Abstract

The acute effects of ethanol were studied on the guanylate cyclase system of cultured murine neuroblastoma clone N1E-115. Using intact cells, we found that although ethanol had no effect on basal levels of cyclic GMP synthesis, it rapidly inhibited in a concentration-dependent manner cyclic GMP synthesis mediated by the agonists histamine (histamine H1 receptor) and carbachol (low-affinity muscarinic receptor) and by ionophore X537A and melittin, agents which bypass these receptors. At 200 mM ethanol, inhibition was about 40 to 50% with the agonists, X537A and melittin. Ethanol had no effect on the high-affinity muscarinic receptor, that mediates inhibition of cyclic AMP synthesis. With carbachol ethanol's inhibition was reversible and was a mixed competitive/noncompetitive type. For a series of alcohols, inhibitory potency with carbachol correlated with chain length directly. In addition, sucrose and sodium chloride, which like ethanol increases the osmolality of the incubation medium, mimicked the effects of ethanol. In a crude cellular homogenate, ethanol and other alcohols inhibited both basal and sodium nitroprusside-stimulated guanylate cyclase activity. The effect of ethanol on basal enzyme activity was noncompetitive. Thus, the inhibition by ethanol and other alcohols of receptor-mediated cyclic GMP synthesis appears to be at the level of guanylate cyclase.