PRESYNAPTIC MODULATION BY L-GLUTAMATE AND GABA OF SYMPATHETIC COTRANSMISSION IN RAT ISOLATED VAS-DEFERENS

1 The modulatory effects of L-glutamate and its structural analogues, and of gamma-aminobutyric acid (GABA), on sympathetic co-transmission were studied in the rat isolated vas deferens exposed to electrical fi eld stimulation (EFS). 2 Application of exogenous L-glutamate caused a concentration-dependent (1 mu M-3 mM) inhibition of the rapid twitch component of the biphasic EFS contraction. However, L-glutamate (1 mu M-3 mM) had a minimal effect on the phasic contraction induced by exog enous adenosine 5'-triphosphate (ATP, 150 mu M) and noradrenaline (50 mu M) Unlike L-glutamate, D-glutamate had no effect on the EFS contrac tion. 3 The L-glutamate-induced inhibition of the EFS contractions was significantly attenuated by the glutamate decarboxylase (GAD) inhibit or 3-mercapto-propionic acid (150 mu M) and was abolished in the prese nce of the GABA transaminase (GABA-T) inhibitor, 2-aminoethyl hydrogen sulphate (500 mu M). 4 The L-glutamate-induced inhibition of the elec trically evoked contraction was not affected by the adenosine A(1)-rec eptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX)(30 nM), r eactive blue 2 (30 mu M) or the GABA(A) receptor antagonist bicucullin e (50 mu M). However, the GABA(B) receptor antagonist 2-hydroxysaclofe n (50 mu M) significantly inhibited the L-glutamate effect. 5 Similar to L-glutamate, GABA also caused a concentration-dependent (0.1 - 100 mu M) inhibition of the EFS contractions. This GABA-induced inhibition was not affected by either the GABA(A) receptor antagonist bicucullin e (50 mu M) or reactive blue 2 (30 mu M). However, a significant atten uation of the GABA-mediated effect was recorded with the GABA(B) recep tor antagonist 2-hydroxysaclofen (50 mu M). Contractions of the vas de ferens induced by exogenous ATP and noradrenaline were not affected by GABA (0.1-100 mu M). 6 The L-glutamate analogues, N-methyl-D-aspartat e (NMDA) (1 mu M-1 mM) and quisqualate (Quis 0.1 mu M-0.3 mM) had no e ffect, whilst kainate (Kain, 1 mu M-1 mM) caused an inhibition of the EFS-induced contractions. Effects of Kain could be abolished by the no n-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dioxine (CNQ X, 10 mu M). NMDA, Quis and Kain had no effect on the exogenous ATP- o r noradrenaline-induced contractions. 7 It is concluded that the excit atory amino acid L-glutamate modulates the electrically evoked vas def erens contraction through conversion to the inhibitory amino acid GABA by a specific GABA transaminase. The GABA formed may then act on GABA (B) receptors and cause inhibition of the contraction through a presyn aptic mechanism.