DiTullio N W, Cieslinski L, Matthews W D, Storer B
J Pharmacol Exp Ther. 1984 Jan;228(1):168-73.
Clonidine induced a dose-dependent hyperglycemic response in fed rats, a minimal hyperglycemic response in 48-hr fasted rats and had no effect on blood glucose in 16-hr fasted, streptozotocin-diabetic rats. At a dose of 0.1 mg/kg, there was an equivalent hyperglycemic response in fed rats whether clonidine was administered orally, i.v. or i.p. A hyperglycemic effect was also observed with the central and peripheral alpha-2 adrenoceptor agonist, guanabenz (0.1 mg/kg i.v.). In contrast, 2-(3-4-dihydroxyphenylimino) imidazoline, an alpha-2 agonist which does not penetrate into the central nervous system, caused a lowering of blood glucose at the same dose. The hyperglycemic response induced by clonidine was partially inhibited by the selective alpha-2 antagonists, yohimbine and rauwolscine, and the nonselective alpha antagonist, phentolamine. The hyperglycemic response induced by clonidine was not affected by the selective alpha-1 adrenoceptor antagonists, prazosin or corynanthine. Methoxamine, an alpha-1 agonist, had no effect on clonidine-induced hyperglycemia. The hyperglycemic response to clonidine was partially inhibited by 3-mercaptopicolinic acid, an inhibitor of gluconeogenesis, but was not affected by pretreatment with the H2-histamine receptor antagonist, metiamide, the prostaglandin syntheses inhibitor, idomethacin, or the beta adrenoceptor antagonist, propranolol. These results suggest that 1) the hyperglycemic response induced by clonidine and other alpha-2 adrenergic agonists is mediated by alpha-2 adrenergic receptors located within the central nervous system and 2) clonidine-induced hyperglycemia is effected, in part, by enhanced gluconeogenesis.
可乐定在喂食大鼠中引起剂量依赖性的高血糖反应，在禁食48小时的大鼠中引起最小的高血糖反应，而对禁食16小时的链脲佐菌素诱导的糖尿病大鼠的血糖没有影响。在0.1mg/kg的剂量下，无论可乐定是口服、静脉注射还是腹腔注射，喂食大鼠都会出现同等的高血糖反应。中枢和外周α-2肾上腺素能激动剂胍那苄（静脉注射0.1mg/kg）也观察到了高血糖作用。相比之下，一种不能穿透中枢神经系统的α-2激动剂2-(3,4-二羟基苯基亚氨基)咪唑啉在相同剂量下会导致血糖降低。可乐定诱导的高血糖反应被选择性α-2拮抗剂育亨宾和萝芙木碱以及非选择性α拮抗剂酚妥拉明部分抑制。可乐定诱导的高血糖反应不受选择性α-1肾上腺素能拮抗剂哌唑嗪或育亨宾的影响。α-1激动剂甲氧明对可乐定诱导的高血糖没有影响。对可乐定的高血糖反应被糖异生抑制剂3-巯基吡啶甲酸部分抑制，但不受H2组胺受体拮抗剂甲硫米特、前列腺素合成抑制剂吲哚美辛或β肾上腺素能拮抗剂普萘洛尔预处理的影响。这些结果表明：1）可乐定和其他α-2肾上腺素能激动剂诱导的高血糖反应是由位于中枢神经系统内的α-2肾上腺素能受体介导的；2）可乐定诱导的高血糖部分是由糖异生增强所致。
