Presynaptic modulation by L‐glutamate and GABA of sympathetic co‐transmission in rat isolated vas deferens

Abstract

1 The modulatory effects of L-glutamate and its structural analogues, and of y-aminobutyric acid (GABA), on sympathetic co-transmission were studied in the rat isolated vas deferens exposed to electrical field stimulation (EFS). 2 Application of exogenous L-glutamate caused a concentration-dependent (1 /M -3 mM) inhibition of the rapid twitch component of the biphasic EFS contraction. However, L-glutamate (1 MM-3 mM) had a minimal effect on the phasic contraction induced by exogenous adenosine 5'-triphosphate (ATP, 150 MM) and noradrenaline (50 Mm). Unlike L-glutamate, D-glutamate had no effect on the EFS contraction. 3 The L-glutamate-induced inhibition of the EFS contractions was significantly attenuated by the glutamate decarboxylase (GAD) inhibitor 3-mercapto-propionic acid (150 Mm) and was abolished in the presence of the GABA transaminase (GABA-T) inhibitor, 2-aminoethyl hydrogen sulphate (500 gM).4 The L-glutamate-induced inhibition of the electrically evoked contraction was not affected by the adenosine Al-receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX)(30 nM), reactive blue 2 (30 Mm) or the GABAA receptor antagonist bicuculline (50 gM). However, the GABAB receptor antagonist 2-hydroxysaclofen (50 uM) significantly inhibited the L-glutamate effect. 5 Similar to L-glutamate, GABA also caused a concentration-dependent (0.1 -100 Mm) inhibition of the EFS contractions. This GABA-induced inhibition was not affected by either the GABAA receptor antagonist bicuculline (50 gM) or reactive blue 2 (30 gM). However, a significant attenuation of the GABA-mediated effect was recorded with the GABAB receptor antagonist 2-hydroxysaclofen (50 gM).Contractions of the vas deferens induced by exogenous ATP and noradrenaline were not affected by GABA (0.1-100 gM).6 The L-glutamate analogues, N-methyl-D-aspartate (NMDA) (1 MM-I mM) and quisqualate (Quis 0.1 Mm -0.3 mM) had no effect, whilst kainate (Kain, 1 MM-I mM) caused an inhibition of the EFSinduced contractions. Effects of Kain could be abolished by the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dioxine (CNQX, 10 gM). NMDA, Quis and Kain had no effect on the exogenous ATP-or noradrenaline-induced contractions. 7 It is concluded that the excitatory amino acid L-glutamate modulates the electrically evoked vas deferens contraction through conversion to the inhibitory amino acid GABA by a specific GABA transaminase. The GABA formed may then act on GABAB receptors and cause inhibition of the contraction through a presynaptic mechanism.

Effects of GABA on noradrenaline release and vasoconstriction induced by renal nerve stimulation in isolated perfused rat kidney

“…Our present study could thus provide further evidence for the modulation by GABA of renal functions, although we did not measure changes in urine formation. Kwan et al (1996) have demonstrated that GABA suppresses electrical stimulation-evoked purinergic contraction of the isolated rat vas deferens in the presence of phentolamine. In our present study, prazosin even at the high dose (30 nM) failed to abolish the RNS-induced PP response; about 20 ± 30% of the increases in PP still remained, and addition of rauwolscine failed to suppress this residual PP response.…”

Premature ejaculation: focus on therapeutic targets

“…Rats [151] Inhibitory Rat VD [152] GABA Inhibitory Rats [153] Inhibitory Rat VD [152] Rat ischiocavernosus [154] Serotonin Inhibitory Humans [29] Rats: 5-HT 2C agonists [155] Rats: 5-HT 1B agonists [48] Rats: 5-HT 2B agonists [156] Inhibitory Rat VD and SV [157] Excitatory Rats: 5-HT 1A agonists [48] Excitatory Mouse VD: 5-HT 1A stimulation [158] Angiotensin II Inhibitory Rats [159] Excitatory Rat VD [160] Oxytocin Excitatory Rats [71] Humans [73,161] Excitatory Rat and rabbit: prostatic urethra, bladder neck and ejaculatory duct [76] No effect Rat and rabbit: VD, SV, epididymis, and prostate [76] Nitric oxide Excitatory (MPOA)…”

Role of Potassium Channels in the GABA Inhibitory Action on the Purinergic Response to Electrical Field Stimulation in Rat Isolated Vas Deferens

“…The prostatic half of the rat vas deferens was used because, in this part, the purinergic mechanism responsible for the initial rapid twitch in response to EFS is dominant (Kwan et al 1996). Under our experimental conditions the two phases were not always clearly distinguishable.…”

“…g-Aminobutyric acid (GABA) is quantitatively one of the most important inhibitory transmitters in the CNS. It has been shown that GABA is also present in peripheral tissues such as the bladder (Maggi et al 1985), fallopian tube (Erdo È et al 1982) and rat vas deferens (Kwan et al 1996).…”

“…The response is sustained by adenosine 5 H -triphosphate (ATP) and noradrenaline, respectively, co-released from the sympathetic varicosities (Brown et al 1983). GABA, activating presynaptic GABA B receptors (Bowery 1993), produces an inhibition of the purinergic response to electrical ®eld stimulation (EFS), while the adrenergic component is unaffected (Kwan et al 1996). Depression of transmitter release by activation of GABA B receptors may be caused by an increase in K conductance or by a decrease in Ca 2 conductance.…”