title: The homologous rat chromogranin A1-64 (rCGA1-64) modulates myocardial and coronary function in rat heart to counteract adrenergic stimulation indirectly via endothelium-derived nitric oxide.
abstract: Chromogranin A (CGA), produced by human and rat myocardium, generates several biologically active peptides processed at specific proteolytic cleavage sites. A highly conserved cleavage N-terminal site is the bond 64-65 that reproduces the native rat CGA sequence (rCGA1-64), corresponding to human N-terminal CGA-derived vasostatin-1. rCGA1-64 cardiotropic activity has been explored in rat cardiac preparations. In Langendorff perfused rat heart, rCGA1-64 (from 33 nM) induced negative inotropism and lusitropism as well as coronary dilation, counteracting isoproterenol (Iso) - and endothelin-1 (ET-1) -induced positive inotropic effects and ET-1-dependent coronary constriction. rCGA1-64 also depressed basal and Iso-induced contractility on rat papillary muscles, without affecting calcium transients on isolated ventricular cells. Structure-function analysis using three modified peptides on both rat heart and papillary muscles revealed the disulfide bridge requirement for the cardiotropic action. A decline in Iso intrinsic activity in the presence of the peptides indicates a noncompetitive antagonistic action. Experiments on rat isolated cardiomyocytes and bovine aortic endothelial cells indicate that the negative inotropism observed in rat papillary muscle is probably due to an endothelial phosphatidylinositol 3-kinase-dependent nitric oxide release, rather than to a direct action on cardiomyocytes. Taken together, our data strongly suggest that in the rat heart the homologous rCGA1-64 fragment exerts an autocrine/paracrine modulation of myocardial and coronary performance acting as stabilizer against intense excitatory stimuli.
authors.affiliation: B.T., Department of Cell Biology, University of Calabria, 87030 Arcavacata di Rende (CS), Calabria, Italy.
authors.forename: M C
authors.initials: MC
authors.lastname: Cerra
authors.forename: M P
authors.initials: MP
authors.lastname: Gallo
authors.forename: T
authors.initials: T
authors.lastname: Angelone
authors.forename: A M
authors.initials: AM
authors.lastname: Quintieri
authors.forename: E
authors.initials: E
authors.lastname: Pulerà
authors.forename: E
authors.initials: E
authors.lastname: Filice
authors.forename: B
authors.initials: B
authors.lastname: Guérold
authors.forename: P
authors.initials: P
authors.lastname: Shooshtarizadeh
authors.forename: R
authors.initials: R
authors.lastname: Levi
authors.forename: R
authors.initials: R
authors.lastname: Ramella
authors.forename: A
authors.initials: A
authors.lastname: Brero
authors.forename: O
authors.initials: O
authors.lastname: Boero
authors.forename: M H
authors.initials: MH
authors.lastname: Metz-Boutigue
authors.forename: B
authors.initials: B
authors.lastname: Tota
authors.forename: G
authors.initials: G
authors.lastname: Alloatti
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D019898:Autocrine Communication / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology; D002417:Cattle; D053379:Chromogranin A / Q000378:metabolism* / Q000494:pharmacology; D003331:Coronary Vessels / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D019332:Endothelin-1 / Q000494:pharmacology; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D010210:Papillary Muscles / Q000166:cytology / Q000378:metabolism*; D019899:Paracrine Communication / Q000187:drug effects / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
chemical_list: D002316:Cardiotonic Agents; D053379:Chromogranin A; D019332:Endothelin-1; D009569:Nitric Oxide; D019869:Phosphatidylinositol 3-Kinases; D007545:Isoproterenol; D002118:Calcium