[Pyr1]Apelin-13 Identified as the Predominant Apelin Isoform in the Human Heart: Vasoactive Mechanisms and Inotropic Action in Disease

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2009-09, Vol.54 (3), p.598-604
• Main Authors: Maguire, Janet J, Kleinz, Matthias J, Pitkin, Sarah L, Davenport, Anthony P
• Format: Article
• Language: English
• Subjects: Aged; Apelin; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiotonic Agents - blood; Cardiotonic Agents - metabolism; Cardiotonic Agents - pharmacology; Cells, Cultured; Chromatography, High Pressure Liquid; Coronary Artery Disease - blood; Coronary Artery Disease - metabolism; Coronary Artery Disease - physiopathology; Culture Media, Conditioned - chemistry; Dose-Response Relationship, Drug; Endothelial Cells - cytology; Endothelial Cells - metabolism; Endothelium, Vascular - physiopathology; Experimental diseases; Female; Humans; In Vitro Techniques; Intercellular Signaling Peptides and Proteins - blood; Intercellular Signaling Peptides and Proteins - metabolism; Intercellular Signaling Peptides and Proteins - pharmacology; Male; Mammary Arteries - drug effects; Mammary Arteries - physiopathology; Medical sciences; Myocardium - metabolism; Myocardium - pathology; Protein Isoforms - blood; Protein Isoforms - metabolism; Protein Isoforms - pharmacology; Radioimmunoassay; Saphenous Vein - drug effects; Saphenous Vein - physiopathology; Spectrometry, Mass, Electrospray Ionization; Vasodilation - drug effects
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.109.134619

Apelin receptors, present on vascular smooth muscle cells, endothelium, and cardiomyocytes, are activated by the family of apelin peptides to elicit cardiovascular effects in experimental animals, but functional activity in humans has not been studied in detail. We detected low levels of apelin immunoreactivity in plasma of volunteers consistent with an autocrine/paracrine action and detected apelin immunoreactivity in the supernatant from human cultured endothelial cells. We found that [Pyr]apelin-13 was the predominant isoform in cardiac tissue from patients with coronary artery disease. We tested the hypothesis that apelins have vascular and cardiac actions in human tissues in vitro and compared responses to [Pyr]apelin-13, apelin-13, and apelin-36. In endothelium-intact mammary artery, all 3 of the apelins induced concentration-dependent vasodilatation with comparable potency (EC500.6 to 1.6 nM; maximum response40% to 50%). Vasodilatation was abolished after endothelial removal or preincubation with indomethacin but was unaffected by preincubation with N-nitro-l-arginine methyl ester, indicating involvement of prostanoids but not NO in dilatation by apelins in this patient group. Apelins were potent constrictors of endothelium-denuded saphenous vein (EC500.6 to 1.6 nM; maximum response17% to 26%) and mammary artery ([Pyr]apelin-13; EC500.2 nM; maximum response29%). In paced atrial strips, all 3 of the peptides increased the force of contraction with subnanomolar potencies (EC5040 to 125 pM). For the first time, we demonstrate that the 3 principal forms of apelin have comparable potency and efficacy in human cardiovascular tissues. Apelins are potent endothelium-dependent vasodilators acting via a prostanoid-dependent mechanism; however, removal of the endothelium revealed direct vasoconstrictor actions in both the artery and vein. Furthermore, in human cardiac tissue, the apelin peptides are among the most potent endogenous positive inotropic agents yet reported.