Prototypical imidazoline-1 receptor ligand moxonidine activates alpha2-adrenoceptors in bulbospinal neurons of the RVL

Moxonidine is an antihypertensive drug that lowers sympathetic vasomotor to ne by stimulating either alpha2-adrenergic (alpha 2-AR) or imidazoline Il r eceptors within the rostral ventrolateral medulla (RVL). In this study, we investigated the effects of moxonidine (10 mu M) on RVL neurons in brain st em slices of neonatal rats. We recorded mainly from retrogradely labeled RV L bulbospinal neurons (putative presympathetic neurons) except for some ext racellular recordings. Prazosin was used to block alphal-adrenoceptors, Mox onidine inhibited the extracellularly recorded discharges of all spontaneou sly active RVL neurons tested (bulbospinal and unidentified). This effect w as reversed or blocked by the selective alpha 2-AR antagonist SKF 86466 (10 mu M). In contrast, the Il imidazoline ligand AGN 192403 (10 mu M) had no effect on the spontaneous activity. In whole cell recordings (holding poten tial -70 mV), moxonidine produced a small and variable outward current (mea n 7 pA). This current was observed in both tyrosine hydroxylase-immunoreact ive and other bulbospinal neurons and was blocked by SKF 86466. Excitatory postsynaptic currents (EPSCs) evoked by focal electrical stimulation were i solated by incubation with gabazine and strychnine, and inhibitory postsyna ptic currents (IPSCs) were isolated with 6-cyano-7-nitroquinoxaline-2,3-dio ne (CNQX). Moxonidine reduced the amplitude of the evoked EPSCs (EC50 = 1 m u M; 53% inhibition at 10 mu M) bur not their decay time constant (5.6 ms). The effect of moxonidine on EPSCs persisted in barium (300 mu M) and was r educed similar to 80% by SKF 86466. Moxonidine also reduced the amplitude o f evoked IPSCs by 63%. In conclusion, moxonidine inhibits putative RVL pres ympathetic neurons both presynaptically and postsynaptically. All observed effects in the present study are consistent with an alpha 2-AR agonist acti vity of moxonidine.