Zonation of the metabolic action of vasopressin in the bivascularly perfused rat liver Angelita Polato Schmeisch, Denise Silva de Oliveira, Luci Tiemi Ide, Fumie Suzuki-Kemmelmeier, Adelar Bracht * Laboratory of Liver Metabolism, Department of Biochemistry University of Maringa ´ , 87020900 Maringa ´, Brazil Received 23 November 2004; received in revised form 22 February 2005; accepted 2 March 2005 Available online 4 May 2005 Abstract Predominance of the vasopressin binding capacity in the hepatic perivenous area leads to the hypothesis that the metabolic effects of the hormone should also be more pronounced in this area. Until now this question has been approached solely by experiments with isolated hepatocytes where an apparent absence of metabolic zonation was found. We have reexamined this question using the bivascularly perfused liver. In this system periportal cells can be reached in a selective manner with substrates and effectors via the hepatic artery when retrograde perfusion (hepatic vein Y portal vein) is done. The action of vasopressin (1 – 10 nM) on glycogenolysis, initial calcium efflux, glycolysis and oxygen uptake were measured. The results revealed that the action of vasopressin in the liver is heterogeneously distributed. Glycogenolysis stimulation and initial calcium efflux were predominant in the perivenous area, irrespective of the vasopressin concentration. Oxygen uptake was stimulated in the perivenous area; in the periportal area it ranged from inhibition at low vasopressin concentrations to stimulation at high ones. Lactate production was generally greater in the perivenous zone, whereas the opposite occurred with pyruvate production. Analysis of these and other results suggests that at least three factors are contributing to the heterogenic response of the liver parenchyma to vasopressin: a) receptor density, which tends to favour the perivenous zone; b) cell-to-cell interactions, which tend to favour situations where the perivenous zone is amply supplied with vasopressin; and c) the different response capacities of perivenous and periportal cells. D 2005 Elsevier B.V. All rights reserved. Keywords: Vasopressin; Liver; Zonation; Glycogenolysis; Calcium 1. Introduction Vasopressin (arginine–vasopressin) affects liver metab- olism in several ways. It increases glycogen breakdown [1,2], stimulates oxygen uptake [3] and increases the flux through the tricarboxylic acid cycle [4]. As a general hypertensive agent it also increases resistance of the hepatic artery [5] but is without effect on portal resistance [6]. These actions in the liver are all directly or indirectly mediated by Ca 2+ in the cytosol, whose concentration is increased under the influence of the hormone [7,8]. This increase takes the form of concentration spikes (oscillations) at subsaturating levels of vasopressin. The increased Ca 2+ concentrations can also propagate intra- and intercellularly, creating apparent intercellular waves. Such coordinated and sequential signals elicited by vasopressin in the intact perfused liver originate waves of Ca 2+ concentration increases running along the hepatocyte plates across the lobules, at a dose-dependent speed of 20–120 Ams  1 [9]. These waves propagate towards only one direction and coupling between adjacent cells is believed to be provided by gap junctions [10,11]. Most experimental data indicate that the starting area of the vasopressin-induced Ca 2+ concentration waves in the liver lobule is the perivenous zone [12,13]. In one study waves initiating in the periportal region have been detected at low vasopressin concentrations (< 1 nM, [14]). At these low concentrations, however, other investigators failed to detect coordinated Ca 2+ waves [13]. The direction perivenous to 0167-0115/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.regpep.2005.03.005 * Corresponding author. Tel.: +55 44 261 4896; fax: +55 44 263 3655. E-mail address: adebracht@uol.com.br (A. Bracht). Regulatory Peptides 129 (2005) 233 – 243 www.elsevier.com/locate/regpep