Effect of vigabatrin on contractile response to arachidonic acid and prostaglandins in smooth muscle preparations and platelet aggregation in experimental laboratory animals.
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.
Department of Pharmacology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia. mrsheikh@ksu.edu.sa
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D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D016718:Arachidonic Acid / Q000378:metabolism / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology / Q000502:physiology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009215:Myometrium / Q000187:drug effects* / Q000502:physiology; D010974:Platelet Aggregation / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D020888:Vigabatrin / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D016718:Arachidonic Acid; D005680:gamma-Aminobutyric Acid; D000612:4-Aminobutyrate Transaminase; D020888:Vigabatrin; D015232:Dinoprostone; D007213:Indomethacin