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Proceedings of the Society for Experimental Biology and Medicine 224:50-55 (2000)
© 2000 Society for Experimental Biology and Medicine

Original Article

Intraluteal Administration of a Nitric Oxide Synthase Blocker Stimulates Progesterone and Oxytocin Secretion and Prolongs the Life Span of the Bovine Corpus Luteum

Jerzy Jan Jaroszewski2, and William Hansel1,


Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana 70803


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
To test the role of nitric oxide (NO) in secretory functions of bovine corpora lutea (CL), two groups of four Holstein heifers each were treated as follows: Group 1, N{omega}-Nitro-L-Arginine Methyl Ester (L-NAME), an inhibitor of nitric oxide synthase (NOS), on Day 11 or 12 of the cycle and Group 2, L-NAME on Days 17 and 18 of the cycle. All treatments were administered by an intraluteal microdialysis system (MDS). Drugs were infused for 4-hr periods on the designated days, and the treatment periods were preceded and followed by 4-hr control periods. Perfusate and jugular blood samples were collected at half-hour intervals. Perfusate samples were analyzed for progesterone (P4), oxytocin (OT), prostaglandin F2{alpha} (PGF2{alpha}), and leukotriene C4 (LTC4); jugular plasma samples were analyzed for P4, OT, and LH. Perfusion of L-NAME on Day 11 or 12 consistently increased P4 concentration in the perfusate, but had no effect on the life span of the CL. Perfusion of L-NAME on Days 17–18 also elevated P4 levels in the perfusate, and in addition, maintained P4 levels in the plasma of three of the four treated animals through Day 25 of the cycle. L-NAME perfusion also increased OT release concomitant with P4 into the perfusate at both the mid- and late-luteal phase treatments. For the most part, concentrations of LH, OT, and P4 in the jugular plasma samples collected during the perfusions were unaffected by treatments. L-NAME perfusion caused small, but significant (P < 0.05) increases in perfusate PGF2{alpha} and LTC4 at Days 17 and 18 and in LTC4 on Day 11 or 12. These data indicate that NO plays a direct luteolytic role in regression of the bovine CL.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The current concept that luteolysis in cattle is brought about by PGF2{alpha} of uterine origin secreted in response to OT released by the CL is inadequate to explain many of the events that actually occur at the time of regression (1). Although luteolytic in vivo, PGF2{alpha} in vitro does not inhibit basal P4 production by the large luteal cells (LLC) and actually stimulates P4 production by small luteal cells (SLC). There is very little OT present in the CL at the time of luteolysis, and several recent studies indicate that luteolysis can occur after depletion of luteal OT (2) and in the absence of measurable OT release from the luteal tissue (3). A number of studies indicate that the products of the lipoxygenase pathway of the arachidonic acid (AA) cascade, particularly LTC4 play major roles in luteolysis. Intrauterine infusions of a blocker of the lipoxygenase pathway prolong the functional life of the CL (4), and lipoxygenase products, including LTC4, markedly inhibit P4 production in vitro. In a previous microdialysis study, leukotriene B4 (LTB4) and LTC4 were found in the perfusate and rose prior to the decline in progesterone during luteolysis (3).

Bovine ovaries are richly supplied by adrenergic and peptidergic nerves (5) as well as nerves synthesizing NO (6). Neuropeptides such as neuropeptide Y, substance P, vasoactive intestinal peptide (7), and norepinephrine (2, 8) act on P4 secretion in bovine CL. NO, a highly reactive free radical acts as an important regulator of many physiological events, including blood pressure, neurotransmission, and host defense (9, 10). NO is synthesized via the oxidation of L-arginine by nitric oxide synthase (NOS). This enzyme catalyzes the mixed function oxidation of a guanidino nitrogen atom of L-arginine to yield L-citrulline and NO (9). The presence of NO has been shown in ovaries of many mammalian species (11-20) including bovine cumulus cells (21). In rats and rabbits, NO influences follicular development, rupture, and atresia (11, 13-15, 20), and participates in the regulation of CL function (17, 19). In women undergoing in vitro fertilization, a positive correlation was found between circulating and follicular fluid nitrite/nitrate concentrations and follicular development (22, 23). Moreover, it was shown that the cells obtained from rat ovaries at all stages of follicular development (preantral, Graafian, ovulatory, and atretic) and luteinization synthesized NO in a linear manner over time, but the basal production of NO was 6- to 14-fold higher in cells obtained from luteinized ovaries than from cells obtained from ovaries at all other stages (16).

In vitro experimental evidence indicates that NO negatively regulates estradiol (E2) and P4 secretion in human granulosa cells (12) and rat luteinized ovarian cells (16), whereas inhibition of NOS activity significantly increases E2 secretion without changes in P4 production (12, 16). Furthermore, it was shown that NO increased PG production in perfused rabbit ovaries (20), and addition of NOS inhibitors to incubated luteal tissue from late pseudopregnant rats significantly diminished PGF2{alpha} production (19). These in vitro studies suggest that NO functions as an important autocrine and/or paracrine agent in ovarian secretion, but there is little or no information about its actions in vivo, especially in ruminant animals in which the uterus plays a key role in luteolysis. Therefore, the aim of these experiments was to determine the role of NO in the secretory function of bovine CL during the middle and late luteal phases of the estrous cycle.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
MDS Implantation.
Normally cycling Holstein heifers (n = 8) were injected intramuscularly (i.m.) with 25 mg of PGF2{alpha} (Lutalyse; Pharmacia and Upjohn, Bridgewater, NJ) during the luteal phase to induce luteolysis and estrus. The MDS was implanted, as described by Blair et al. (3), into the CL on Days 10 or 11 (n = 4) and 16 (n = 4) of the subsequent estrous cycle (Day 0 = estrus). The animals were premedicated with xylazine, 50 mg/animal i.m. (Rompun; Miles, Shawnee Mission, KS) and local anesthesia (epidural and at the site of incision), using 2% lidocaine hydrochloride (Lidocaine 2% injectable; Butler, Columbus, OH), was induced immediately prior to surgery. The ovaries were exteriorized through a flank laparotomy, and the MDS was threaded through the CL such that the dialysis tubing (Fresenius SPS 960; Frankfurt, Germany; MW cutoff = 1,000,000 Da; o.d. = 500 µm; i.d. = 340 µm) was localized within the CL. The MDS was fixed to the surface of the CL at the points of entrance and exit by tissue glue, and the ovary was replaced into the peritoneal cavity. The connecting tubes were exteriorized through a puncture in the paralumbar fossa and connected to Teflon tubing. One end of the Teflon tubing was connected to a syringe pump (KDS Scientific Model 100; Cole Palmer, Vernon Hills, IL), whereas the other was connected to a fraction collector (Model 2110; Bio Rad, Hercules, CA). Animals were kept in individual stalls in a temperature-controlled room, and the CL was perfused with Ringer's solution immediately after surgery. All infusions were at a flow rate of 3 ml/hr. All animal procedures were approved by the Cornell University Institutional Animal Care and Use Committee.

The recovery rates of hormones across the MDS were measured as previously described (24) and amounted to {approx} 0.1% for OT and LTC4, 0.3% for PGF2{alpha}, and 1% for P4.

Schedule of Experiments.
Experiment 1.
The CL of 4 animals were perfused on Day 11 or 12 of the cycle for 4 hr with 100 mg of N{omega}-Nitro-L-Arginine Methyl Ester (L-NAME; Cayman Chemical Co., Ann Arbor, MI), an inhibitor of NOS. Perfusate and jugular blood samples were collected every 30 min before, during, and after L-NAME infusion. Each 4-hr treatment period was preceded and followed by 4-hr control periods during which physiological saline solution was perfused at the same rate (3 ml/ hr). Blood samples were collected through catheters implanted into the jugular vein. Additional blood samples were taken once daily by jugular venipuncture through Day 22 of the estrous cycle to determine the functional life of the CL.

Experiment 2.
The CL of 4 animals were perfused on Day 17 and again on Day 18 of the estrous cycle for 4 hr with 100 mg of L-NAME. As in Exp. 1, treatment periods were preceded and followed by 4-hr control periods. The perfusate and blood samples were collected with the same frequency as in Exp. 1. Moreover, blood samples were taken once daily by jugular venipuncture from Days 19–25 of the estrous cycle to determine the functional life of the CL.

All samples were stored at –80°C until hormone determinations were made.

Hormone Determinations.
P4 concentrations in perfusate and plasma samples were determined by radioimmunoassay (RIA) as previously described (25). The P4 antiserum used had 11.64% cross-reaction with 5ß-dihydroprogesterone, 1.97% with 5{alpha}-dihydroprogesterone, 2.64% with 20ß-OH-progesterone, 1.90% with 20{alpha}-OH-progesterone, 3.22% with 17{alpha}-OH-progesterone, 0.09% with pregnenolone, 0.96% with corticosterone, 0.03% with testosterone, 0.01% with cortisol, and less than 0.01% with estrone, 17ß-estradiol, 17{alpha}-estradiol, estriol, androstendione, 5{alpha}-dihydrotestosterone, dehydroepiandrostendione, and cholesterol. The assay sensitivity was 0.15 ng/ml, and the intra- and interassay coefficients of variation (CVs) were 5.30% and 9.44%, respectively.

OT concentrations in perfusate and plasma samples were measured by RIA as previously described (26, 27). The detection limit of the assay was 0.34 pg/ml, and intra- and interassay CVs were 4.6% and 9.5%, respectively.

LH concentration in plasma samples was determined by RIA as described by Thompson et al. (28). The assay sensitivity was 0.44 ng/ml and intra- and interassay CVs were 3.7% and 9.6%, respectively.

LTC4 and PGF2{alpha} concentrations were determined in perfusate samples using commercially available enzyme immunoassay kits (Cayman Chemical Co.) according to instructions of the manufacturer. The assay sensitivities were 9.81 pg/ml for LTC4 and 4.51 pg/ml for PGF2{alpha}, respectively. The intra- and interassay CVs were 4.1% and 9.0% for LTC4 and 5.4% and 8.7% for PGF2{alpha}, respectively.

Data Analysis.
Experimental data are shown as mean ± SEM. Treatment differences in each experiment were assessed by one-way analysis of variance (ANOVA) using Bonferroni's Multiple Comparison Test (Graph Pad Prism). Differences with P < 0.05 were regarded as statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Experiment 1.
Perfusion of L-NAME on Day 11 or 12 of the cycle caused marked synchronous increases in P4 and OT (P < 0.001) in the perfusate samples (Fig. 1)Go. L-NAME perfusion also caused a relatively small, but significant (P < 0.001) increase in LTC4 concentration, but did not change the PGF2{alpha} level (P > 0.05) in the perfusate samples (Fig. 1)Go. No changes were observed in P4, OT, and LH concentrations in plasma samples collected during perfusion (Fig. 2)Go. Plasma P4 concentrations of all treated animals declined between Days 18 and 22 (Fig. 3)Go.



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  		Figure 1.   Concentrations of progesterone (P4), oxytocin (OT), prostaglandin F2{alpha} (PGF2{alpha}), and leukotriene C4 (LTC4) in perfusate samples during L-NAME infusion on Day 11 or 12 of the estrous cycle.

 


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  		Figure 2.   Concentrations of progesterone (P4), oxytocin (OT), and luteotropic hormone (LH) in plasma samples collected during L-NAME infusion on Day 11 or 12 of the estrous cycle.

 


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  		Figure 3.   Plasma progesterone concentrations in samples collected once daily after L-NAME infusion on Day 11 or 12 to Day 22 of the estrous cycle.

 
Experiment 2.
L-NAME perfusion on Days 17 and 18 also caused increases in P4 concentrations (P < 0.001) in perfusate samples on both Days 17 and 18 (Fig. 4a)Go, even though the level of P4 in the plasma decreased slightly on both Day 17 (P < 0.05) and Day 18 (P < 0.01; Fig. 4bGo). The concentrations of P4 in plasma samples collected during Days 19–25 of the estrous cycle were maintained above 3 ng/ml in three of the four treated animals (Fig. 5)Go. Increased levels of both LTC4 (P < 0.01) and PGF2{alpha} (P < 0.05) were found in the perfusate samples (Fig. 6)Go. As was the case at Day 11 or 12, L-NAME perfusions increased OT concentrations (P < 0.001) in the perfusate samples (Fig. 7)Go on Days 17 and 18 of the cycle, but did not affect the concentration of OT or LH in the plasma samples (unpublished data).



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  		Figure 4.   Concentration of progesterone in (a) perfusate and (b) blood plasma samples during L-NAME infusion on Days 17 and 18 of the estrous cycle.

 


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  		Figure 5.   Concentration of progesterone in plasma samples collected once daily after L-NAME infusion on Days 17 and 18 of the estrous cycle.

 


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  		Figure 6.   Concentrations of prostaglandin F2{alpha} (PGF2{alpha}) and leukotriene C4 (LTC4) in perfusate samples during L-NAME infusion on Days 17 and 18 of the estrous cycle.

 


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  		Figure 7.   Concentration of oxytocin (OT) in perfusate samples during L-NAME infusion on Days 17 or 18 of the estrous cycle.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The abilities of infused L-NAME to cause marked increases in P4 release at Day 11 or 12 and at Days 17 and 18, and to prolong the functional life of the CL to at least 25 days, when administered at Days 17 and 18, indicate that NO plays an important role at the ovarian level in inhibiting P4 production and initiating luteal regression. NO inhibited both P4 and E2 secretion in human granulosa cells (12) and luteinized rat ovarian cells (16) and inhibited P4 secretion in cultured bovine luteal cells (29). NO has also been shown to inhibit several P450 steroidogenic enzymes (30). It is also known that NO activates heme-containing enzymes, among them a cyclooxygenase (COX) which is rate-limiting in the biosynthesis of prostaglandins, tromboxane A2, and prostacyclin (9, 31). A most interesting feature of these data is the precise coincidence of the changes in secretion of P4 and OT into the perfusate before, during, and after L-NAME administration at mid- (Day 11 or 12) and late (Days 17–18) luteal phases of the cycle. A linkage between P4 secretion and secretory granule exocytosis from the LLC was first reported for the ewe in 1974 (32) and later for the cow (33). Since the secretory granules of the LLC are known to contain OT (34), it would appear that L-NAME, through NO inhibition, may act primarily on the LLC. However, it should be noted that SLC secrete P4 in response to LH, even though they contain few, if any secretory granules.

The fact that infusion of L-NAME on Days 17 and 18 elevated P4 and prevented luteolysis at the normal time, despite the fact that it increased both PGF2{alpha} and LTC4 in the perfusate, suggests that NO exerts its luteolytic effects directly on the CL. This local luteolytic effect might involve direct effects on the luteal cells, a mobilization of endothelin which has been shown to have luteolytic properties (35), or a combination of both. Activation of endothelial nitric oxide synthase (eNOS) by endothelins results in release of NO that mediates the vasorelaxing effects of bovine endothelial cells, which are numerous in bovine luteal tissue.

The administration of L-NAME may reduce or abolish the vasorelaxing effect of NO and endothelin. However, the marked increases in P4 and OX in the present study were precisely limited to the period of L-NAME infusion, and it seems unlikely that they were influenced by previous accumulations due to vasoconstriction. Blood flow alterations play important roles in luteal regression. A marked decline in blood flow occurs during both normal and PGF2{alpha}-induced luteolysis (1). Sclerotic changes involving hypertrophy and hyperplasia of cells in the walls of small arterioles leading to a reduced blood flow have been associated with luteal regression in cattle (1).

The increase in PGF2{alpha} and LTC4 in the perfusate after L-NAME administration was a surprising result. However, accumulating evidence suggests that NO, and endothelin-1 as well, exert their effects by enhancing or mediating the effects of PGF2{alpha} and LTC4 rather than by controlling their production (36, 37). The ability of PGF2{alpha} to cause an initial increase in P4 production in vivo after intraluteal administration of PGF2{alpha} by microdialysis was recently demonstrated (38), and PGF2{alpha} is known to increase P4 production by bovine luteal cells in vitro.

For the most part, concentrations of LH, OT, and P4 in the jugular plasma were not affected by changes in concentrations in the perfusate samples, although the functional life of the CL was prolonged after L-NAME administration on Days 17 and 18, as indicated by continued high plasma P4 levels until Day 25. Plasma P4 concentrations in normal Holstein heifers begin to decline on about Day 18 of the cycle and are usually less than 1 ng/ml by Day 20 (1, 4). P4 plasma concentrations had clearly declined in all of the animals treated with L-NAME by Day 22 (Fig. 2)Go. The small but significant (P < 0.05) decline in plasma P4 levels during L-NAME perfusion on Days 17 and 18 did not appear to be due to decreased LH secretion. It is known that NO increases LHRH release in rats (39, 40) and that LH stimulates P4 secretion by the bovine CL (1, 41).

In summary, intraluteal infusion of the NOS inhibitor, L-NAME at either mid- or late phases of the estrous cycle increased the secretion of both P4 and OT in the perfusate samples, and L-NAME administered on Days 17–18 of the cycle prolonged the functional life of the CL. Moreover, L-NAME perfusion marginally increased LTC4 in both phases and PGF2{alpha} in the late luteal phase. The levels of OT, LH, and P4 in the plasma samples, for the most part, were unaffected by the intraluteal treatments of L-NAME. These data are the first to show that NO acts as a significant auto/paracrine factor in the mid- and late luteal phases and plays an important local role in the initiation of luteal regression in a ruminant.


   Acknowledgments
 
The cooperation of Dr. Joanne Fortune, who provided the surgical facilities at Cornell University where the experiments were conducted and the P4 antiserum used, is gratefully acknowledged. The assistance of R.A. Saatman, Cornell University, with the surgical procedures is also acknowledged. The laboratory assistance of Dr. Shuenn Liou and Meng Wang is gratefully acknowledged. The OT antiserum was kindly supplied by Dr. D. Schams, Technical University of Munich, Germany and the LH antiserum by Dr. D.L. Thompson, Louisiana State University.


   Footnotes
 
Supported by a grant provided by the Gordon and Mary Cain Foundation.

Parts of these data were presented at the 32nd annual meeting of The Society for the Study of Reproduction, July 31–August 3, 1999.

1 To whom requests for reprints should be addressed at the Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Road, Baton Rouge, LA 70808. E-mail: HanselW{at}mhs.pbrc.edu Back

2 Present address: Warmia and Masuria University in Olsztyn, Faculty of Veterinary Medicine, Department of Pharmacology, Oczapowskiego 13, 10–957 Olsztyn, Poland. Back


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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Received for publication October 4, 1999. Accepted for publication January 19, 2000.




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Characterization of endothelin-1 and nitric oxide generating systems in corpus luteum-derived endothelial cells
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T.P. Neuvians, D. Schams, B. Berisha, and M.W. Pfaffl
Involvement of Pro-Inflammatory Cytokines, Mediators of Inflammation, and Basic Fibroblast Growth Factor in Prostaglandin F2{alpha}-Induced Luteolysis in Bovine Corpus Luteum
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D. J. Skarzynski, M. M. Bah, K. M. Deptula, I. Woclawek-Potocka, A. Korzekwa, M. Shibaya, W. Pilawski, and K. Okuda
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Biol Reprod, December 1, 2003; 69(6): 1907 - 1913.
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J. J. Jaroszewski, D. J. Skarzynski, and W. Hansel
Nitric Oxide as a Local Mediator of Prostaglandin F2{alpha}-Induced Regression in Bovine Corpus Luteum: An In Vivo Study
Experimental Biology and Medicine, October 1, 2003; 228(9): 1057 - 1062.
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J. J. Jaroszewski, D. J. Skarzynski, R. M. Blair, and W. Hansel
Influence of Nitric Oxide on the Secretory Function of the Bovine Corpus Luteum: Dependence on Cell Composition and Cell-to-Cell Communication
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D. J. Skarzynski, J. J. Jaroszewski, M. M. Bah, K. M. Deptula, B. Barszczewska, B. Gawronska, and W. Hansel
Administration of a Nitric Oxide Synthase Inhibitor Counteracts Prostaglandin F2-Induced Luteolysis in Cattle
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T. A. Towle, P. C.W. Tsang, R. A. Milvae, M. K. Newbury, and J. A. McCracken
Dynamic In Vivo Changes in Tissue Inhibitors of Metalloproteinases 1 and 2, and Matrix Metalloproteinases 2 and 9, During Prostaglandin F2{alpha}-Induced Luteolysis in Sheep
Biol Reprod, May 1, 2002; 66(5): 1515 - 1521.
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T. J. Acosta, N. Yoshizawa, M. Ohtani, and A. Miyamoto
Local Changes in Blood Flow Within the Early and Midcycle Corpus Luteum after Prostaglandin F2{alpha} Injection in the Cow
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Distinct Cellular Localization and Regulation of Endothelin-1 and Endothelin-Converting Enzyme-1 Expression in the Bovine Corpus Luteum: Implications for Luteolysis
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