MIVAZEROL, A NOVEL ALPHA(2)-AGONIST AND POTENTIAL ANTIISCHEMIC DRUG, INHIBITS KCL-STIMULATED NEUROTRANSMITTER RELEASE IN RAT NERVOUS-TISSUEPREPARATIONS

In this study, we have investigated the effect of mivazerol, [3-(1H-im idazol-4-yl)methyl-1]-2-hydroxybenzamide hydrochloride, a new alpha(2) -agonist lacking hypotensive properties and a potential anti-ischemic drug, on the evoked release of norepinephrine, aspartate, and glutamat e in tissue preparations from hippocampus, spinal cord T1 - T5 section , rostrolateral ventricular medulla, and nucleus tractus solitarii of the brainstem of rat. A simple and efficient in vitro procedure to stu dy pharmacologically the release of norepinephrine and glutamate is de scribed. Tissues were chopped into (0.3 x 0.2 x 0.2 mm(3)) sections an d the resulting minces were used for this study. Exposure to KCI (10-7 5 mM) for 5 min served as a stimulus for the release response. One, S (for aspartate and for glutamate release), or two such stimuli, S-1 an d S-2 (for norepinephrine release) were conducted, The release of nore pinephrine (+ 150% above baseline) was inhibited in a dose-dependent m anner by mivazerol in hippocampus (IC50 = 1.5 x 10(-8) M), spinal cord (IC50 = 5 x 10(-8) M), rostrolateral ventricular medulla (IC50 = 10(- 7) M), and nucleus tractus solitarii (IC50 = 7.5 x 10(-8) M), and by c lonidine in hippocampus (IC50 = 5 x 10(-8) M), spinal cord (IC50 = 4.5 x 10(-8) M), rostrolateral ventricular medulla (IC50 = 2.5 x 10(-7) M ), and nucleus tractus solitarii (IC50 = 10(-7) M). This effect was co unteracted by the selective alpha(2)-antagonists yohimbine and rauwols cine. A significant glutamate and aspartate release response was also induced by KCI (35 mmol/L) in hippocampus (+250 and +135%, respectivel y) and spinal cord (+120 and +55%, respectively), in vitro. However, n either mivazerol nor clonidine, at doses up to 10 mu M, had any signif icant effect on KCI-induced glutamate release in spinal cord, whereas mivazerol blocked completely the release of both amino acids in hippoc ampus and only the release of aspartate in spinal cord. On the other h and, clonidine (1 mu M) was only effective in reducing by 40% the rele ase of aspartate in hippocampus. These data indicate that (1) inhibiti on of KCI-induced norepinephrine release by mivazerol is mediated by i ts action on alpha(2)-adrenergic receptors; (2) at concentrations sele ctive for alpha(2)-adrenergic receptors, only mivazerol was effective in blocking the KCI-induced glutamate release in hippocampal tissue; a nd (3) at the same concentrations, both mivazerol and clonidine were u nable to inhibit glutamate release in the spinal cord, These data sugg est that prevention of hyperadrenergic activity by mivazerol in periop erative patients may be mediated through its effect on the release of norepinephrine and/or the release of glutamate and aspartate in region s of the CNS that are involved in the control of cardiovascular homeos tasis.