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The effect of anandamide on uterine nitric oxide synthase activity depends on the presence of the blastocyst.
PLoS One. 2011 Apr 29; 6(4):e18368.Plos

Abstract

Nitric oxide production, catalyzed by nitric oxide synthase (NOS), should be strictly regulated to allow embryo implantation. Thus, our first aim was to study NOS activity during peri-implantation in the rat uterus. Day 6 inter-implantation sites showed lower NOS activity (0.19±0.01 pmoles L-citrulline mg prot(-1) h(-1)) compared to days 4 (0.34±0.03) and 5 (0.35±0.02) of pregnancy and to day 6 implantation sites (0.33±0.01). This regulation was not observed in pseudopregnancy. Both dormant and active blastocysts maintained NOS activity at similar levels. Anandamide (AEA), an endocannabinoid, binds to cannabinoid receptors type 1 (CB1) and type 2 (CB2), and high concentrations are toxic for implantation and embryo development. Previously, we observed that AEA synthesis presents an inverted pattern compared to NOS activity described here. We adopted a pharmacological approach using AEA, URB-597 (a selective inhibitor of fatty acid amide hydrolase, the enzyme that degrades AEA) and receptor selective antagonists to investigate the effect of AEA on uterine NOS activity in vitro in rat models of implantation. While AEA (0.70±0.02 vs 0.40±0.04) and URB-597 (1.08±0.09 vs 0.83±0.06) inhibited NOS activity in the absence of a blastocyst (pseudopregnancy) through CB2 receptors, AEA did not modulate NOS on day 5 pregnant uterus. Once implantation begins, URB-597 decreased NOS activity on day 6 implantation sites via CB1 receptors (0.25±0.04 vs 0.40±0.05). While a CB1 antagonist augmented NOS activity on day 6 inter-implantation sites (0.17±0.02 vs 0.27±0.02), a CB2 antagonist decreased it (0.17±0.02 vs 0.12±0.01). Finally, we described the expression and localization of cannabinoid receptors during implantation. In conclusion, AEA levels close to and at implantation sites seems to modulate NOS activity and thus nitric oxide production, fundamental for implantation, via cannabinoid receptors. This modulation depends on the presence of the blastocyst. These data establish cannabinoid receptors as an interesting target for the treatment of implantation deficiencies.

Authors+Show Affiliations

Laboratorio de Fisiología y Farmacología de la Reproducción, CEFYBO (CONICET-UBA), Buenos Aires, Argentina.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21559512

Citation

Sordelli, Micaela S., et al. "The Effect of Anandamide On Uterine Nitric Oxide Synthase Activity Depends On the Presence of the Blastocyst." PloS One, vol. 6, no. 4, 2011, pp. e18368.
Sordelli MS, Beltrame JS, Burdet J, et al. The effect of anandamide on uterine nitric oxide synthase activity depends on the presence of the blastocyst. PLoS One. 2011;6(4):e18368.
Sordelli, M. S., Beltrame, J. S., Burdet, J., Zotta, E., Pardo, R., Cella, M., Franchi, A. M., & Ribeiro, M. L. (2011). The effect of anandamide on uterine nitric oxide synthase activity depends on the presence of the blastocyst. PloS One, 6(4), e18368. https://doi.org/10.1371/journal.pone.0018368
Sordelli MS, et al. The Effect of Anandamide On Uterine Nitric Oxide Synthase Activity Depends On the Presence of the Blastocyst. PLoS One. 2011 Apr 29;6(4):e18368. PubMed PMID: 21559512.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The effect of anandamide on uterine nitric oxide synthase activity depends on the presence of the blastocyst. AU - Sordelli,Micaela S, AU - Beltrame,Jimena S, AU - Burdet,Juliana, AU - Zotta,Elsa, AU - Pardo,Romina, AU - Cella,Maximiliano, AU - Franchi,Ana M, AU - Ribeiro,Maria Laura, Y1 - 2011/04/29/ PY - 2010/12/13/received PY - 2011/02/28/accepted PY - 2011/5/12/entrez PY - 2011/5/12/pubmed PY - 2011/12/13/medline SP - e18368 EP - e18368 JF - PloS one JO - PLoS One VL - 6 IS - 4 N2 - Nitric oxide production, catalyzed by nitric oxide synthase (NOS), should be strictly regulated to allow embryo implantation. Thus, our first aim was to study NOS activity during peri-implantation in the rat uterus. Day 6 inter-implantation sites showed lower NOS activity (0.19±0.01 pmoles L-citrulline mg prot(-1) h(-1)) compared to days 4 (0.34±0.03) and 5 (0.35±0.02) of pregnancy and to day 6 implantation sites (0.33±0.01). This regulation was not observed in pseudopregnancy. Both dormant and active blastocysts maintained NOS activity at similar levels. Anandamide (AEA), an endocannabinoid, binds to cannabinoid receptors type 1 (CB1) and type 2 (CB2), and high concentrations are toxic for implantation and embryo development. Previously, we observed that AEA synthesis presents an inverted pattern compared to NOS activity described here. We adopted a pharmacological approach using AEA, URB-597 (a selective inhibitor of fatty acid amide hydrolase, the enzyme that degrades AEA) and receptor selective antagonists to investigate the effect of AEA on uterine NOS activity in vitro in rat models of implantation. While AEA (0.70±0.02 vs 0.40±0.04) and URB-597 (1.08±0.09 vs 0.83±0.06) inhibited NOS activity in the absence of a blastocyst (pseudopregnancy) through CB2 receptors, AEA did not modulate NOS on day 5 pregnant uterus. Once implantation begins, URB-597 decreased NOS activity on day 6 implantation sites via CB1 receptors (0.25±0.04 vs 0.40±0.05). While a CB1 antagonist augmented NOS activity on day 6 inter-implantation sites (0.17±0.02 vs 0.27±0.02), a CB2 antagonist decreased it (0.17±0.02 vs 0.12±0.01). Finally, we described the expression and localization of cannabinoid receptors during implantation. In conclusion, AEA levels close to and at implantation sites seems to modulate NOS activity and thus nitric oxide production, fundamental for implantation, via cannabinoid receptors. This modulation depends on the presence of the blastocyst. These data establish cannabinoid receptors as an interesting target for the treatment of implantation deficiencies. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/21559512/The_effect_of_anandamide_on_uterine_nitric_oxide_synthase_activity_depends_on_the_presence_of_the_blastocyst_ L2 - https://dx.plos.org/10.1371/journal.pone.0018368 DB - PRIME DP - Unbound Medicine ER -