In vivo metabolic pharmacology of imidazoline receptors.

摘要

The concept that imidazoline agonists interact with a novel I₁ imidazoline receptor (I₁R) in addition to alpha-adrenergic receptors originated in the mid 1980's. Since that time, second generation imidazoline agonists (i.e., moxonidine and rilmenidine) were developed and used to treat hypertension. Both moxonidine and rilmenidine have been advocated in the treatment of hypertension complicated by obesity, insulin resistance and diabetes. These agonists lower blood pressure by centrally inhibiting the sympathoadrenal system.; Studies have also shown that imidazoline agonists improve glucose tolerance and hyperlipidemia along with hypertension, a cluster of abnormalities known as metabolic syndrome X. The site of action is unknown. However, I₁R are expressed in peripheral tissues (i.e., liver, pancreas, kidney, adipose tissue and retina).; The first goal was to determine if imidazoline agonists (i) exert their effect(s) by activating I₁R and/or α₂AR and (ii) affect metabolic functions regulated by the pancreas, liver and/or adipose tissue. The second goal was to examine the mechanism of action of imidazoline agonists. For example, researchers believe that imidazolines exert their effects by reducing sympathetic outflow or by circulatory changes. I hypothesized that the improvements in metabolic syndrome X after acute and chronic treatment are not primarily mediated by reduced sympathetic outflow, but rather by activating I₁R in tissues involved in glucose and lipid homeostasis.; Acute administration of moxonidine and rilmenidine resulted in hyperglycemia, which was related to a reduction in insulin secretion. In addition, there was a decrease in plasma glucagon and a marked improvement in hyperlipidemia. When I blocked the α₂AR component of moxonidine with rauwolscine, there was a dramatic improvement in glucose tolerance. The improvements in glucagon levels and circulating lipids were maintained. These studies suggest that activation of I₁R improves metabolic syndrome X.; Studies to address mechanisms demonstrated that chronic administration of moxonidine also improves glucose tolerance, hyperinsulinemia, hyperglucagonemia and hyperlipidemia. To determine whether moxonidine acted directly on cellular metabolic functions and not via changes in sympathetic outflow or α₂AR activation, a second group of rats was given αMD (this agent directly reduces sympathetic outflow by activating α ₂AR). These studies suggest that imidazoline agonists exert their effects by directly activating cellular metabolic functions.; Additional studies were designed to examine some of the biochemical mechanisms responsible for improving glucose and lipid homeostasis. I found that imidazoline agonists restore the ability to deposit glycogen in the liver and reduce hepatic triglyceride production.; In summary, my results support the hypothesis that activation of I ₁R improves carbohydrate and lipid homeostasis. These beneficial effects resulted from direct actions on peripheral I₁R and not reductions in sympathetic outflow. In fact, several novel in vivo functions of peripheral I₁R were discovered. My research suggests that activation of the I₁R holds tremendous potential in developing a mono-therapy for metabolic syndrome X.