The development of tolerance to antilipolytic agents in rats

The development of tolerance to the action of certain antilipolytic agents has been investigated in vivo in rats. Tolerance to oral nicotinic acid developed during twice daily dosing for 4 days at 100 and 250 mg/kg but not at 10, 25 or 50 mg/kg. Tolerance induced by high doses of nicotinic acid was no longer detectable after a further week without treatment. Tolerance developed to a dose of 10 mg/kg nicotinic acid when dosing was repeated at hourly intervals for up to 6 hr. Rats made tolerant to nicotinic acid also became tolerant to both 5-methylpyrazole-3-carboxylic acid and to pyridyl-3-tetrazole and rats made tolerant to these antilipolytic agents were also tolerant to nicotinic acid. Rats made tolerant to nicotinic acid still responded to the antilipolytic activity of the prostaglandin analogue, sulprostone. These results suggest that nicotinic acid, pyridyl-3-tetrazole and 5-methylpyrazole-3-carboxylic acid act through a common mechanism or receptor and that the development of tolerance is associated with this receptor or the mechanism by which it is linked to adenylate cyclase.