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.
Raza
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Department of Pharmacology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia. mrsheikh@ksu.edu.sa
Al-Shabanah
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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