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Experimental Biology and Medicine 228:1057-1062 (2003)
© 2003 Society for Experimental Biology and Medicine

ORIGINAL RESEARCH ARTICLE

Nitric Oxide as a Local Mediator of Prostaglandin F2{alpha}-Induced Regression in Bovine Corpus Luteum: An In Vivo Study

Jerzy J. Jaroszewski*,1, Dariusz J. Skarzynski{dagger} and William Hansel{ddagger}

* Department of Pharmacology, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, 10-718 Olsztyn, Poland;
{dagger} Division of Reproductive Endocrinology and Pathophysiology, Institute of Animal Reproduction and Food Research, PAS, Olsztyn, Poland; and
{ddagger} Department of Reproductive Biotechnology, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana 70808


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
To test whether nitric oxide (NO) is involved in prostaglandin (PG) F2{alpha}-induced regression of the bovine corpus luteum (CL) in vivo, heifers were treated as follows: Group 1, saline (3 ml/h); Group 2, dinoprost, an analogue of prostaglandin F2{alpha} (aPGF2{alpha}; 5 mg/0.5 h); Group III, N{omega}-nitro-L-arginine methyl ester (L-NAME; 200 mg/4 h), an inhibitor of nitric oxide synthase; and Group IV, L-NAME (400 mg/4 h) and aPGF2{alpha} (5 mg/0.5 h). All treatments were administered by an intraluteal microdialysis system (MDS) on day 15 of the cycle. Perfusate and jugular plasma samples were collected at half-hour intervals; additionally, jugular plasma samples were collected once daily from day 16 to day 21 of the cycle. In the perfusate samples, aPGF2{alpha} increased P4 (P < 0.05), PGE2 (P < 0.001), and LTC4 (P < 0.05) concentrations; L-NAME increased P4 (P < 0.05) but did not change PGE2 and LTC4 (P > 0.05) concentrations as compared with the period before treatment. Simultaneous perfusion of CL with L-NAME and aPGF2{alpha} caused a further increase of P4 concentration (P < 0.05) induced by L-NAME or aPGF2{alpha} treatment and increased PGE2 and LTC4 (P < 0.001) concentrations to the level observed after aPGF2{alpha} treatment. Perfusion of CL with aPGF2{alpha} caused luteal regression within 24 h, while perfusion with L-NAME prolonged the life span of CL to day 21 (P < 0.05). Concomitant L-NAME and aPGF2{alpha} treatment partially counteracted (P < 0.05) the luteal regression caused by aPGF2{alpha} administration. These results show that NO is involved in the process of luteolysis in the bovine CL and suggest that the luteolytic effect of aPGF2{alpha} may be mediated by NO as an important component of an autocrine/paracrine luteolytic cascade.

Key Words: nitric oxide • progesterone • prostaglandins • corpus luteum • bovine


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The mechanism controlling the development, secretion, and regression of the bovine corpus luteum (CL) involves many factors produced both within and without the CL (1–3). The current concept that luteolysis in cattle is brought about by prostaglandin (PG) F2{alpha} of uterine origin secreted in response to oxytocin (OT) released by the CL is inadequate to explain many of the events that actually occur at the time of regression (2). It has been well documented that PGF2{alpha} acts as a luteolytic agent when administered parenterally in ruminants (2, 4). However, when added to pure populations of steroidogenic luteal cells, PGF2{alpha} does not inhibit basal P4 secretion by the large luteal cells and actually stimulates P4 production by the small luteal cells (5, 6) and by a mixture of large and small luteal cells (7, 8). There is very little OT present in the CL at the time of luteal regression, and several recent studies indicate that luteolysis can occur after depletion of luteal OT (9, 10) and in the absence of measurable OT release from the luteal tissue (11). Moreover, the products of the lipoxygenase pathway of the arachidonic acid cascade, particularly leukotriene C4 (LTC4) play a role in luteolysis (12). In microdialysis studies leukotriene B4 and LTC4 were found in perfusate samples from CL and rose prior to the decline in progesterone during luteolysis in untreated control heifers (11). These results suggest that the effects of parenterally administered PGF2{alpha} may be mediated, at least in part, by vascular changes.

A number of studies indicate that substances, produced locally in the bovine CL, may mediate the luteolytic action of PGF2{alpha}. Pate (13) suggested that the immune cells and their secreted products, cytokines, are involved in the process of luteal regression. At the time of luteolysis, macrophages invade the bovine CL (14) and release cytokines, especially tumor necrosis factor-{alpha} (TNF{alpha}) and interferon-{gamma} (IFN{gamma}), which can participate in the apoptotic events that finally lead to structural luteolysis (15–18). In addition to immune cells and cytokines, it has been documented that endothelial cells and their main secreted product, endothelin-1 (ET-1), may mediate the luteolytic action of PGF2{alpha} in bovine steroidogenic luteal cells (19, 20). Yet another factor that may mediate PGF2{alpha} action during luteolysis in cattle is nitric oxide (NO) (21, 22). We have previously shown that administration of a nitric oxide synthase (NOS) inhibitor (L-NAME) into the ovary during the late luteal phase increases P4 secretion and prolongs the functional life span of the bovine CL (21). Moreover, NO directly inhibits P4 secretion from bovine luteal cells in vitro (23, 24) and pre-exposing luteal cells to nitric oxide (NO) increases the effect of PGF2{alpha}. These results suggest that NO, produced locally in the bovine CL, is needed to complete luteolysis (25). It has been recently shown that local administration (infusion into the aorta abdominals) of L-NAME into the reproductive tract counteracts the luteolytic action of PGF2{alpha} on the bovine CL (22). Therefore, in the present study we determined whether NO is involved as a local auto/paracrine factor in PGF2{alpha}-induced regression of the bovine CL.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Microdialysis System Implantation In Vivo.
Normally cycling Holstein/Polish Black and White heifers (380–430 kg; n = 15) were injected intramuscularly (i.m.) with 25 mg of dinoprost, an analogue of PGF2{alpha} (Dinolytic; Pharmacia & Upjohn, Belgium) during the luteal phase to induce luteolysis and estrus. On day 14 of the subsequent estrous cycle the MDS was implanted into the CL as described by Blair et al. (11). The animals were premedicated with xylazine at a dose of 15 to 20 mg/animal i.m. (Xylavet 2%, Scan Vet, Poland) and local anesthesia (epidural, paravertebral, and infiltration at the site of incision), was induced using 2% procaine hydrochloride (Polocainum Hydrochloricum 2%, Biowet Drwalew, Poland) prior to surgery. The MDS was threaded through the CL such that an 8-mm long dialysis tubing (Fresenius SPS 960, Frankfurt, Germany; MW cutoff = 1,000,000 Daltons; o.d. = 500 µm; i.d. = 340 µm) was localized within the CL. After surgery heifers were kept in individual stalls in a temperature-controlled room, and the CL were perfused with Ringer’s solution. All perfusions were at a flow rate of 3 ml/h. The recovery rates of hormones across the MDS were measured as previously described (26) and amounted to {approx} 0.1%, 0.3%, and 1% for LTC4, PGE2 and P4, respectively. All animal procedures were approved by the Local Committee of Animal Care and Use (Agreement No. 25/N).

Experimental Procedures.
At day 15 of the estrous cycle 15 heifers were divided into 4 groups and treated as follows: Group 1 (n = 4), CL were perfused with saline (3 ml/h) for 4 hrs; Group II (n = 4), CL were perfused with saline for 4 hrs and beginning at the second hour of treatment, CL were perfused simultaneously for 0.5 h (at a total flow rate of 3 ml/h) with 5 mg of dinoprost (aPGF2{alpha}); Group III (n = 3), CL were perfused with L-NAME (N{omega}-Nitro-L-Arginine Methyl Ester; Sigma-Aldrich, USA), a NOS inhibitor (50 mg/h) for 4 hrs; Group IV (n = 3), CL were perfused with L-NAME (50 mg/h) for 4 hrs and beginning at the second hour of treatment, CL were perfused simultaneously for 0.5 h with 5 mg of aPGF2{alpha}. Each 4-hr treatment period was preceded and followed by 2- and 4-hr control periods, respectively, during which saline (3 ml/h) was perfused.

Perfusate samples were taken at half-hour intervals during the 10-hr experimental period; simultaneously, blood samples were collected through catheters implanted into the jugular vein. Additional blood samples were collected once daily by jugular venipuncture from day 16 to day 21 of the estrous cycle.

Hormone Determinations.
Concentrations of P4 in perfusate and jugular blood plasma samples were assayed using a direct enzyme immunoassay (EIA), as described by Okuda et al. (27). Cross-reactivities of the anti-P4 serum (donated by Dr. S. Okrasa, University of Warmia and Mazury in Olsztyn, Poland), were determined by comparing the inhibition of binding of P4-HRP to antiserum. Results were as follows: 100% with P4, 38.9% with pregnenolone, 11.1% with 17{alpha}-hydroxy-progesterone, 9.8% with 17ß-estradiol, 1.2% with dihydrotestosterone and testosterone, and less than 0.5% with 11-desoxycortisol, estrone, cortisol, and 4-androsten-3,17-dione. Since the bovine CL secretes very little pregnenolone, no adjustment was made in the data for its cross-reaction. The assay sensitivity was 0.3 ng/ml and intra- and interassay coefficients of variation (CVs) were 6.6% and 8.7%, respectively.

Concentrations of PGE2 in perfusate samples were determined using a direct EIA, as previously described (23). Cross-reactivities of the anti-PGE2 serum (donated by Dr. S. Ito, Kansai Medical University, Osaka, Japan), validated by comparing the inhibition of binding of peroxidase-labeled PGE2 to antiserum, were as follows: PGE2, 100%; PGE1, 18%; PGJ2, 14%; PGA1, 10%; 15-keto PGE2, 8.8%; PGB2, 6.7%; PGA2, 4.6%; PGD2, 0.13%; PGF2{alpha}, 2.8%, and with dinoprost 7.9%. The assay sensitivity was 6.9 pg/ml and intra- and interassay CVs were 5.9% and 9.6%, respectively. The total concentrations of PGE2 (without adjustment for dinoprost cross-reactivity) are presented.

Concentrations of LTC4 in perfusate samples were determined by use of a commercially available EIA kit (Cayman Chemical Co., USA) according to instructions of the manufacturer. The assay sensitivity was 9.81 pg/ml and intra- and interassay CVs were 5.4% and 9.2%, respectively.

Statistical Analyses.
The analysis of P4, PGE2, and LTC4 in the perfusate and P4 in the jugular plasma samples, collected during administration of the tested substances on day 15 of the cycle and P4 in jugular plasma samples, collected daily from day 16 to day 21 of the estrous cycle, was performed using a repeated measure design approach with L-NAME, aPGF2{alpha}, and time (hours or days, respectively) being fixed effects with all interactions included. Time was considered a repeated factor. The dependencies on time were modeled by an autoregressive type I covariance structure. The particular hypotheses were tested as slice effects in a corresponding mixed model. All analyses were done using SAS Version 9.0; P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
P4 Concentrations.
Concentrations of P4 in the jugular plasma after perfusion of CL with saline (Group I) and L-NAME (Group III) were higher (P < 0.05) compared with both Groups receiving aPGF2{alpha} (Fig. 1Go). Moreover, an increase in P4 concentrations was observed in Group III when compared with the period before treatment (Fig. 1Go). Perfusion of CL with aPGF2{alpha} (Group II) and L-NAME with aPGF2{alpha} (Group IV) caused significant decreases (P < 0.05) in P4 concentrations in the jugular plasma when compared with concentrations of this hormone to the period before treatment (Fig. 1Go). However, the decrease in P4 concentrations after aPGF2{alpha} administration was preceded by a brief increase (Fig. 1Go).



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  		Figure 1. Concentrations (mean ± SEM) of progesterone in jugular plasma samples after simultaneous intraluteal administration of saline (4 h) or L-NAME (200 mg/4 h) and saline (0.5 h) or dinoprost (5 mg; aPGF2{alpha}) on day 15 of the estrous cycle. * P < 0.05 vs. period before treatment; a–bdifferent subscripts indicate differences (P < 0.05) between groups at the same time point.

 
In the perfusate samples, concentrations of P4 were significantly increased (P < 0.05) by aPGF2{alpha} as well as by administration of L-NAME when compared with the periods before treatment (Fig. 2Go). Moreover, P4 concentrations after aPGF2{alpha} treatment were significantly higher (P < 0.05) when compared with the concentrations of this hormone after saline administration (Fig. 2Go). Simultaneous perfusion of CL with L-NAME and aPGF2{alpha} caused a further significant increase (P < 0.05) in P4 concentrations compared with aPGF2{alpha} or L-NAME treatment (Fig. 2Go).



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  		Figure 2. Concentrations (mean ± SEM) of progesterone in perfusate samples after simultaneous intraluteal administration of saline or dinoprost (5 mg), a PGF2{alpha} analog, for 0.5 h during intraluteal perfusion (4 h) of either saline or L-NAME (200 mg), an inhibitor of nitric oxide synthase, on day 15 of the estrous cycle. *P < 0.05 vs. period before treatment; a–cdifferent subscripts indicate differences (P < 0.05) between groups at the same time point.

 
For P4 concentrations the three-way interactions were measured between place of sample collection, L-NAME, and aPGF2{alpha} treatment (P < 0.05) as well as for place of sample collection, L-NAME, and time of sample collection (P < 0.01). Two-way interactions were observed between place of blood collection and treatment with aPGF2{alpha} (P < 0.01) and between place of sample collection and time of sample collection (P < 0.01) as well as treatment with aPGF2{alpha} and time of sample collection (P < 0.01).

There were no significant changes (P > 0.05) in P4 concentrations in jugular plasma samples collected daily during days 14 to 21 of the estrous cycle in the animals treated simultaneously with L-NAME and aPGF2{alpha} when compared with saline administration (Fig. 3Go). After administration of aPGF2{alpha} the average concentration of P4 decreased in all heifers to less than 20% of baseline (day 14) at day 16 of the cycle and remained significantly (P < 0.05) lower until day 17 or 18 when compared with Group IV (simultaneous L-NAME and aPGF2{alpha} treatment) or Group I (saline), respectively (Fig. 3Go). The concentrations of P4 after CL perfusion with L-NAME remained high until day 21 of the cycle and were significantly higher (P < 0.05) than in heifers treated with saline, aPGF2{alpha}, and L-NAME and aPGF2{alpha} on days 18 to 21, 16 to 21, and 17 to 21, respectively (Fig. 3Go).



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  		Figure 3. Concentrations (mean ± SEM) of progesterone in jugular plasma samples (from day 14–21) after intraluteal administration of saline or dinoprost (5 mg), a PGF2{alpha} analog, for 0.5 h during intraluteal perfusion (4 h) of either saline or L-NAME (200 mg), an inhibitor of nitric oxide synthase, on day 15 of the estrous cycle. a–cDifferent subscripts indicate differences (P < 0.05) between groups at the same day.

 
PGE2 Concentrations.
Perfusion of CL with saline or L-NAME did not affect (P > 0.05) PGE2 concentrations in the perfusate samples compared with the periods before treatment (Fig. 4Go). Perfusion of CL with aPGF2{alpha} or with L-NAME and aPGF2{alpha} increased (P < 0.001) PGE2 concentrations as compared with the periods before treatment as well as with PGE2 concentrations after saline (Group I) and L-NAME (Group III) treatment (Fig. 4Go).



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  		Figure 4. Concentrations (mean ± SEM) of prostaglandin E2 in perfusate samples after intraluteal administration of saline or dinoprost (5 mg), a PGF2{alpha} analog, for 0.5 h during intraluteal perfusion (4 h) of either saline or L-NAME (200 mg), an inhibitor of nitric oxide synthase, on day 15 of the estrous cycle. * P < 0.05 vs. period before treatment; a–cdifferent subscripts indicate differences (P < 0.05) between groups at the same time point.

 
For PGE2 concentrations, a two-way interaction was found only between treatment with aPGF2{alpha} and time of sample collection (P < 0.001).

LTC4 Concentrations.
Perfusion of CL with saline or L-NAME had no effect (P > 0.05) on LTC4 concentrations in perfusate samples as compared with the period before treatment (Fig. 5Go). LTC4 concentrations were significantly (P < 0.05) increased by treatment with aPGF2{alpha} and concomitant L-NAME and aPGF2{alpha} administration as compared with the periods before treatment or with saline (Group I) and L-NAME (Group III) administration (Fig. 5Go).



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  		Figure 5. Concentrations (mean ± SEM) of leukotriene C4 in perfusate samples after intraluteal administration of saline or dinoprost (5 mg), a PGF2{alpha} analog, for 0.5 h during intraluteal perfusion (4 h) of either saline or L-NAME (200 mg), an inhibitor of nitric oxide synthase, on day 15 of the estrous cycle. * P < 0.05 vs. period before treatment; a–cdifferent subscripts indicate differences (P < 0.05) between groups at the same time point.

 
For LTC4 concentrations two-way interactions were measured between L-NAME treatment and time of sample collection (P < 0.05) and between aPGF2{alpha} treatment and time of sample collection (P < 0.001). A three-way interaction was found between L-NAME and aPGF2{alpha} treatment and time of sample collection (P < 0.01).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our study showed that intraluteal administration of aPGF2{alpha} caused a decrease of P4 concentrations in peripheral blood samples to less than 20% of baseline after 24 h, a result similar to that reported after intramuscular injection (28, 29). Despite the fact that aPGF2{alpha} administered by MDS reduced plasma P4 concentration within 24 h, it caused a brief temporary increase in P4 concentration. A similar brief increase in P4 concentration after aPGF2{alpha} treatment was also observed in microdialysed bovine CL in vitro (30) and in peripheral blood plasma samples after aPGF2{alpha} administration into the aorta abdominalis (4, 22). These results, obtained from different experimental models, clearly indicate that the final decrease in P4 concentration observed after PGF2{alpha}-induced luteolysis is preceded by a transient increase. The mechanism responsible for these changes is not fully understood, but the transient increase in P4 secretion may result from a direct influence of PGF2{alpha} on steroidogenic activity of luteal cells, particularly the small luteal cells. This phenomenon may explain the stimulatory effect of PGF2{alpha} on P4 production by bovine steroidogenic luteal cells in vitro reported by many authors (5, 7, 24, 31). The final decrease in P4 secretion after intraluteal administration of a PGF2{alpha} may be a consequence of changes in intraluteal blood flow (28) caused by disruption of the normal balance of vasodilatory (NO) and vasoconstrictive (endothelin) activities.

Perfusion of CL with L-NAME increased P4 concentrations in the perfusate samples and maintained concentrations of this hormone in peripheral blood at a high level until day 21 of the cycle. This result is in agreement with our previous study showing that spontaneous luteolysis was inhibited by L-NAME administered by MDS on days 17 and 18 of the cycle (21). In the present study we also showed that intraluteal administration of aPGF2{alpha} during L-NAME perfusion intensified the L-NAME-induced P4 secretion by the CL and that the luteolytic action of aPGF2{alpha} was partially counteracted by L-NAME. Collectively, these results suggest that NO plays a role as an auto/paracrine factor in regulation of luteal steroidogenesis, and that it may mediate PGF2{alpha} action during luteolysis. It has been shown that a number of NO donors negatively affect P4 secretion, while NOS inhibitors stimulate P4 production by dispersed bovine luteal cells (20, 24), confirming the role of NO as a regulator of steroidogenesis.

Our present study indicates that the luteolytic action of aPGF2{alpha} was partially counteracted by L-NAME. An evident blockade of PGF2{alpha} action was also observed when an analog of aPGF2{alpha} (cloprostenol) and L-NAME were administered into the aorta abdominalis (22). PGF2{alpha} is most effective as a luteolytic factor when it reaches the CL through blood vessels (32). We suggest that the discrepancy in the potency of L-NAME in inhibiting aPGF2{alpha}-induced luteolysis observed in our two different experimental procedures (local versus systemic application of L-NAME) are a consequence of the fact that the PGF2{alpha} reached the luteal tissue by way of blood vessels after systemic administration.

Nitric oxide is a potent vasodilator and increases blood flow (33). Acosta et al. (20) showed that blood flow within the bovine CL initially increased at 0.5 to 2 h, decreased at 4 h to the level observed at 0 h and then decreased to a lower level beginning at 8 h after aPGF2{alpha} treatment. In our previous study (22), plasma concentrations of nitrite/nitrate were also elevated during the first 2 hr after aPGF2{alpha} injection; after that they slowly decreased, indicating that the factor responsible for the increase in blood flow after aPGF2{alpha} treatment is NO. Therefore, the inhibition of luteolysis observed after L-NAME treatment that reduces NO release may also be a consequence of the changes in the blood flow within the bovine reproductive tract. Moreover, Lopez Collazo et al. (34) showed that [Ca2+]i-mobilizing agents and cytokines elicit an apoptotic response in the vascular endothelial cells through mechanisms that require NO synthesis. The expression of inducible NOS is correlated with cytotoxic/cytostatic events and results in a sustained synthesis of NO, which in turn induces apoptotic cell death (35). Recently we showed that spermine NONOate, an NO donor, strongly reduced viability of the bovine luteal cells, while L-NAME had opposite effects (Korzekwa A, Okuda K, Jaroszewski JJ, Skarzynski DJ, unpublished data). Therefore, the administration of L-NAME may also protect against apoptosis induced by PGF2{alpha} during luteolysis.

It was recently shown that intraluteal administration of a NO donor in vivo strongly stimulated both LTC4 and PGF2{alpha} (36), two factors involved in the process of luteal regression in bovine CL (2, 12). It has been shown in our previous study that another analogue of PGF2{alpha} (cloprostenol) strongly stimulated output of two luteolytic factors: PGF2{alpha} (4, 22) and NO (22) in the bovine reproductive tract. Our present study showed that aPGF2{alpha} increased secretion of another luteolytic factor—LTC4. Thus, PGF2{alpha}-induced regression of the CL is a very complex process, which involves not only an utero-ovarian PGF2{alpha} auto-amplification loop (4, 29), but also several paracrine mechanisms including immune (6, 11, 13, 16, 17) and vascular factors (6, 19, 20, 22, 28). Indeed, in our present study aPGF2{alpha} also increased concentrations of luteotropic PGE2. Both NO and PGE2 are potent vasodilators and increase blood flow. Thus, our previous (22) and present findings can explain the recent data of Acosta et al. (20) showing that blood flow in the bovine CL is increased just after PGF2{alpha} treatment, not decreased as is commonly assumed. During the first 2 hr of PGF2{alpha} action, NO may act in concert with PGE2 to relax vascular smooth muscle cells and maintain the luteal blood flow required for invasion of immune cells into the CL during luteolysis (14, 16, 17).

In summary, our previous data showed that that NO is produced locally in the bovine CL with the highest production occurring during the late luteal phase (22) and that NO directly inhibits P4 secretion in cattle (23, 24). The increased effects of PGF2{alpha} on luteal cells previously exposed to NO suggest that priming of bovine CL by NO is needed for complete luteal regression (25). This suggestion is confirmed by our previous (21) and present data showing that an inhibition of ovarian NO production by perfusion of the CL with an NOS inhibitor prolonged the functional life span of CL. Moreover, the luteolytic action of aPGF2{alpha} is inhibited (22) or partially prevented, as shown in the present study, by administration of an NOS inhibitor. Therefore, NO appears to play an important role in both functional and structural luteolysis, acting as a component of an autocrine/paracrine luteolytic cascade induced by PGF2{alpha}.


   Acknowledgments
 
We thank Dr. Stanislaw Okrasa of the University of Warmia and Mazury in Olsztyn, Poland for the P4 antiserum and Dr. Seiji Ito of Kansai Medical University, Osaka, Japan for antisera to PGE2. We thank Julia Voloufova (Biostatistics and Data Management Core, PBRC) for help with statistical analyses and Dr. Marek Bogacki (Department of Reproductive Biotechnology, PBRC) for his review and editorial assistance.


   Footnotes
 
Supported by grants of the State Committee for Scientific Research (KBN 5P06K012 19) and the Gordon and Mary Cain Foundation.

1 To whom requests for reprints should be addressed at Department of Pharmacology, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Oczapowskiego 13, 10-718 Olsztyn, Poland. E-mail: jerzyj{at}uwm.edu.pl Back


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Received for publication November 26, 2002. Accepted for publication May 23, 2003.





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