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Mivazerol, a Novel α 2 ‐Agonist and Potential Anti‐Ischemic Drug, Inhibits KCl‐Stimulated Neurotransmitter Release in Rat Nervous Tissue Preparations
Author(s) -
El Tamer Ahmed,
Prokopenko Igor,
Wülfert Ernst,
Hanin Israel
Publication year - 1996
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1996.67020636.x
Subject(s) - spinal cord , glutamate receptor , neurotransmitter , yohimbine , endocrinology , norepinephrine , medicine , chemistry , nucleus , medulla , anesthesia , pharmacology , central nervous system , biology , neuroscience , antagonist , dopamine , receptor
In this study, we have investigated the effect of mivazerol, [3‐(1 H ‐imidazol‐4‐yl)methyl‐1]‐2‐hydroxy‐benzamide hydrochloride, a new α 2 ‐agonist lacking hypotensive properties and a potential anti‐ischemic drug, on the evoked release of norepinephrine, aspartate, and glutamate 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 study pharmacologically the release of norepinephrine and glutamate is described. Tissues were chopped into (0.3 × 0.2 × 0.2 mm 3 ) sections and the resulting minces were used for this study. Exposure to KCl (10–75 m M ) 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 and S 2 (for norepinephrine release) were conducted. The release of norepinephrine (+150% above baseline) was inhibited in a dose‐dependent manner by mivazerol in hippocampus (IC 50 = 1.5 × 10 −8 M ), spinal cord (IC 50 = 5 × 10 −8 M ), rostrolateral ventricular medulla (IC 50 = 10 −7 M ), and nucleus tractus solitarii (IC 50 = 7.5 × 10 −8 M ), and by clonidine in hippocampus (IC 50 = 5 × 10 −8 M ), spinal cord (IC 50 = 4.5 × 10 −8 M ), rostrolateral ventricular medulla (IC 50 = 2.5 × 10 −7 M ), and nucleus tractus solitarii (IC 50 = 10 −7 M ). This effect was counteracted by the selective α 2 ‐antagonists yohimbine and rauwolscine. A significant glutamate and aspartate release response was also induced by KCl (35 mmol/L) in hippocampus (+250 and +135%, respectively) and spinal cord (+120 and +55%, respectively), in vitro. However, neither mivazerol nor clonidine, at doses up to 10 µ M , had any significant effect on KCl‐induced glutamate release in spinal cord, whereas mivazerol blocked completely the release of both amino acids in hippocampus and only the release of aspartate in spinal cord. On the other hand, clonidine (1 µ M ) was only effective in reducing by 40% the release of aspartate in hippocampus. These data indicate that (1) inhibition of KCl‐induced norepinephrine release by mivazerol is mediated by its action on α 2 ‐adrenergic receptors; (2) at concentrations selective for α 2 ‐adrenergic receptors, only mivazerol was effective in blocking the KCl‐induced glutamate release in hippocampal tissue; and (3) at the same concentrations, both mivazerol and clonidine were unable to inhibit glutamate release in the spinal cord. These data suggest that prevention of hyperadrenergic activity by mivazerol in perioperative patients may be mediated through its effect on the release of norepinephrine and/or the release of glutamate and aspartate in regions of the CNS that are involved in the control of cardiovascular homeostasis.