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(Hypertension. 1998;31:384.)
© 1998 American Heart Association, Inc.

Scientific Contributions

AT₁ and AT₂ Receptor Blockade and Epinephrine Release During Insulin-Induced Hypoglycemia

René H. Worck; Erik Frandsen; Hans Ibsen; Jørgen Søberg Petersen

From the Department of Pharmacology, University of Copenhagen, Denmark (R.H.W., J.S.P.); the Department of Medicine C, University Hospital Glostrup, Glostrup, Denmark (R.H.W., H.I.); and the Department of Clinical Physiology and Nuclear Medicine, University Hospital Glostrup, Denmark (E.F.).

Correspondence to René H. Worck, MD, Department of Pharmacology, University of Copenhagen, The Panum Institute, 3, Blegdamsvej, Bldg. 18.6, DK-2200 Copenhagen N, Denmark. E-mail rene.worck{at}farmakol.ku.dk

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 IV), the AT₂ receptor antagonist PD123319 (30 mg/kg IV), combined losartan + PD123319, the converting enzyme inhibitor enalapril (1 mg/kg IV), 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 nmolxh/L), while pretreatment with PD123319 tended to reduce the response (87±10 nmolxh/L; P=.08 versus vehicle). However, AUC(plasma epinephrine) was significantly reduced in rats that were pretreated with combined losartan + PD123319 (68±5 nmolxh/L; P<.001 versus vehicle) or enalapril: 86±10 nmolxh/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.

Key Words: hypoglycemia • angiotensin receptor subtypes • epinephrine • catecholamines

Abbreviations: AT₁, AT₂ receptor = type 1 or type 2 Ang II receptor • AUC = area under the curve • CEI = converting enzyme inhibition • HR = heart rate • MAP = mean arterial blood pressure • PRA = plasma renin activity

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