Prevention and Reversal of Cholera Enterotoxin Effects in Rabbit Jejunum by Nicotinic Acid

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Abstract

The cholera enterotoxin produces intestinal secretion associated with an elevation of tissue levels of cyclic adenosine 3′,5′-monophosphate levels of cyclic adenosine 3′,5′-monosphosphate (cAMP). The objectives of this study were to determine whether intestinal secretion and cAMP elevation induced by cholera toxin could be prevented, or once initiated, reversed by nicotinic acid, an agent known to lower tissue levels of cAMP. In rabbits, four jejunal loops were constructed as alternating control (3-ml isotonic electrolyte solution) and cholera toxin (same solution containing 50 μg purified cholera toxin) loops. Net intestinal secretion was determined by measuring fluid accumulation, after which intestinal biopsies were taken for cAMP assay. The animals were pretreated either subcutaneously with 50 mg/kg nicotinic acid in saline 3 h and 1 h before the introduction of cholera toxin, or intraluminally with 200 mg/kg nicotinic acid in Ringer's lactate solution 15 min before the instillation of cholera toxin. Under these conditions, nicotinic acid blocked the cholera toxin-induced secretion and the rise in cAMP measured 3 h after the loops were exposed to cholera toxin. The effect of the nicotinic acid administered within the lumen on net intestinal secretion was studied. Maximal inhibition of net intestinal secretion was achieved with an intraluminally administered dose of nicotinic acid of 100 mg/kg. This dose was chosen for testing the ability of nicotinic acid to reverse the effects of cholera toxin. When nicotinic acid was instilled into a fifth loop constructed distally to the four experimental loops 3 h after exposure of these loops to cholera toxin, both intestinal secretion and elevation of cAMP were reversed. These results suggest that nicotinic acid can prevent and reverse the secretory effects of cholera toxin and may have a role in the therapy of cholera and other cAMP-associated diarrheal diseases.

Authors

Nabila Turjman, Gerald S. Gotterer, Thomas R. Hendrix