The ability of asymmetric dimethylarginine (ADMA) or monomethylarginine (L-NMMA) to block endothelium-dependent, nitric oxide-mediated relaxation in rat aorta is inversely related to the efficacy of the relaxant stimulus

Previous work on rat aorta has shown that L-NMMA and ADMA each enhance vasoconstrictor-induced tone, consistent with blockade of basal nitric oxide activity, whereas they exert little inhibitory effect on acetylcholine-induced relaxation when tone is matched carefully to that of control tissues. The aim of this study was to determine if the ability of L-NMMA or ADMA to inhibit nitric oxide-mediated relaxation was critically determined by the efficacy of the relaxant stimulus. The effects of L-NMMA or ADMA were examined on relaxation to a range of agonists producing different maximal responses, namely, acetylcholine, the muscarinic partial agonist, butyrylcholine, and calcitonin gene-related peptide-1 (CGRP-1). The effects of L-NMMA or ADMA were also examined on relaxation to acetylcholine when its apparent efficacy at the M3 muscarinic receptor was reduced using the irreversible receptor blocking agent, phenoxybenzamine. Maximal relaxation induced by butyrylcholine or CGRP-1 was lower than to acetylcholine. While acetylcholine-induced relaxation was largely resistant to blockade by L-NMMA or ADMA (0.1 or 1 mM), relaxation to butyrylcholine or CGRP-1 was powerfully suppressed. Phenoxybenzamine (0.1–10 μM for 30 min) concentration-dependently reduced maximal acetylcholine-induced relaxation. When the efficacy of acetylcholine was reduced by phenoxybenzamine, its residual relaxant effect was powerfully inhibited by L-NMMA or ADMA (0.1 or 1 mM). Thus, in rat aorta, the ability of L-NMMA or ADMA to block agonist-induced nitric oxide activity is critically determined by the efficacy of the relaxant stimulus

Memantine and its role in parkinsonism, seizure, depression, migraine headache, and Alzheimer’s disease

Alzheimer’s disease (AD) is a neurological disorder characterized by mental and behavioral changes that develop progressively with a decline in brain function. Dysfunctions in glutamatergic and cholinergic pathways, along with an increased concentration of beta-amyloid protein (Aβ), lead to synapses that are full of phosphorylated protein. These changes result in several pathological, biochemical, cellular, and molecular alterations that increase neural excitation directly or indirectly at the neural level, affecting the synapse, axons, signal transmission, and all parts of neurons. All these alterations, with continuous excitatory effects, eventually lead to neural loss and degradation due to stimulation of the immune response. However, memantine is a non-competitive antagonist of N-methyl-D-aspartic acid (NMDA) glutamatergic receptors of moderate affinity and voltage-dependent that blocks the effects of pathologically elevated glutamate tonic levels, which can lead to neuronal dysfunction. Memantine has shown improvement in cognition, global clinical status, activities of daily living, and behavioral disturbances in moderate and severe AD. In this review, we will discuss the effects of memantine use and side effects, as well as its application in treating other diseases or pathological conditions with the prospective use of memantine or an alternative. Memantine is generally well-tolerated, and the most common adverse reactions are vertigo, headache, and hallucinations, which are usually mild