科研之友
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摘要
The Lund project (1992) recommended treatment with clonidine (alpha(2)-adrenergic agonist) and metoprolol (beta(1)-adrenergic antagonist) to improve recovery after brain trauma, and discouraged use of the V-1 agonist vasopressin (ADH). Brain effects of these drugs and the ability of a post-traumatic elevation of extracellular K+ concentrations ([K+](o)) to activate mechanism(s) leading to secondary cytotoxic (cellular) edema were then virtually unknown. Now, it is established that interactions occur between effects on astrocytes by high [K+](o) and vasopressin or alpha(2)- and beta(1)-adrenergic agonists and antagonists, and that the effects modify edema and thus intracranial pressure. In mouse astrocytes in primary cultures, reliably expressing characteristics of their in vivo counterparts, high [K+](o) and each of the transmitters agonists activate a signal mechanism, transactivation, in which Ca2+ entry through depolarization-mediated channel opening or stimulation of G(q)- or G(i/o) protein-coupled receptors via PKC-, Ca2+- and metalloproteinase-mediated signaling leads to release of an epidermal growth factor (EGF) receptor agonist. Minor, but important, differences exist between individual pathways. The agonist released by dexmedetomidine decreases neuronal vulnerability to oxidative damage by a paracrine effect, and in all cases the released EGF receptor agonist has autocrine effects. These include mitogen-activated protein (MAP) kinase-mediated phosphorylation of astrocytic extracellular-regulated kinase (ERK), and with high [K+](o) also the cotransporter NKCC1, accumulating Na+ and K+ together with 2 Cl- and water, causing edema. This effect, exerted specifically on astrocytes, is enhanced by beta(1)-adrenergic or vasopressinergic V-1 signaling, explaining the beneficial effect of beta(1)-adrenergic antagonists and why vasopressin should be omitted in edema treatment after brain trauma.
- 出版日期2012-1
- 单位中国医科大学
