| Dose-dependent therapeutic effects of 2-Methoxyestradiol on Monocrotaline-Induced pulmonary hypertension and vascular remodelling. | |
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MedLine Citation:
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PMID: 20693947 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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(Full text is available at http://www.manu.edu.mk/prilozi). 2-Methoxyestradiol (2ME) is a major non-oestrogenic metabolite of oestradiol. Our previous studies, performed in several models of cardiac and/or vascular injury, suggest that 2ME strongly inhibits both pressure-dependent and pressure-independent cardiac and vascular remodelling. Furthermore, recently we have shown that in male rats 2ME attenuates the development and retards the progression of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH); and in female rats 2ME eliminates the exacerbation of PAH and increased mortality due to ovariectomy. In the present study we compared the therapeutic effects of three different doses of 2ME (3, 10 and 30 microg/kg/hour; 2ME-3, 2ME-10 and 2ME-30, respectively) in male rats with MCT-induced PAH. The animals were also monitored for plasma 2ME levels and potential oestrogenic effects. Treatments were initiated 12 days after administration of MCT (60 mg/kg, i.p.). Twenty-eight days post MCT, right ventricular peak systolic pressure (RVPSP) was measured and morphometric analysis was conducted. All three doses of 2ME produced beneficial therapeutic effects in pulmonary hypertensive animals, i.e. reduced pulmonary artery pressure and right ventricular hypertrophy, attenuated pulmonary vascular remodelling and inflammatory response, and had favourable effects on survival. Notably, none of the three doses had any effect on plasma testosterone levels or on seminal vesicle or testicle weight. Dose-dependent increases in 2ME plasma levels were observed only with 2ME-3 and 2ME-10; 2ME-30 produced 2ME plasma levels similar to those seen with 2ME10. Nonetheless, 2ME-30 was significantly more efficacious than 2ME-3 or 2ME-10 and eliminated the high mortality (34%) induced by MCT. In summary, the present study indicates that 2ME, used in doses that produce plasma levels similar to those seen in the last trimester of pregnancy (1000-3000pg/ml), is effective and safe (i.e. has no oestrogenic effects) in experimental PAH. These data also suggest that 2ME disposition, rather than plasma concentration, determines the therapeutic effects of 2ME in PAH. Key words: Pulmonary hypertension, 2-methoxyestradiol, vascular remodelling. |
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Authors:
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S P Tofovic; T Jones; G Petrusevska |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Prilozi / Makedonska akademija na naukite i umetnostite, Oddelenie za biološki i medicinski nauki = Contributions / Macedonian Academy of Sciences and Arts, Section of Biological and Medical Sciences Volume: 31 ISSN: 0351-3254 ISO Abbreviation: Prilozi Publication Date: 2010 Jul |
Date Detail:
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Created Date: 2010-08-09 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101189513 Medline TA: Prilozi Country: Macedonia |
Other Details:
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Languages: eng Pagination: 279-95 Citation Subset: IM |
Affiliation:
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Center for Clinical Pharmacology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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