Inhibition of adenylate cyclase and stimulation of a high affinity GTPase by the antilipolytic agents, nicotinic acid, acipimox and various related compounds.

In hamster adipocyte ghosts, the influence of the antilipolytic agents, nicotinic acid, 5-methyl-pyrazine-2-carboxylic acid 4-oxide (acipimox) and various related compounds, was studied on adenylate cyclase and low Km GTPase activities. As shown before for hormonal factors and nicotinic acid, the new drug, acipimox, inhibited adenylate cyclase by a GTP-dependent process, which was amplified by sodium ions; half-maximal inhibition occurred at about 10 mumol/l acipimox. For the various compounds studied, the following rank order of potency in inhibition of adenylate cyclase was obtained, nicotinic acid greater than 3-carboxy-5-methylpyrazole greater than acipimox greater than 3-carboxy-5-methylisoxazole; 6-hydroxynicotinic acid and beta-pyridylcarbinol had no effect up to 300 mumol/l. In the same membrane system the antilipolytic drugs increased GTP hydrolysis by stimulation of a low Km GTPase as shown before for antilipolytic hormones. The potency order of the antilipolytic agents studied was identical for GTPase stimulation and adenylate cyclase inhibition. The data suggest that the antilipolytic drugs studied act on adipocyte adenylate cyclase via membrane-bound receptors in a hormone-like manner and that stimulation of a high affinity GTPase is involved in the mechanism of adenylate cyclase inhibition by these agents.