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

Abstract

γ-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 γ-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 6.1×10 −5 and 12.2×10 −5 M concentrations highly significantly ( P<0.001) inhibited contractile responses induced by AA (4.3×10 −5 M) in the isolated GPI. Incubation of the GPI segments with VGB at different concentrations (25, 100 and 200 mM) failed to inhibit AA-induced contractile responses in the same preparation. In fact, VGB at 25 mM significantly ( P<0.05) potentiated the contractile effect of AA 4.3×10 −5 M. Incubation of the same tissue with GABA at 13×10 −3 and 26×10 −3 M inhibited responses elicited by AA at 4.3×10 −5 M that was significant ( P<0.05) only with low concentration of GABA. Conversely, a higher concentration (64×10 −3 M) of GABA was needed to antagonise PGE 2 (9.4×10 −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 μl 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 (96.8 mM) 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.