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Endothelium-derived nitric oxide mediates the antiadrenergic effect of human vasostatin-1 in rat ventricular myocardium.
- Source :
-
American journal of physiology. Heart and circulatory physiology [Am J Physiol Heart Circ Physiol] 2007 Jun; Vol. 292 (6), pp. H2906-12. Date of Electronic Publication: 2007 Feb 09. - Publication Year :
- 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.
- Subjects :
- Adrenergic beta-Agonists pharmacology
Adrenergic beta-Antagonists pharmacology
Androstadienes pharmacology
Animals
Calcium Channels, L-Type metabolism
Cattle
Cells, Cultured
Chromogranin A pharmacology
Dose-Response Relationship, Drug
Endothelial Cells drug effects
Female
Heart Ventricles cytology
Heart Ventricles metabolism
Humans
In Vitro Techniques
Isoproterenol antagonists & inhibitors
Isoproterenol pharmacology
Muscle Strength
Myocytes, Cardiac drug effects
NG-Nitroarginine Methyl Ester pharmacology
Nitric Oxide Synthase antagonists & inhibitors
Nitric Oxide Synthase metabolism
Papillary Muscles drug effects
Peptide Fragments pharmacology
Phosphatidylinositol 3-Kinases metabolism
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors pharmacology
Rats
Recombinant Proteins metabolism
Wortmannin
Adrenergic beta-Antagonists metabolism
Calcium Signaling drug effects
Chromogranin A metabolism
Endothelial Cells metabolism
Myocardial Contraction drug effects
Myocytes, Cardiac metabolism
Nitric Oxide metabolism
Papillary Muscles metabolism
Peptide Fragments metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0363-6135
- Volume :
- 292
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Heart and circulatory physiology
- Publication Type :
- Academic Journal
- Accession number :
- 17293489
- Full Text :
- https://doi.org/10.1152/ajpheart.01253.2006