Carrier G O, Aronstam R S
J Pharmacol Exp Ther. 1987 Aug;242(2):531-5.
The cardiac cholinergic system was studied in streptozotocin (STZ)-diabetic and age-matched control rats. STZ-diabetic rats (8-10 weeks) were supersensitive to the negative chronotropic effects of acetylcholine, carbamylcholine and bethanechol; inotropic responses to these muscarinic agonists were unaltered. This phenomenon was associated with a decrease in acetylcholinesterase activity but no change in the rate and extent of neuronal choline uptake. [3H]N-methylscopolamine bound to muscarinic receptors in atria from both groups of rats with the same high affinity. The density of [3H]N-methylscopolamine binding sites, however, was 34% lower in atria from STZ-diabetic rats. Agonist binding affinity was lower in diabetes; carbamylcholine had a lower affinity for both the high- and low-affinity receptors. These results indicate that cardiac cholinergic supersensitivity in right atria in diabetes occurs before the development of autonomic neuropathy insofar as neuronal [3H]choline uptake is unaltered at this stage of STZ diabetes. Changes in agonist binding conformation, without a concomitant change in antagonist binding affinity, suggest that supersensitivity of right atria to muscarinic agonist may be a consequence of altered coupling of muscarinic receptor to transduction mechanisms involved in chronotropism in diabetes.
在链脲佐菌素（STZ）诱导的糖尿病大鼠和年龄匹配的对照大鼠中研究了心脏胆碱能系统。STZ诱导的糖尿病大鼠（8 - 10周龄）对乙酰胆碱、氨甲酰胆碱和氯贝胆碱的负性变时作用超敏感；对这些毒蕈碱激动剂的变力反应未改变。这种现象与乙酰胆碱酯酶活性降低有关，但神经元胆碱摄取的速率和程度没有变化。[3H]N - 甲基东莨菪碱以相同的高亲和力与两组大鼠心房中的毒蕈碱受体结合。然而，STZ诱导的糖尿病大鼠心房中[3H]N - 甲基东莨菪碱结合位点的密度低34%。糖尿病时激动剂结合亲和力降低；氨甲酰胆碱对高亲和力和低亲和力受体的亲和力均较低。这些结果表明，在STZ糖尿病的这个阶段，由于神经元[3H]胆碱摄取未改变，糖尿病右心房的心脏胆碱能超敏感性在自主神经病变发展之前就已出现。激动剂结合构象的变化，而拮抗剂结合亲和力没有相应变化，表明右心房对毒蕈碱激动剂的超敏感性可能是糖尿病中毒蕈碱受体与变时性相关转导机制偶联改变的结果。
