Apelin effects in human splanchnic arteries. Role of nitric oxide and prostanoids
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).
References (24)
- et al.
Immunocytochemical localization of the endogenous vasoactive peptide apelin to human vascular and endocardial endothelial cells
Regulatory Pept
(2004) - et al.
The novel peptide apelin lowers blood pressure via a nitric oxide-dependent mechanism
Regulatory Pept
(2001) - et al.
Site-specific effects of apelin-13 in the rat medulla oblongata on arterial pressure and respiration
Auton Neurosci
(2002) - et al.
In vitro evidence for vascular hyporesponsiveness in clinical and experimental cirrhosis
Pharmacol Ther
(1997) - et al.
The paradox of nitric oxide in cirrhosis and portal hypertension: too much, not enough
Hepatology
(2002) - et al.
Mesenteric vasodilator responses in cirrhotic rats: a role for nitric oxide?
Hepatology
(1996) - et al.
Circulating and cardiac levels of apelin, the novel ligand of the orphan receptor APJ, in patients with heart failure
Biochem Biophys Res Commun
(2003) - et al.
Opposing cardiovascular roles for the angiotensin and apelin signaling pathways
J Mol Cell Cardiol
(2006) - et al.
Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor
Biochem Biophys Res Commun
(1998) - et al.
Apelin, a new enteric peptide: localization in the gastrointestinal tract, ontogeny, and stimulation of gastric cell proliferation and of cholecystokinin secretion
Endocrinology
(2004)
[(125)I]-(Pyr(1)) Apelin-13 is a novel radioligand for localizing the APJ orphan receptor in human and rat tissues with evidence for a vasoconstrictor role in man
Br J Pharmacol
Apelin—a novel biologically active peptide releases CCK from isolated mucosal cells and the neuroendocrine cell line STC-1
Gastroenterology
Cited by (82)
Therapeutic potential of apelin and Elabela in cardiovascular disease
2023, Biomedicine and PharmacotherapyElabela relaxes rat pulmonary artery and trachea via BK<inf>Ca</inf>, K<inf>V</inf>, and K<inf>ATP</inf> channels
2023, Prostaglandins and Other Lipid MediatorsVascular Functional Effect Mechanisms of Elabela in Rat Thoracic Aorta
2022, Annals of Vascular SurgeryApelin pathway in cardiovascular, kidney, and metabolic diseases: Therapeutic role of apelin analogs and apelin receptor agonists
2022, PeptidesCitation Excerpt :Additionally, apelin increases eNOS phosphorylation at Ser1176 [55] and enhances the transport of L-arginine, the substrate of eNOS, via CAT-1A and CAT-2B [61]. In human splanchnic and mesenteric arteries, apelin causes dose-dependent vasodilation, which can be prevented by blocking NOS but not prostanoids [42]. in vivo studies further confirmed that apelin administration causes NO-dependent arterial vasodilation, supporting a role and a translational potential for the apelin/ApelinR axis in controlling human vascular function [14].
The role of adropin, HIF-1α and apelin biomarkers in the diagnosis of acute mesentaric ischemia
2022, American Journal of Emergency Medicine