Apelin, the Novel Endogenous Ligand of the Orphan Receptor APJ, Regulates Cardiac Contractility

Author:

Szokodi István1,Tavi Pasi1,Földes Gábor1,Voutilainen-Myllylä Sari1,Ilves Mika1,Tokola Heikki1,Pikkarainen Sampsa1,Piuhola Jarkko1,Rysä Jaana1,Tóth Miklós1,Ruskoaho Heikki1

Affiliation:

1. From the Departments of Pharmacology and Toxicology (I.Sz., H.T., S.P., J.P., J.R., H.R.) and Physiology (P.T., S.V.-M, M.I.), Biocenter Oulu, University of Oulu, Oulu, Finland; and the Heart Institute (I.Sz.), Faculty of Medicine, University of Pécs, Pécs, Hungary; and the First Department of Internal Medicine (G.F., M.T.), Semmelweis University, Budapest, Hungary.

Abstract

The orphan receptor APJ and its recently identified endogenous ligand, apelin, exhibit high levels of mRNA expression in the heart. However, the functional importance of apelin in the cardiovascular system is not known. In isolated perfused rat hearts, infusion of apelin (0.01 to 10 nmol/L) induced a dose-dependent positive inotropic effect (EC 50 : 33.1±1.5 pmol/L). Moreover, preload-induced increase in dP/dt max was significantly augmented ( P <0.05) in the presence of apelin. Inhibition of phospholipase C (PLC) with U-73122 and suppression of protein kinase C (PKC) with staurosporine and GF-109203X markedly attenuated the apelin-induced inotropic effect ( P <0.001). In addition, zoniporide, a selective inhibitor of Na + -H + exchange (NHE) isoform-1, and KB-R7943, a potent inhibitor of the reverse mode Na + -Ca 2+ exchange (NCX), significantly suppressed the response to apelin ( P <0.001). Perforated patch-clamp recordings showed that apelin did not modulate L-type Ca 2+ current or voltage-activated K + currents in isolated adult rat ventricular myocytes. Apelin mRNA was markedly downregulated in cultured neonatal rat ventricular myocytes subjected to mechanical stretch and in vivo in two models of chronic ventricular pressure overload. The present study provides the first evidence for the physiological significance of apelin in the heart. Our results show that apelin is one of the most potent endogenous positive inotropic substances yet identified and that the inotropic response to apelin may involve activation of PLC, PKC, and sarcolemmal NHE and NCX.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine,Physiology

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