Dopamine agonist-induced hyperglycemia in rats: Structure-activity relationships and mechanisms of action

The concentration of blood glucose was measured in rats after administration of a number of drugs characterized as dopamine agonists. Compounds that cause release of dopamine, or agents that block the reuptake of dopamine, did not elevate blood glucose. Some direct dopamine receptor stimulants (lergotrile, bromocriptine, apomorphine) caused hyperglycemia, but other agonists (e.g. pergolide) did not. Further experiments with lergotrile, the most active hyperglycemic dopamine agonist, revealed that the blood glucose increase was accompanied by a marked elevation in liver glycogen, indicating a gluconeogenic effect of the compound. This hypothesis was supported by using inhibitors of gluconeogenesis (L-tryptophan or 3-mercaptopicolinic acid) to block lergotrile's hyperglycemic action. Structure-activity relationships among close analogues of lergotrile suggest that the cyano moiety in the lergotrile molecule may be of importance in the hyperglycemic action of lergotrile. These results indicate that central dopamine stimulation per se does not cause hyperglycemia in rats.