP regulation and, if so, whether autocrine/paracrine or endocrine IGF-I is the most important. To our knowledge, there is only one previous report on the hemodynamic effects of IGF-I deficiency, showing elevated BP in mice with a mutant IGF-I allele and 30% of wild-type IGF-I levels present in all tissues and serum (8). In the present study of LI-IGF-I-/- mice, we found an elevation of BP similar to that in the IGF-I mutant mice, with a similar decrease in serum IGF-I. Together, these studies suggest that circulating, liver-derived IGF-I, rather than locally produced IGF-I, is of importance for BP regulation. Our findings are supported by the fact that a negative correlation between serum IGF-I and BP has been found in borderline hypertension (18).
GH and BP
LI-IGF-I-/- mice have increased GH secretion, attributable to loss of feedback inhibition from circulating liver-derived IGF-I (10, 11). Thus, some of the characteristics of the phenotype may be caused by the high levels of GH. The increased relative liver weight is likely a GH-effect, given that GH status is known to influence liver size (11). Hypertension is reported to affect approximately one third of acromegalic patients (19), raising the possibility that the increased systolic BP in LI-IGF-I-/- mice could be an effect of the increased GH levels. However, in most studies, GH administration to humans does not result in increased BP (20). In fact, decreased total peripheral resistance is reported in early acromegalic disease (19). Also, most studies of GH administration to experimental animals report reduced total peripheral resistance, but no change in mean arterial BP, while cardiac output is concomitantly increased (3). Thus, we believe that the increased BP seen in LI-IGF-I-/- mice is attributable to the low levels of circulating IGF-I, rather than the secondary increase of GH secretion. Furthermore, GH deficiency is associated with low serum IGF-I levels, increased total peripheral resistance (2), and increased prevalence of hypertension (21). Studies have shown that GH substitution reduces total peripheral resistance in GH deficiency (2, 22), and our present study indicates that altered levels of liver-derived IGF-I in serum may contribute to this effect.
Extrahepatic IGF-I expression
Despite the increased GH levels in LI-IGF-I-/- mice, IGF-I mRNA expression is unchanged in all examined tissues without Cre-expression (10), except for hypothalamus, where IGF-I mRNA expression is slightly increased (11). In the present study, we also found increased IGF-I mRNA in aorta of LI-IGF-I-/- mice. IGF-I expression is known to increase in vascular smooth muscle cells in response to stretch (23), and hypertensive rats have increased vascular and cardiac IGF-I expression (24, 25). Therefore, we believe that the increased IGF-I expression in aorta reflects a vascular adaptive response to the increased BP after hepatic IGF-I inactivation, rather than a response to increased GH secretion. In contrast to aorta, overall cardiac IGF-I expression was unchanged in LI-IGF-I-/- mice, but associated with increased LV wall thickness, suggesting that the cardiac adaptation may have been accomplished at 7 months of age.
Mechanisms of increased peripheral resistance
Cardiac output was decreased in LI-IGF-I-/- mice; hence, the basic mechanism behind the increased BP in LI-IGF-I-/- mice must be increased peripheral resistance. In accordance, we found vascular alterations in LI-IGF-I-/- mice, including impaired vasorelaxation and changed expression of ET-1. LI-IGF-I-/- mice showed no marked cardiac phenotype, compared with controls; stroke volume and cardiac output were decreased but associated with normal fractional shortening and stress response, suggesting that the reductions in stroke volume and cardiac output are secondary to the increased afterload in this model. There are different aspects of the increased peripheral resistance in LI-IGF-I-/- mice, which prompt separate discussions (below).
Endothelial dysfunction
We found an impaired endothelium-dependent vascular response to ACh in LI-IGF-I-/- mice, whereas endothelium-independent response to SNP was similar in LI-IGF-I-/- and control mice. These findings suggest the presence of endothelial dysfunction, implying an imbalance in the relative contribution of endothelium-derived relaxing and contracting factors, in LI-IGF-I-/- mice.
Enhanced ET-1 production.
Vascular expression of the vasoconstrictor ET-1 was increased in LI-IGF-I-/- mice, as evidenced by increased ET-1 mRNA levels in aorta. It has been suggested that the pressor effect of ET-1 is buffered by the NO-system and unmasked by NO-synthase blockade (26). This is in line with our current data, showing increased vascular expression of ET-1 in association with dramatically increased systolic BP after NO-synthase blockade in LI-IGF-I-/- mice.
To our knowledge, there are no in vivo data of IGF-I regulation of ET-1 expression. In vitro studies report increased or unchanged ET-1 production during IGF-I exposure (27, 28, 29), suggesting that the increased IGF-I mRNA levels in aorta may promote ET-1 expression. Alternatively, circulating liver-derived IGF-I may influence vascular ET-1 expression through a mediating factor. However, increased activities of the renin-angiotensin or sympathetic systems seem less likely as inducers of ET-1 expression in LI-IGF-I-/- mice.
Compensatory increase in NO production.
ET-1 expression is known to be influenced by activity in the NO-system (26), and several studies suggest that IGF-I-induced vasodilatation is mediated by a NO-dependent mechanism (5, 6). Thus, it would be reasonable to suggest that the increased BP in LI-IGF-I-/- mice is associated with reduced endothelial NO production. Surprisingly, levels of plasma nitrate, the major metabolite of NO, were increased in LI-IGF-I-/- mice, compared with control mice. eNOS mRNA levels in aorta were similar in knockout and control mice, arguing against increased NO production in LI-IGF-I-/- mice through up-regulation of eNOS, suggesting that eNOS activity (rather than mRNA expression) is increased. The markedly enhanced pressor response to L-NAME in LI-IGF-I-/- mice supports the notion of a compensatory increase of NO production in LI-IGF-I-/- mice, counterbalancing the pressor effect of ET-1. In isolated vessels in vitro, NO-synthase blockade with L-NNA did not further reduce the sensitivity to ACh-induced relaxation. This result suggests that other mediators, such as endothelium-derived hyperpolarizing factor or prostaglandin I2, may be more important than NO for the ACh-induced vasodilatation in both control and LI-IGF-I-/- mice.
Impaired cholinergic responsiveness.
Our finding of decreased sensitivity to ACh-induced relaxation in LI-IGF-I-/- mice is supported by a recent study showing impaired vasodilatory response to ACh- in GH-deficient patients, with a 63% reduction of serum IGF-I levels (30). An alternative mechanism for the decreased sensitivity to ACh-induced relaxation in LI-IGF-I-/- mice may be down-regulation of ACh receptors or reduced activity of components in the local cholinergic system. In a recent study in humans, cholinergic blockade, using atropine, dramatically potentiated the pressor response to NO-synthase inhibition (31). Therefore, our result of increased BP response to L-NAME may be consistent with decreased vascular sensitivity to ACh as a primary cause of increased peripheral resistance in LI-IGF-I-/- mice.
Sympathetic activity
There is evidence to suggest that IGF-I may act to decrease sympathetic nervous activity (32) and affect ß adrenergic coupling (8). In the present study, we did not assess sympathetic activity. However, the lack of differences in cardiac NE contents, heart rate, isoprenaline-response, NE sensitivity in resistance vessels, and BP reduction by prazosin do not support increased sympathetic activity in LI-IGF-I-/- mice.
Renal mechanisms
In the present study, plasma renin and serum and urinary creatinine levels were unchanged in LI-IGF-I-/- mice, arguing against renal hypoperfusion or severe renal failure as a cause of the elevated BP. The increased levels of GH in LI-IGF-I-/- mice may cause fluid retention (33) and a compensatory increase of peripheral resistance, but cardiac output should, in such steady state, be normal and not reduced as in our study. However, given that IGF-I may affect renal size and function (34), further studies are required to assess possible renal effects in LI-IGF-I-/- mice.
Conclusion
Although previous studies have shown linkage between the IGF-I gene and systolic BP (7), evidence of a physiological role of circulating liver-derived IGF-I in BP regulation has not been demonstrated. Our data provide the first evidence of a role of liver-derived IGF-I in the regulation of peripheral resistance. The present study also introduces a new concept of a link between the liver and BP, opening new perspectives of the liver as an endocrine organ involved in physiological BP regulation.
In conclusion, liver-specific knockout of IGF-I results in increased BP and peripheral resistance, with secondary changes of cardiac performance and wall thickness in mice. We suggest that the mechanism behind the increased peripheral resistance in LI-IGF-I-/- mice is endothelial dysfunction associated with increased vascular expression of ET-1 and impaired vasorelaxation of resistance vessels. Our findings suggest that liver-derived IGF-I may play a physiological role in the regulation of BP.
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Acknowledgments |
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Footnotes |
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Abbreviations: ACh, Acetylcholine; BP, blood pressure; bpm, beats per minute; BW, body weight; eNOS, endothelial NO-synthase; ET-1, endothelin-1; LI-IGF-I-/- mice, mice with liver-specific, inducible inactivation of IGF-I; L-NAME, N[]-nitro-L-arginine methylester hydrochloride; L-NNA, N[]-nitro-L-arginine; LV, left ventricular; NE, norepinephrine; NO, nitric oxide; NS, not significant; PiPc, polyinosinic-polycytidylic acid; SNP, sodium-nitroprusside; Vcf, velocity of circumferential shortening.
Received May 17, 2002.
Accepted for publication July 29, 2002.
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