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EnglishVasostatins (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 beta-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 microM)-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.
| Titolo: | Endothelium-derived Nitric Oxide mediates the anti-adrenergic effect of Human Vasostatin-1 (CgA 1-76) in rat ventricular myocardium. | |
| Autori Riconosciuti: | ||
| Autori: | GALLO MP; LEVI R; RAMELLA R; BRERO A; BOERO O; TOTA B; G. ALLOATTI | |
| Data di pubblicazione: | 2007 | |
| Abstract: | 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 beta-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 microM)-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. | |
| Volume: | 292(6) | |
| Pagina iniziale: | H2906 | |
| Pagina finale: | H2912 | |
| Digital Object Identifier (DOI): | 10.1152/ajpheart.01253.2006 | |
| Rivista: | AMERICAN JOURNAL OF PHYSIOLOGY. HEART AND CIRCULATORY PHYSIOLOGY | |
| Appare nelle tipologie: | 03A-Articolo su Rivista |
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http://hdl.handle.net/2318/6292
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