Effects of urapidil on neurotransmitter release in CNS tissue in vitro.

The effects of the antihypertensive drug urapidil on the electrically evoked release of [3H]-noradrenaline (NA) in rabbit cortex slices, of [3H]-acetylcholine (ACh) and [3H]-5-hydroxytryptamine (5-HT) in rabbit hippocampus slices, and of [3H]-ACh and [3H]-dopamine (DA) in rabbit caudate nucleus slices were investigated. Urapidil significantly increased basal tritium outflow in slices preincubated with [3H]-NA and showed weak alpha 2-adrenoceptor antagonism on the evoked NA-release. The pA2-value of urapidil against the inhibitory effect of the alpha 2-agonist clonidine was about 6.3. In contrast to phentolamine, urapidil exhibited no partial agonistic properties at alpha 2-adrenoceptors in this model when stimulation was performed at low frequency and in the absence of cocaine. Neither the evoked ACh- nor 5-HT-release in hippocampal slices were affected by urapidil in concentrations up to 10 microM, but basal tritium outflow was significantly enhanced from slices preincubated with [3H]-5-HT. In caudate nucleus slices urapidil (greater than 1 microM) significantly facilitated both the evoked ACh- and DA-release, effects which were enhanced by the DA-reuptake inhibitor nomifensine. The effects of the D2-dopamine receptor selective agonist LY 171555 and the D2-receptor antagonist domperidone on the evoked DA-release were reduced by 1 microM urapidil. In addition, urapidil (10 microM) increased basal tritium outflow from slices preincubated with [3H]-DA. It is concluded that the antihypertensive effect of urapidil is not mediated by presynaptic actions affecting NA- or 5-HT-release within the CNS. Whether an increased dopaminergic or cholinergic transmission following the observed enhancement of DA- or ACh-release (due to a weak D2-receptor antagonism) is involved, remains to be further elucidated.