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FASEB J ; 22(11): 3992-4004, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18697842

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.


Subject(s)
Chromogranin A/metabolism , Coronary Vessels/metabolism , Endothelial Cells/metabolism , Myocardial Contraction/physiology , Myocytes, Cardiac/metabolism , Nitric Oxide/metabolism , Papillary Muscles/metabolism , Vasodilation/physiology , Animals , Aorta/cytology , Aorta/metabolism , Autocrine Communication/drug effects , Autocrine Communication/physiology , Calcium/metabolism , Cardiotonic Agents/pharmacology , Cattle , Chromogranin A/pharmacology , Endothelial Cells/cytology , Endothelin-1/pharmacology , Humans , Isoproterenol/pharmacology , Male , Myocardial Contraction/drug effects , Myocytes, Cardiac/cytology , Papillary Muscles/cytology , Paracrine Communication/drug effects , Paracrine Communication/physiology , Phosphatidylinositol 3-Kinases/metabolism , Rats , Rats, Wistar , Structure-Activity Relationship , Vasodilation/drug effects
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