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Nitrones, 4-[2-(ethoxycarbonyl)ethyl]-3,3,5,5-tetramethyl-1-pyrroline N-oxide (7a) and 4-[2-(ethoxycarbonyl)ethyl]-5,5-di[( 2 H 3 ]methyl)-3,3-dimethyl-1-pyrrolidine N-oxide (7b) have been synthetized. The ability of the nitrone (7a) to spin trap hydroxyl and superoxide radicals has been compared with nitrones 11a and 5,5-dimethyl-1-pyrroline N-oxide (DMPO, 8)

The effects of aging on the inhibition of forskolin-stimulated cyclic AMP formation by muscarinic receptors were investigated. There were no detectable changes in the magnitude of maximal inhibition by carbamylcholine or the potency of the agonist in inducing this response in either the striatum or hippocampus obtained from young or old Fisher 344 rats.

This study evaluates the role of N-hydroxylamine (NH2OH) in activating soluble guanylate cyclase in the mouse neuroblastoma clone N1E-115. It has been proposed that NH2OH is a putative intermediate in the biochemical pathway for the generation of nitric oxide (NO)/endothelium-derived relaxing factor (EDRF) from L-arginine. NH2OH caused a time- and concentration-dependent increase in cyclic GMP formation in intact cells. This response was not dependent on Ca2+. In cytosol preparations the activation of guanylate cyclase by L-arginine was dose-dependent and required Ca2+ and NADPH. In contrast, NH2OH itself did not activate cytosolic guanylate cyclase but it inhibited the basal activity of this enzyme in a concentration-dependent manner. The formation of cyclic GMP in the cytosolic fractions in response to NH2OH required the addition of catalase and H2O2. On the other hand, catalase and/or H2O2 lead to a decrease in L-arginine-induced cyclic GMP formation. Furthermore, NH2OH inhibited L-arginine- and sodium nitroprusside-induced cyclic GMP formation in the cytosol. The inhibition of L-arginine-induced cyclic GMP formation in the cytosol by NH2OH was not reversed by the addition of superoxide dismutase. These data strongly suggest that NH2OH is not a putative intermediate in the metabolism of L-arginine to an activator of guanylate cyclase.

We investigated whether this pathway is involved in the effects of agents such as the Ca 2+ ionophors which increase cyclic GMP synthesis bypassing neurotransmitter receptors in N1E-115 cells

Agonist-induced reduction in both the number of ml muscarinic receptors and the mRNA coding for the receptor protein was investigated in Chinese hamster ovary (CHO) cells which were transfected with the ml muscarinic receptor gene. Receptor concentration was measured by the specific binding of the muscarinic ligand, [3H]quinuclidinyl benzilate ([3H]QNB), and Northern blot hybridization analysis was used to evaluate the levels of receptor mRNA. Incubation of cells with 1 mM of the muscarinic agonist, carbamylcholine (CBC), for 24 h decreased receptor density and mRNA levels in cells by 65% and 73%, respectively. These results indicate that agonist-induced down-regulation of ml muscarinic receptors might be due to, at least in part, a decrease in receptor synthesis resulting from a reduction in the steady-state level of their mRNA.