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Thalidomide ameliorates portal hypertension via nitric oxide synthase independent reduced systolic blood pressure.
World J Gastroenterol. 2015 Apr 14; 21(14):4126-35.WJ

Abstract

AIM

Portal hypertension is a common complication of liver cirrhosis and significantly increases mortality and morbidity. Previous reports have suggested that the compound thalidomide attenuates portal hypertension (PHT). However, the mechanism for this action is not fully elucidated. One hypothesis is that thalidomide destabilizes tumor necrosis factor α (TNFα) mRNA and therefore diminishes TNFα induction of nitric oxide synthase (NOS) and the production of nitric oxide (NO). To examine this hypothesis, we utilized the murine partial portal vein ligation (PVL) PHT model in combination with endothelial or inducible NOS isoform gene knockout mice.

METHODS

Wild type, inducible nitric oxide synthase (iNOS)(-/-) and endothelial nitric oxide synthase (eNOS)(-/-) mice received either PVL or sham surgery and were given either thalidomide or vehicle. Serum nitrate (total nitrate, NOx) was measured daily for 7 d as a surrogate of NO synthesis. Serum TNFα level was quantified by enzyme-linked immunosorbent assay. TNFα mRNA was quantified in liver and aorta tissue by reverse transcription-polymerase chain reaction. PHT was determined by recording splenic pulp pressure (SPP) and abdominal aortic flow after 0-7 d. Response to thalidomide was determined by measurement of SPP and mean arterial pressure (MAP).

RESULTS

SPP, abdominal aortic flow (Qao) and plasma NOx were increased in wild type and iNOS(-/-) PVL mice when compared to sham operated control mice. In contrast, SPP, Qao and plasma NOx were not increased in eNOS(-/-) PVL mice when compared to sham controls. Serum TNFα level in both sham and PVL mice was below the detection limit of the commercial ELISA used. Therefore, the effect of thalidomide on serum TNFα levels was undetermined in wild type, eNOS(-/-) or iNOS(-/-) mice. Thalidomide acutely increased plasma NOx in wild type and eNOS(-/-) mice but not iNOS(-/-) mice. Moreover, thalidomide temporarily (0-90 min) decreased mean arterial pressure, SPP and Qao in wild type, eNOS(-/-) and iNOS(-/-) PVL mice, after which time levels returned to the respective baseline.

CONCLUSION

Thalidomide does not reduce portal pressure in the murine PVL model by modulation of NO biosynthesis. Rather, thalidomide reduces PHT by decreasing MAP by an undetermined mechanism.

Links

Authors+Show Affiliations

Nicholas G Theodorakis, Mary A Maluccio, Nicholas J Skill, Division of Transplant Surgery, Department of Surgery, School of Medicine, Indiana University, Indianapolis, IN 46202, United States.

Nicholas G Theodorakis, Mary A Maluccio, Nicholas J Skill, Division of Transplant Surgery, Department of Surgery, School of Medicine, Indiana University, Indianapolis, IN 46202, United States.

Nicholas G Theodorakis, Mary A Maluccio, Nicholas J Skill, Division of Transplant Surgery, Department of Surgery, School of Medicine, Indiana University, Indianapolis, IN 46202, United States.

Nicholas G Theodorakis, Mary A Maluccio, Nicholas J Skill, Division of Transplant Surgery, Department of Surgery, School of Medicine, Indiana University, Indianapolis, IN 46202, United States.

Nicholas G Theodorakis, Mary A Maluccio, Nicholas J Skill, Division of Transplant Surgery, Department of Surgery, School of Medicine, Indiana University, Indianapolis, IN 46202, United States.

Pub Type(s)

Journal Article

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

Language

eng

PubMed ID

25892862

Citation

Theodorakis, Nicholas G., et al. "Thalidomide Ameliorates Portal Hypertension Via Nitric Oxide Synthase Independent Reduced Systolic Blood Pressure." World Journal of Gastroenterology, vol. 21, no. 14, 2015, pp. 4126-35.

Theodorakis NG, Wang YN, Korshunov VA, et al. Thalidomide ameliorates portal hypertension via nitric oxide synthase independent reduced systolic blood pressure. World J Gastroenterol. 2015;21(14):4126-35.

Theodorakis, N. G., Wang, Y. N., Korshunov, V. A., Maluccio, M. A., & Skill, N. J. (2015). Thalidomide ameliorates portal hypertension via nitric oxide synthase independent reduced systolic blood pressure. World Journal of Gastroenterology, 21(14), 4126-35. https://doi.org/10.3748/wjg.v21.i14.4126

Theodorakis NG, et al. Thalidomide Ameliorates Portal Hypertension Via Nitric Oxide Synthase Independent Reduced Systolic Blood Pressure. World J Gastroenterol. 2015 Apr 14;21(14):4126-35. PubMed PMID: 25892862.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - Thalidomide ameliorates portal hypertension via nitric oxide synthase independent reduced systolic blood pressure. AU - Theodorakis,Nicholas G, AU - Wang,Yining N, AU - Korshunov,Vyacheslav A, AU - Maluccio,Mary A, AU - Skill,Nicholas J, PY - 2014/06/12/received PY - 2014/07/30/revised PY - 2014/10/15/accepted PY - 2015/4/21/entrez PY - 2015/4/22/pubmed PY - 2016/1/27/medline KW - Endothelial nitric oxide synthase KW - Inducible nitric oxide synthase KW - Knockout mice KW - Nitric oxide KW - Portal hypertension KW - Thalidomide KW - Tumor necrosis factor alpha SP - 4126 EP - 35 JF - World journal of gastroenterology JO - World J Gastroenterol VL - 21 IS - 14 N2 - AIM: Portal hypertension is a common complication of liver cirrhosis and significantly increases mortality and morbidity. Previous reports have suggested that the compound thalidomide attenuates portal hypertension (PHT). However, the mechanism for this action is not fully elucidated. One hypothesis is that thalidomide destabilizes tumor necrosis factor α (TNFα) mRNA and therefore diminishes TNFα induction of nitric oxide synthase (NOS) and the production of nitric oxide (NO). To examine this hypothesis, we utilized the murine partial portal vein ligation (PVL) PHT model in combination with endothelial or inducible NOS isoform gene knockout mice. METHODS: Wild type, inducible nitric oxide synthase (iNOS)(-/-) and endothelial nitric oxide synthase (eNOS)(-/-) mice received either PVL or sham surgery and were given either thalidomide or vehicle. Serum nitrate (total nitrate, NOx) was measured daily for 7 d as a surrogate of NO synthesis. Serum TNFα level was quantified by enzyme-linked immunosorbent assay. TNFα mRNA was quantified in liver and aorta tissue by reverse transcription-polymerase chain reaction. PHT was determined by recording splenic pulp pressure (SPP) and abdominal aortic flow after 0-7 d. Response to thalidomide was determined by measurement of SPP and mean arterial pressure (MAP). RESULTS: SPP, abdominal aortic flow (Qao) and plasma NOx were increased in wild type and iNOS(-/-) PVL mice when compared to sham operated control mice. In contrast, SPP, Qao and plasma NOx were not increased in eNOS(-/-) PVL mice when compared to sham controls. Serum TNFα level in both sham and PVL mice was below the detection limit of the commercial ELISA used. Therefore, the effect of thalidomide on serum TNFα levels was undetermined in wild type, eNOS(-/-) or iNOS(-/-) mice. Thalidomide acutely increased plasma NOx in wild type and eNOS(-/-) mice but not iNOS(-/-) mice. Moreover, thalidomide temporarily (0-90 min) decreased mean arterial pressure, SPP and Qao in wild type, eNOS(-/-) and iNOS(-/-) PVL mice, after which time levels returned to the respective baseline. CONCLUSION: Thalidomide does not reduce portal pressure in the murine PVL model by modulation of NO biosynthesis. Rather, thalidomide reduces PHT by decreasing MAP by an undetermined mechanism. SN - 2219-2840 UR - https://www.unboundmedicine.com/medline/citation/25892862/Thalidomide_ameliorates_portal_hypertension_via_nitric_oxide_synthase_independent_reduced_systolic_blood_pressure_ DB - PRIME DP - Unbound Medicine ER -