ABSTRACT
This study investigated the identity of presynaptic receptors involved in dopaminergic modulation of purinergic transmission in peripheral tissues including isolated rat vas deferens and urinary bladder. Isometric muscle twitches were established in the two tissues by low frequency electric field-stimulation (0.05 Hz, 1-ms duration, and supramaximal voltage). Exposure to prazosin, 50 nmol l-1 (vas deferens), or atropine, 3 micromol l-1 (urinary bladder), had no effect on the developed twitches. In contrast, desensitisation of P2X-purinoceptors by alpha,beta-methylene ATP (alpha,beta-mATP, 30 micromol l-1) abolished the twitches in both tissues, confirming their purinergic origin. Dopamine (1.8x10(-7) to 4.2x10(-5) mol l-1) reduced the twitch response in a concentration-related manner. Yohimbine (alpha2-adrenoceptor antagonist, 0.3 micromol l-1) significantly (P<0.05) attenuated the inhibitory effects of dopamine and caused an upward shift in the concentration-response curves in the vas deferens and the urinary bladder. On the other hand, a blockade of DA2-dopaminoceptors by domperidone (1 micromol l-1) produced significant (P<0.05) reductions in dopamine responses only in rat vas deferens, with no effect in the urinary bladder. These data suggest that dopamine exerts inhibitory influences on purinergically-mediated muscle twitches in rat vas deferens and urinary bladder. More importantly, the nature of presynaptic receptors (alpha2-adrenergic and/or DA2-dopaminergic) involved in mediating dopamine effects is dependent on the tissue under investigation.
Subject(s)
Dopamine/pharmacology , Isometric Contraction/drug effects , Neurotransmitter Agents/physiology , Organ Specificity , Receptors, Presynaptic/physiology , Receptors, Purinergic/physiology , Animals , Dose-Response Relationship, Drug , Drug Interactions , Electric Stimulation , In Vitro Techniques , Male , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Rats , Rats, Wistar , Receptors, Adrenergic, alpha/drug effects , Receptors, Dopamine/drug effects , Urinary Bladder/drug effects , Vas Deferens/drug effectsABSTRACT
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.
