Apelin, the novel endogenous ligand of the orphan receptor APJ, regulates cardiac contractility.
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 (EC50: 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+-Ca2+ exchange (NCX), significantly suppressed the response to apelin (P<0.001). Perforated patch-clamp recordings showed that apelin did not modulate L-type Ca2+ 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.
Szokodi
István
I
Department of Pharmacology and Toxicology, Biocenter Oulu, University of Oulu, Oulu, Finland.
Tavi
Pasi
P
Földes
Gábor
G
Voutilainen-Myllylä
Sari
S
Ilves
Mika
M
Tokola
Heikki
H
Pikkarainen
Sampsa
S
Piuhola
Jarkko
J
Rysä
Jaana
J
Tóth
Miklós
M
Ruskoaho
Heikki
H
D053607:Adrenomedullin; D000818:Animals; D030801:Animals, Genetically Modified; D000073861:Apelin; D000075244:Apelin Receptors; D015220:Calcium Channels / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins; D007545:Isoproterenol / Q000494:pharmacology; D008024:Ligands; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects*; D010455:Peptides / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D013314:Stress, Mechanical; D013997:Time Factors; D016276:Ventricular Function
D000073861:Apelin; D000075244:Apelin Receptors; C498579:Apln protein, rat; C491284:Aplnr protein, rat; D015220:Calcium Channels; D002352:Carrier Proteins; D019332:Endothelin-1; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D010455:Peptides; D015221:Potassium Channels; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D043562:Receptors, G-Protein-Coupled; D019831:Sodium-Calcium Exchanger; D017923:Sodium-Hydrogen Exchangers; D053607:Adrenomedullin; D007545:Isoproterenol