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Effect of vigabatrin on contractile response to arachidonic acid and prostaglandins in smooth muscle preparations and platelet aggregation in experimental laboratory animals.

Abstract：

:Gamma-vinyl GABA (vigabatrin; VGB), an irreversible inhibitor of GABA-transaminase, was evaluated for its effect on the contractile responses to PGE(2) or its precursor arachidonic acid (AA) in guinea pig ileum (GPI) and non-pregnant rat uterus. Rationale behind this study was the rise in gamma-aminobutyric acid (GABA) contents in the peripheral organs after treatment with GABAergic agents and extensive interconnections of neuromediators and their interactions.Indomethacin, the standard NSAID, at 6.1x10(-5) and 12.2x10(-5)M concentrations highly significantly (P<0.001) inhibited contractile responses induced by AA (4.3x10(-5)M) in the isolated GPI. Incubation of the GPI segments with VGB at different concentrations (25, 100 and 200mM) failed to inhibit AA-induced contractile responses in the same preparation. In fact, VGB at 25mM significantly (P<0.05) potentiated the contractile effect of AA 4.3x10(-5)M. Incubation of the same tissue with GABA at 13x10(-3) and 26x10(-3)M inhibited responses elicited by AA at 4.3x10(-5)M that was significant (P<0.05) only with low concentration of GABA. Conversely, a higher concentration (64x10(-3)M) of GABA was needed to antagonise PGE(2) (9.4x10(-6)M)-induced contractions in the same tissue. Almost similar results (i.e. inhibition of contractile responses to AA and PGE(2)) were obtained with isolated non-pregnant rat uterus. These findings suggested that GABA had the potential to inhibit prostaglandin (PG) synthesis and/or antagonise PGE(2) responses in isolated GPI and rat uterus. The addition of 35 or 70 micro l of rat aorta incubation medium caused a dose-dependent inhibition of ADP-induced aggregation being 21.5 and 43.5%, respectively, an indication of prostacycline (PGI(2)) contents. Pre-incubation of rat aortic tissues with VGB (96.8mM) significantly (P<0.05) reversed the anti-aggregatory activity of control aortic prostacycline on ADP-induced aggregation. These findings suggested that VGB might inhibit PGI(2) activity through the inhibition of its synthesis.

journal_name

Pharmacol Res

journal_title

Pharmacological research

authors

Raza M,Al-Shabanah OA

doi

10.1016/s1043-6618(03)00045-8

keywords:

subject

Has Abstract

pub_date

2003-06-01 00:00:00

pages

477-83

issue

eissn

1043-6618

issn

1096-1186

pii

S1043661803000458

journal_volume

pub_type

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Effect of vigabatrin on contractile response to arachidonic acid and prostaglandins in smooth muscle preparations and platelet aggregation in experimental laboratory animals.