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.