Rilmenidine acts as a partial agonist at prejunctional α₂-adrenoceptors in guinea-pig atria

1. The present study was carried out to determine whether rilmenidine, a recently introduced antihypertensive agent which acts on α₂‐adrenoceptors, has partial agonist activity on prejunctional α₂‐adrenoceptors in guinea‐pig atria. 2. Isolated preparations of guinea‐pig atria were incubated with [³H]‐noradrenaline and the efflux of radioactivity induced by stimulation of intramural sympathetic nerves was used as an index of release of transmitter noradrenaline. 3. Rilmenidine (1 μmol/1) inhibited noradrenaline release evoked by short trains (five, 20 and 50 pulses) of sympathetic nerve stimulation and this inhibitory effect of rilmenidine was antagonized by the α₂‐adrenoceptor antagonists, idazoxan (0.1 and 0.3 umol/1) and rauwolscine (0.3 umol/1) whereas it was not affected by the α₁‐adrenoceptor antagonist prazosin (0.1 μmol/1). 4. On the other hand, rilmenidine (1 μmol/1) enhanced noradrenaline release evoked by long trains (150 and 300 pulses) of stimulation and this effect was also abolished by idazoxan (0.1 μmol/1). 5. These findings suggest that the effects of rilmenidine on transmitter release depend on the degree of auto‐inhibition: when the concentration of noradrenaline in the biophase of the prejunctional α₂‐adrenoceptors is low, rilmenidine acts as an agonist, but when the concentration is high it acts as an antagonist. Thus, rilmenidine, like clonidine, is a partial agonist on prejunctional α₂‐adrenoceptors in guinea‐pig atria.