Endothelium-derived nitric oxide mediates the antiadrenergic effect of human vasostatin-1 in rat ventricular myocardium

• Published in: American journal of physiology. Heart and circulatory physiology 2007-06, Vol.292 (6), p.H2906-H2912
• Main Authors: Gallo, Maria Pia, Levi, Renzo, Ramella, Roberta, Brero, Alessia, Boero, Ombretta, Tota, Bruno, Alloatti, Giuseppe
• Format: Article
• Language: English
• Subjects: Adrenergic beta-Agonists - pharmacology; Adrenergic beta-Antagonists - metabolism; Adrenergic beta-Antagonists - pharmacology; Androstadienes - pharmacology; Animals; Calcium; Calcium Channels, L-Type - metabolism; Calcium Signaling - drug effects; Cardiology; Cattle; Cell culture; Cells, Cultured; Chromogranin A - metabolism; Chromogranin A - pharmacology; Dose-Response Relationship, Drug; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Female; Heart; Heart Ventricles - cytology; Heart Ventricles - metabolism; Humans; In Vitro Techniques; Isoproterenol - antagonists & inhibitors; Isoproterenol - pharmacology; Muscle Strength; Myocardial Contraction - drug effects; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; NG-Nitroarginine Methyl Ester - pharmacology; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase - metabolism; Papillary Muscles - drug effects; Papillary Muscles - metabolism; Peptide Fragments - metabolism; Peptide Fragments - pharmacology; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; Protein Kinase Inhibitors - pharmacology; Rats; Recombinant Proteins - metabolism; Rodents; Signal transduction; Statins; Tissues
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.01253.2006

1 Dipartimento di Biologia Animale e dell'Uomo, Università di Torino, Turin, and 2 Dipartimento di Biologia Cellulare, Università della Calabria, Arcavacata Di Rende (Cs), Italy Submitted 16 November 2006 ; accepted in final form 4 February 2007 Vasostatins (VSs) are vasoactive peptides derived from chromogranin A (CgA), a protein contained in secretory granules of chromaffin and other cells. The negative inotropic effect and the reduction of isoproterenol (Iso)-dependent inotropism induced by VSs in the heart suggest that they have an antiadrenergic function. However, further investigation of the mechanisms of action of VSs is needed. The aim of the present study was to define the signaling pathways activated by VS-1 in mammalian ventricular myocardium and cultured endothelial cells that lead to the modulation of cardiac contractility. Ca 2+ and nitric oxide (NO) fluorometric confocal imaging was used to study the effects induced by recombinant human VS-1 [STA-CgA-(1-76)] on contractile force, L-type Ca 2+ current, and Ca 2+ transients under basal conditions and after -adrenergic stimulation in rat papillary muscles and ventricular cells and the effects on intracellular Ca 2+ concentration and NO production in cultured bovine aortic endothelial (BAE-1) cells. VS-1 had no effect on basal contractility of papillary muscle, but the effect of Iso stimulation was reduced by 27%. Removal of endocardial endothelium and inhibition of NO synthesis and phosphatidylinositol 3-kinase (PI3K) activity abolished the antiadrenergic effect of VS-1 on papillary muscle. In cardiomyocytes, 10 nM VS-1 was ineffective on basal and Iso (1 µM)-stimulated L-type Ca 2+ current and Ca 2+ transients. In BAE-1 cells, VS-1 induced a Ca 2+ -independent increase in NO production that was blocked by the PI3K inhibitor wortmannin. Our results suggest that the antiadrenergic effect of VS-1 is mainly due to a PI3K-dependent NO release by endothelial cells, rather than a direct action on cardiomyocytes. calcium channel; myocardial contractility; peptide hormones; endothelial cell Address for reprint requests and other correspondence: G. Alloatti, Dipartimento di Biologia Animale e dell'Uomo, Via Accademia Albertina, 13, 10123, Torino, Italy (e-mail: giuseppe.alloatti{at}unito.it )