The Comparative Effects of Tolbutamide and the Non-Hypoglycemic Analog Carboxy-tolbutamide on Guanylate Cyclase Activity

Summary

Tolbutamide and its non-hypoglycemic analog carboxytolbutamide increased soluble and particulate guanylate cyclase [E.C.4.6.1.2] activity twofold in liver, lung, colon, pancreas, kidney cortex, heart and spleen at a concentration of 1 μM. The ED₅₀ for stimulation of guanylate cyclase activity was 50 nM for both agents. No stimulation of guanylate cyclase activity was observed with either agent when their concentrations were decreased to 1 nM. Maximal enhancement was at a concentration of 100 nM for both agents. Butylated hydroxytoluene, an antioxidant and hydroxyl radical scavenger, completely blocked any enhancement of guanylate cyclase by carboxytolbutamide, suggesting that its effect was due to a nonspecific oxidation reaction. Tolbutamide's augmentation of guanylate cyclase activity was not blocked by butylated hydroxytoluene. Varying the concentration of the guanylate cyclase co-factor manganese indicated that these sulfonylureas could not maximally activate guanylate cyclase without manganese being present. In addition to increased insulin receptors in monocytes and fibroblasts, the present findings, plus similar findings with the oral hypoglycemic agent glibenclamide, may help explain the mechanism of the extra-pancreatic effects of oral sulfonylurea agents at the cellular level.

Key-Words

Oral Hypoglycemic Agent - Tolbutamide - Carboxytolbutamide - Non-Specific Oxidation - Cyclic GMP - Guanylate Cyclase