Prototypical Imidazoline-1 Receptor Ligand Moxonidine Activates Alpha2-Adrenoceptors in Bulbospinal Neurons of the RVL

Abstract

Hayar, Abdallah and Patrice G. Guyenet. Prototypical imidazoline-1 receptor ligand moxonidine activates alpha2-adrenoceptors in bulbospinal neurons of the RVL. J. Neurophysiol. 83: 766 -776, 2000. Moxonidine is an antihypertensive drug that lowers sympathetic vasomotor tone by stimulating either alpha2-adrenergic (␣2-AR) or imidazoline I1 receptors within the rostral ventrolateral medulla (RVL). In this study, we investigated the effects of moxonidine (10 M) on RVL neurons in brain stem slices of neonatal rats. We recorded mainly from retrogradely labeled RVL bulbospinal neurons (putative presympathetic neurons) except for some extracellular recordings. Prazosin was used to block alpha1-adrenoceptors. Moxonidine inhibited the extracellularly recorded discharges of all spontaneously active RVL neurons tested (bulbospinal and unidentified). This effect was reversed or blocked by the selective ␣2-AR antagonist SKF 86466 (10 M). In contrast, the I1 imidazoline ligand AGN 192403 (10 M) had no effect on the spontaneous activity. In whole cell recordings (holding potential Ϫ70 mV), moxonidine produced a small and variable outward current (mean 7 pA). This current was observed in both tyrosine hydroxylase-immunoreactive and other bulbospinal neurons and was blocked by SKF 86466. Excitatory postsynaptic currents (EPSCs) evoked by focal electrical stimulation were isolated by incubation with gabazine and strychnine, and inhibitory postsynaptic currents (IPSCs) were isolated with 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Moxonidine reduced the amplitude of the evoked EPSCs (EC 50 ϭ 1 M; 53% inhibition at 10 M) but not their decay time constant (5.6 ms). The effect of moxonidine on EPSCs persisted in barium (300 M) and was reduced ϳ80% by SKF 86466. Moxonidine also reduced the amplitude of evoked IPSCs by 63%. In conclusion, moxonidine inhibits putative RVL presympathetic neurons both presynaptically and postsynaptically. All observed effects in the present study are consistent with an ␣2-AR agonist activity of moxonidine. I N T R O D U C T I O NCentrally acting antihypertensive drugs with an imidazoline structure, like clonidine and moxonidine, are effective in treating moderate to severe forms of hypertension (Armah et al. 1988;Prichard et al. 1997;Schafer et al. 1995;Ziegler et al. 1996). There is general agreement that a major site of action of these drugs is within the rostral ventrolateral medulla (RVL) (Punnen et al. 1987; reviewed by Reis 1996), but their specific neuronal targets are unknown. The RVL is critical for sympathetic tone generation and blood pressure control because it contains bulbospinal neurons (presympathetic neurons) that contribute the major excitatory drive to sympathetic vasoconstrictor and cardiac preganglionic neurons (McAllen et al. 1997;Sun 1995). The presympathetic neurons include a catecholaminergic cell group (C1 cells) that express the A subtype of ␣2-ARs (Guyenet et al. 1994). Activation of ␣2-ARs by norepinephrine (NE) in RVL bulbospinal neurons in vitro (C1 cells and others) acti...

Clonidine‐evoked respiratory effects in anaesthetized rats

“…The significant SKF 86466 pretreatment × time interaction effect with the preserved but smaller initial increase in blood pressure in our study suggests that the α 2 ‐antagonist may counteract the clonidine‐evoked hypotension. While this observation is consistent with the study in humans by Hayar & Guyenet (2000), the trend for a hypotensive effect of SKF 86466 ( P = 0.07) in our study does not permit unequivocal acceptance of this interpretation.…”

Effect of Moxonidine on Putative Sympathetic Neurons in the Rostral Ventrolateral Medulla of the Rat

“…These results are in agreement with previous studies performed in brain stem slices of neonatal rats [30]. Nevertheless, in that study the authors used either an extracellular recording technique or a whole cell recording technique to study putative premotor sympathetic neurons which were identified mainly as retrogradely labeled RVLM bulbospinal neurons [30]. In our present study putative premotor sympathetic neurons were identified by their electrophysiological characteristics, as described in previous publications [13,25].…”

“…However, this hypothesis is not supported by the experiments reported by Hayar and Guyenet [30] showing that: (1) moxonidine, at concentrations similar to those used in the present study, produced a consistent inhibitory effect on different types of RVLM neurons recorded in an in vitro slice preparation, and this effect is due in part to postsynaptic hyperpolarization; (2) the inhibitory effects of moxonidine were substantially blocked by the selective antagonist of · 2 -adrenergic receptors SKF 86466, while on the other hand, the imidazoline type-1 antagonist AGN 192403 was ineffective in changing neuronal activity, and (3) the inhibitory effects of moxonidine characterized at pre-and postsynaptic levels are similar to those generated by norepinephrine and other · 2 -adrenergic agonists on putative presympathetic RVLM neurons. Similar results were reported by Szabo et al [31] in experiments performed on the rat locus coeruleus neurons in vitro.…”

Presynaptic I1-Imidazoline Receptors Reduce GABAergic Synaptic Transmission in Striatal Medium Spiny Neurons

“…Nevertheless, its weak affinity for ␣2-adrenergic receptors (Ferry et al, 1988;Ernsberger et al, 1993) may have accounted for the observed inhibition of IPSCs. Hayar and Guyenet (2000) revealed that inhibition of both EPSCs and IPSCs by moxonidine in bulbospinal neurons of the rostral ventrolateral medulla is mediated via ␣2-adrenergic receptors. Indeed, in the present study, application of noradrenaline under blockade of both ␣1-and ␤-adrenergic receptors with prazosin and propranolol, respectively, resulted in ␣2-adrenergic receptor-mediated inhibition of IPSCs, as was demonstrated by the apparent lack of inhibition by noradrenaline when combined with either yohimbine or SKF86466, which are non-imidazoline antagonists selective for ␣2-adrenergic receptors.…”