In vivo and in vitro desensitization of nicotinic acid-induced adipocyte adenylate cyclase inhibition

Abstract

The influence of pretreatment of hamsters and of intact hamster adipocytes with the heterocyclic carboxylic acid, 3-carboxy-5-methylpyrazole (CMP) was studied on the inhibitory effects of various antilipolytic agents on adenylate cyclase in membrane preparations. In vivo pretreatment of hamsters for 3 days with the potent antilipolytic agent, CMP (40 mg/kg b.w., twice daily), markedly reduced the inhibitory potencies of CMP itself and of nicotinic acid on the adenylate cyclase. In contrast, enzyme inhibition by PGE₁ remained unchanged. Increase in adenylate cyclase activity due to the stimulatory hormone, ACTH, and basal activity were enlarged in adipocyte membranes from CMP-pretreated hamsters compared to controls. In vitro pretreatment of intact hamster adipocytes with CMP at a maximally effective concentration (300 μM) caused a time-dependent decrease in adenylate cyclase inhibition by CMP itself; upon pretreatment for 120 min, inhibition was diminished by about 50%. Identical decreases in the inhibitory potencies were observed for nicotinic acid and for 3-carboxy-5-methylisoxazole, another carboxylic acid. In contrast, inhibitions of the adipocyte adenylate cyclase by PGE₁, adrenaline and N⁶-phenylisopropyladenosine were not changed by the in vitro pretreatment with CMP. The data indicate that adipocyte adenylate cyclase inhibition can desensitize following both in vivo and in vitro administration of an inhibitory agent. The desensitization process and the specificity observed give further support to the idea that inhibition of adipocyte adenylate cyclase by nicotinic acid is mediated by a membrane receptor and, additionally, suggest that nicotinic acid and the heterocyclic carboxylic acids studied act via a common receptor.