Gluconeogenesis activation after intravenous angiotensin II in freely moving rats< C.C. Coimbra a, *, M.A.R. Garofalo b , D.R.C. Foscolo a , A.R. Xavier b , R.H. Migliorini b a Department of Physiology and Biophysics, Institute of Biological Science, Federal University of Minas Gerais, 31270-901 Belo Horizonte, MG, Brazil b Department of Biochemistry, School of Medicine, University of Sao Paulo, 19049-900 Ribeirao Preto, SP, Brazil Received 16 November 1998; accepted 12 February 1999 Abstract Intravenous (IV) administration of angiotensin II (0.95 nmol/100 g body weight) produced a marked increase in plasma glucose of 20 h fasted rats. To investigate the possibility of a stimulation of gluconeogenesis, conscious unrestrained rats were continuously infused with [ 14 C]bicarbonate, 60 ml/min (0.18mCi/min), and label incorporation into circulating glucose was determined before and after angiotensin injection. The rate of 14 C incorporation into blood glucose of fed rats increased significantly after angiotensin II administration, a 279% increase after 20 min (P , 0.01). In conclusion, the results of the present study show that the hyperglycemia induced by intravenous (IV) administration of angiotensin II is accompanied by an activation of gluconeogenesis, as evidenced by a rapid and marked increase in the rate of 14 CO 2 incorporation into circulating glucose. © 1999 Elsevier Science Inc. All rights reserved. Keywords: Angiotensin II; Gluconeogenesis; Plasma glucose 1. Introduction The renin-angiotensin system (RAS), besides affecting fluid volume, electrolytes and hemodynamic states, is also involved in the regulation of metabolic and endocrine func- tions, especially blood glucose homeostasis [2,6,9 –14,28]. We have recently shown that RAS involvement in blood glucose regulation is of physiological significance [12,13], with angiotensin II producing a dose-dependent hypergly- cemic response [13,16]. On the other hand, intravenous (IV) infusion of an angiotensin II peptide-analog antagonist, [1-Sar,8-Thr]-angiotensin II (sarthran), had an inhibitory effect on hemorrhage hyperglycemia [12,13]. This hyper- glycemic effect of angiotensin II can be attributed to its direct action on hepatic glucose production in addition to its stimulatory action on the sympathoadrenal system [12,16]. The direct hyperglycemic action of angiotensin II is presumably related to the peptide-induced increase of phos- phorylase activity, that enhances glycolysis and hepatic glucose output. Angiotensin II also amplifies gluconeogen- esis in vitro, probably stimulating pyruvate carboxylase [5,19] and inhibiting pyruvate-kinase [18,25]. However, the underlying biochemical mechanism of increase in hepatic glucose output induced by IV injection of angiotensin II has not been hitherto investigated. The hyperglycemic response to angiotensin II in the fed state could theoretically be accounted for by the breakdown of a substantial amount of liver glycogen. However, in the experiments reported here, abrupt and marked rises in plasma glucose were elicited by IV injection of angiotensin II in fasted rats, despite the negligible amounts of liver glycogen. Thus, the present study was designed to explore the role of gluconeogenesis in this process. 2. Methods At 11 weeks of age, the rats were placed in individual cages and frequently handled. One week later, they were anesthetized with pentobarbital sodium (30 mg/kg b.wt.), and a silastic catheter was inserted into the right atrium for blood sampling. The sampling catheter was rinsed every 2 < This work was supported by grants from Conselho Nacional de Pesquisas (Brazil), Fundac¸ao de Amparo a` Pesquisa do Estado de Sao Paulo, Financiadora de Estudos e Projetos, and Fundac¸ao de Amparo a` Pesquisa do Estado de Minas Gerais. * Corresponding author. Tel.: 155-31-499-2923; fax: 155-31-499- 2924. E-mail address: coimbrac@mono.icb.ufmg.br (C.C. Coimbra) Peptides 20 (1999) 823– 827 0196-9781/99/$ – see front matter © 1999 Elsevier Science Inc. All rights reserved. PII: S0196-9781(99)00068-6