Worck R H, Frandsen E, Ibsen H, Petersen J S
Department of Pharmacology, University of Copenhagen, Denmark.
Hypertension. 1998 Jan;31(1 Pt 2):384-90. doi: 10.1161/01.hyp.31.1.384.
Angiotensin II facilitates epinephrine release during insulin-induced hypoglycemia, and this effect appears to be independent of type 1 angiotensin II (AT1) receptors in man. In the present study, we hypothesized that the action of angiotensin II on adrenomedullary epinephrine release is mediated by an AT2 receptor-dependent mechanism. In conscious chronically instrumented rats, we measured plasma concentrations of catecholamines during acute insulin-induced hypoglycemia in groups of rats pretreated with the AT1 receptor antagonist losartan (10 mg/kg i.v.), the AT2 receptor antagonist PD123319 (30 mg/kg i.v.), combined losartan + PD123319, the converting enzyme inhibitor enalapril (1 mg/kg i.v.), or vehicle. In vehicle-treated rats, the area under the curve for changes in plasma epinephrine concentration [AUC(plasma epinephrine)] during insulin-induced hypoglycemia was 111+/-8 nmolXh/L (+/-SEM). Pretreatment with losartan alone did not affect AUC(plasma epinephrine) (113+/-17 nmol x h/L), while pretreatment with PD123319 tended to reduce the response (87+/-10 nmol x h/L; P=.08 versus vehicle). However, AUC(plasma epinephrine) was significantly reduced in rats that were pretreated with combined losartan + PD123319 (68+/-5 nmol x h/L; P<.001 versus vehicle) or enalapril: 86+/-10 nmol x h/L (P<.05 versus vehicle). Thus, combined treatment with losartan + PD 123319 proved more effective in attenuating the reflex increase in plasma epinephrine concentration during hypoglycemia than either of the two AT receptor antagonists given alone. We speculate that angiotensin II through binding to both receptor subtypes facilitates the sympathoadrenal reflex response by actions at several anatomical levels of the neural pathways involved in the sympathoadrenal reflex response elicited during insulin-induced hypoglycemia.
血管紧张素II在胰岛素诱导的低血糖期间促进肾上腺素释放，并且这种作用在人类中似乎独立于1型血管紧张素II（AT1）受体。在本研究中，我们假设血管紧张素II对肾上腺髓质肾上腺素释放的作用是由AT2受体依赖性机制介导的。在清醒的长期植入仪器的大鼠中，我们在急性胰岛素诱导的低血糖期间测量了用AT1受体拮抗剂氯沙坦（10mg/kg静脉注射）、AT2受体拮抗剂PD123319（30mg/kg静脉注射）、氯沙坦+PD123319联合用药、转化酶抑制剂依那普利（1mg/kg静脉注射）或赋形剂预处理的大鼠组中儿茶酚胺的血浆浓度。在用赋形剂处理的大鼠中，胰岛素诱导的低血糖期间血浆肾上腺素浓度变化的曲线下面积[AUC(血浆肾上腺素)]为111±8nmol·h/L（±SEM）。单独用氯沙坦预处理不影响AUC(血浆肾上腺素)（113±17nmol·h/L），而用PD123319预处理倾向于降低反应（87±10nmol·h/L；与赋形剂相比P=0.08）。然而，在用氯沙坦+PD123319联合预处理的大鼠中AUC(血浆肾上腺素)显著降低（68±5nmol·h/L；与赋形剂相比P<0.001）或依那普利：86±10nmol·h/L（与赋形剂相比P<0.05）。因此，氯沙坦+PD123319联合治疗在减弱低血糖期间血浆肾上腺素浓度的反射性增加方面比单独给予的两种AT受体拮抗剂中的任何一种都更有效。我们推测，血管紧张素II通过与两种受体亚型结合，在胰岛素诱导的低血糖期间引发的交感肾上腺反射反应所涉及的神经通路的几个解剖水平上起作用，从而促进交感肾上腺反射反应。
