Prazosin-induced Blockade of Extraneuronal Uptake Facilitates Dopaminergic Modulation of Muscle Twitches in Rat Vas Deferens

Abstract

Preliminary findings in our laboratory have shown that prazosin augmented the inhibitory effects of dopamine on the electrically-evoked muscle twitches in rat vas deferens. In this study, we opted to investigate the underlying mechanism and whether a prazosin-induced blockade of extraneuronal uptake process may be involved. Cumulative additions of dopamine (1.8 x 10(-7)-4.4 x 10(-5) M) elicited slight (< 30%) but dose-related inhibition of electrically-evoked (0.05 Hz, 1 ms duration and supramaximal voltage) muscle twitches of the vas deferens. Pretreatment with cocaine (10 microM), prazosin (50 nM) or oestradiol (10 microM) produced comparable potentiation of the inhibitory responses of dopamine; the pD2 values to dopamine amounted to 4.47 +/- 0.20, 4.72 +/- 0.21 and 4.56 +/- 0.19, respectively. A lower concentration of prazosin (5 nM) failed to alter dopaminergic responses. Further potentiation of dopamine responses was demonstrated in tissues preincubated with a combination of cocaine plus prazosin (50 nM), or cocaine plus oestradiol (pD2, 5.40 +/- 0.11 and 5.42 +/- 0.05, respectively). However, a mixture of all three drugs failed to elicit any further increase in dopamine responses, a finding that may suggest an extraneuronal uptake blocking activity for prazosin. Inhibition of muscle twitches evoked by bromocriptine, a dopaminoceptor agonist which is not a substrate for extraneuronal uptake, was not affected by prazosin (50 nM) pretreatment. The findings presented in this study emphasize the role of dopamine in modulating noradrenergic neurotransmission in rat vas deferens. More importantly, the results suggest that prazosin may act to block the extraneuronal uptake at noradrenergic sites, an effect that may account for its capability to facilitate dopaminergic modulation of noradrenergic neurotransmission.