Elsevier

Regulatory Peptides

Volume 144, Issues 1–3, 1 December 2007, Pages 50-55
Regulatory Peptides

Apelin effects in human splanchnic arteries. Role of nitric oxide and prostanoids

https://doi.org/10.1016/j.regpep.2007.06.005Get rights and content

Abstract

Apelin effects were examined in human splanchnic arteries from liver donors (normal arteries) and from liver recipients. Segments 3 mm long were obtained from mesenteric arteries taken from liver donors (normal arteries), and from hepatic arteries taken from cirrhotic patients undergoing liver transplantation (liver recipients), and the segments were mounted in organ baths for isometric tension recording. In arteries under resting conditions, apelin (10 10–10 6 M) caused no effect in any of the arteries tested. In arteries precontracted with the thromboxane A2 analogue U46619 (10 7–10 6 M), apelin (10 10–10 6 M) produced concentration-dependent relaxation that was lower in hepatic than in mesenteric arteries, whereas sodium nitroprusside (10 8–10 4 M) produced a similar relaxation in both types of arteries. The inhibitor of nitric oxide synthesis Nw-nitro-l-arginine methyl ester (l-NAME, 10 4 M) diminished the relaxation to apelin in mesenteric but not in hepatic arteries. The inhibitor of cyclooxygenase meclofenamate (10 5 M) did not affect the relaxation provoked by apelin in both types of arteries. Therefore, apelin may produce relaxation in normal human splanchnic arteries, and this relaxation may be mediated in part by nitric oxide without involvement of prostanoids. This relaxation as well as the role of nitric oxide may be decreased in splanchnic arteries from cirrhotic patients.

Introduction

Apelin is a peptide recently isolated that seems to act as an endogenous ligand for the previously orphaned G-protein-coupled APJ receptor. The mature apelin likely is derived from the C-terminal region of the propeptide of 77 AA, either as a 36, 17 or 13 amino acid peptide, and the shorter isoforms have shown to be more potent than apelin-36 at several functions [1]. Apelin receptors and apelin are expressed in various tissues, including the gastrointestinal tract [2], [3] and the cardiovascular system [1], [4], [5], and under normal conditions apelin enters the circulation and is maintained at concentrations that are in the range that has been shown to have physiological effects [1].

The physiological role of apelin is uncertain, and several studies suggest that it might play a role in the regulation of the gastrointestinal tract [2], [3], [6] and cardiovascular system [5], [7], [8], [9]. Binding sites for apelin-13 were localized using autoradiography to human coronary artery, aorta and saphenous vein grafts [5]. Studies in anesthetized rats report that i.v. injection of apelin decreases systemic arterial pressure [10], [11], and those performed in conscious unrestrained rats show that apelin could function both as an arterial and venous dilator [1]. Also, it has been described that the hemodynamic effects of apelin are abolished after treatment with an inhibitor of nitric oxide synthesis, suggesting that this peptide decreases arterial pressure via a nitric oxide-dependent mechanism [7]. Intracerebroventricular injection of apelin did not change arterial pressure in anesthetized rats [12], but when it is performed in conscious rats apelin increases arterial pressure [11]. Relatively little is known about the effects of apelin in human blood vessels. One in vitro study performed in endothelium-denuded, isolated human saphenous vein reports that apelin produces constriction with a nanomolar potency [5].

The present in vitro study was performed to examine the effects of apelin in human splanchnic arteries, analyzing the role of nitric oxide and prostanoids in these effects. This study was made using mesenteric arteries from liver donors (normal arteries) and hepatic arteries from cirrhotic patients undergoing liver transplantation. As apelin might be involved in the regulation of the gastrointestinal tract [2], [3], [6], this peptide could be of significance in the regulation of splanchnic circulation under normal and some abnormal conditions. Patients with liver cirrhosis exhibit hemodynamic alterations characterized by a hyperdynamic circulatory state with increased cardiac output, and systemic and splanchnic vasodilatation, but the mechanisms involved in this abnormal circulatory state are not well known [13], [14]. The effects of apelin in human arteries have been not explored yet, to our knowledge.

Section snippets

Patients

Eight patients with cirrhosis undergoing liver transplantation were included in this study (mean age: 54 years (range: 33–68), 5 males, 3 females). Etiology of cirrhosis was virus C in 5 patients, alcohol-related in 1 patient, primary biliary cirrhosis in 1 patient, and cryptogenic in 1 patient. One patient was Child-Pugh grade A, 4 patients grade B, and 3 patients grade C. The diagnosis of cirrhosis was made by liver biopsy in all patients. All the patients exhibited systemic hypotension, and

Results

For untreated arteries, at the beginning of the experiments the contraction in response to KCl (100 mM) was higher (P > 0.001) in untreated hepatic arteries (5836 ± 477 mg for 25 segments from 8 cirrhotic patients) than in untreated mesenteric arteries (3189 ± 271 mg for 14 segments from 5 donors). This contraction to KCl was not significantly affected by the treatments used in both hepatic and mesenteric arteries.

Under resting conditions, apelin (10 10–10 6 M) did not cause any effect in hepatic

Discussion

The present results show that in arteries under resting conditions, apelin-13 produced no effect in mesenteric arteries taken from liver donors and hepatic arteries taken from cirrhotic patients during liver transplantation. Also, they show that in precontracted arteries apelin-13 resulted in relaxation, but this effect was lower in hepatic arteries from cirrhotic patients than in mesenteric arteries from liver donors. This study was performed using isolated mesenteric arteries from liver

Acknowledgements

We are indebted to Esther Martínez and Hortensia Fernández-Lomana for technical assistance.

This work was supported, in part, by FMMMA and MEyC (BFU2004-04054).

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