The cholinergic system is critically involved in the modulation of cognitive functions, including learning and memory. Acetylcholine acts through muscarinic (mAChRs) and nicotinic receptors (nAChRs), which are both abundantly expressed in the hippocampus. Previous evidence indicates that choline, the precursor and degradation product of Acetylcholine, can itself activate nAChRs and thereby affects intrinsic and synaptic neuronal functions. Here, we asked whether the cellular actions of choline directly affect hippocampal network activity. Using mouse hippocampal slices we found that choline efficiently suppresses spontaneously occurring sharp wave-ripple complexes (SPW-R) and can induce gamma oscillations. In addition, choline reduces synaptic transmission between hippocampal subfields CA3 and CA1. Surprisingly, these effects are mediated by activation of both mAChRs and a7-containing nAChRs. Most nicotinic effects became only apparent after local, fast application of choline, indicating rapid desensitization kinetics of nAChRs. Effects were still present following block of choline uptake and are, therefore, likely because of direct actions of choline at the respective receptors. Together, choline turns out to be a potent regulator of patterned network activity within the hippocampus. These actions may be of importance for understanding state transitions in normal and pathologically altered neuronal networks.
Acute pulmonary arterial hypertension in acute lung injury aggravates the clinical course and complicates treatment. Increased release and turnover of endogenous endothelin-1 is known to be a major determinant in the pathophysiology of pulmonary arterial hypertension of various etiologies. We tested whether intravenous tezosentan, a dual endothelin receptor antagonist, reduced pulmonary artery pressure in a pig model of acute lung injury induced by meconium aspiration. Acute pulmonary arterial hypertension was induced in 12 anesthetized and instrumented pigs by instillation of human pooled meconium in a 20% solution. Hemodynamic and gas exchange parameters were recorded every 30 min. Six animals received tezosentan 5 mg/kg after 0 and 90 min; six animals served as controls. Tezosentan led to a decrease of mean pulmonary artery pressure ( A cute pulmonary arterial hypertension accompanies acute lung injury (ALI) and acute respiratory distress syndrome. Aspiration of meconium induces acute parenchymal lung disease with diffuse inflammation of the alveolarcapillary membrane. Obliteration of the pulmonary capillary bed and subsequent pulmonary vasoconstriction induces pulmonary arterial hypertension, which may be severe and may lead to right ventricular failure and subsequent multiorgan failure (1-4). Effective pharmacological therapy is limited. Endothelial dysfunction of the small pulmonary arteries is known to play a key role in the pathophysiology of pulmonary arterial hypertension of various etiologies (5-8). Impaired production of vasodilative mediators, such as nitric oxide and prostacyclin, along with increased production of vasoconstrictive endothelin-1 (ET-1) are regarded as key factors in the pathophysiology of pulmonary hypertensive disorders (9). ET-1 is a polypeptide, which is released by vascular endothelial cells in response to hypoxic and acute or chronic toxic lung injury (10,11). Induction of transcription of ET-1 mRNA and synthesis and secretion of ET-1 takes place within minutes after promoting stimuli by, for example, hypoxia, cytokines, adhesion molecules, and catecholamines (12). ET-1 exerts a direct and sustained vasoconstrictive effect via ET A receptors, expressed on vascular smooth muscle cells. Activation of ET B receptors, expressed on vascular endothelial cells, mediates pulmonary endothelin clearance and induces production of nitric oxide and prostacyclin, which both exert vasodilative effects. In addition, ET-1 stimulates proliferation of vascular smooth muscle cells and acts as a proinflammatory mediator (13). Indeed, up-regulation of ET-1 gene expression and increased levels of circulating ET-1 have been demonstrated in animal models of meconium aspiration (14,15) and in hypoxia-induced pulmonary arterial hypertension (16). Therefore, blocking the effects of ET-1 should attenuate the concomitant rise of pulmonary artery pressure in acute lung injury and thus diminish stress imposed on the right heart. The orally active combined ET A and ET B receptor antagonist bosentan h...
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