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Midgut active ion transport changes during the final larval stage of the tobacco hornworm. The short-circuit current (Isc) of the posterior midguts dissected from feeding fifth instars (day 2) is higher than that of midguts from wandering larvae (day 5). The Isc of midguts from day 2 larvae is inhibited by 1 mM cAMP and 0.1mM cGMP, whereas the midguts from day 5 larvae are stimulated by cAMP but unaffected by cGMP. A similar pattern is observed if the midguts are exposed to the cyclic nucleotide derivative, 8-bromo-cGMP. Exposure to the calcium ionophore, A23187, or the endoplasmic calcium ATPase inhibitor, thapsigargin, slightly inhibited the Isc of day 2 larval midguts, but this inhibition was not significant. Pharmacological agents known to modulate the activities of protein kinase A, protein kinase C, or protein phosphatases did not change the Isc. These results indicate that midgut active ion transport is modulated by cyclic nucleotides, but the manner of the response depends on the developmental status of the insect.