Chromogranin A (CGA), produced byhuman and rat myocardium, generates several biologicallyactive peptides processed at specific proteolyticcleavage sites. A highly conserved cleavage N-terminalsite is the bond 64–65 that reproduces the native ratCGA sequence (rCGA1–64), corresponding to humanN-terminal CGA-derived vasostatin-1. rCGA1–64 cardiotropicactivity has been explored in rat cardiacpreparations. In Langendorff perfused rat heart,rCGA1–64 (from 33 nM) induced negative inotropismand lusitropism as well as coronary dilation, counteractingisoproterenol (Iso) - and endothelin-1 (ET-1)-induced positive inotropic effects and ET-1-dependentcoronary constriction. rCGA1–64 also depressed basaland Iso-induced contractility on rat papillary muscles,without affecting calcium transients on isolated ventricularcells. Structure-function analysis using three modifiedpeptides on both rat heart and papillary musclesrevealed the disulfide bridge requirement for the cardiotropicaction. A decline in Iso intrinsic activity in thepresence of the peptides indicates a noncompetitiveantagonistic action. Experiments on rat isolated cardiomyocytesand bovine aortic endothelial cells indicatethat the negative inotropism observed in rat papillarymuscle is probably due to an endothelial phosphatidylinositol3-kinase-dependent nitric oxide release, ratherthan to a direct action on cardiomyocytes. Taken together,our data strongly suggest that in the rat heartthe homologous rCGA1–64 fragment exerts an autocrine/paracrine modulation of myocardial and coronaryperformance acting as stabilizer against intenseexcitatory stimuli.—
The homologous rat Chromogranin A1-64 (rCGA1-64) modulates myocardial and coronary function in the rat heart counteracting the adrenergic modulation through endothelium-derived Nitric Oxide mechanisms
CERRA, Maria Carmela;ANGELONE, Tommaso;
2008-01-01
Abstract
Chromogranin A (CGA), produced byhuman and rat myocardium, generates several biologicallyactive peptides processed at specific proteolyticcleavage sites. A highly conserved cleavage N-terminalsite is the bond 64–65 that reproduces the native ratCGA sequence (rCGA1–64), corresponding to humanN-terminal CGA-derived vasostatin-1. rCGA1–64 cardiotropicactivity has been explored in rat cardiacpreparations. In Langendorff perfused rat heart,rCGA1–64 (from 33 nM) induced negative inotropismand lusitropism as well as coronary dilation, counteractingisoproterenol (Iso) - and endothelin-1 (ET-1)-induced positive inotropic effects and ET-1-dependentcoronary constriction. rCGA1–64 also depressed basaland Iso-induced contractility on rat papillary muscles,without affecting calcium transients on isolated ventricularcells. Structure-function analysis using three modifiedpeptides on both rat heart and papillary musclesrevealed the disulfide bridge requirement for the cardiotropicaction. A decline in Iso intrinsic activity in thepresence of the peptides indicates a noncompetitiveantagonistic action. Experiments on rat isolated cardiomyocytesand bovine aortic endothelial cells indicatethat the negative inotropism observed in rat papillarymuscle is probably due to an endothelial phosphatidylinositol3-kinase-dependent nitric oxide release, ratherthan to a direct action on cardiomyocytes. Taken together,our data strongly suggest that in the rat heartthe homologous rCGA1–64 fragment exerts an autocrine/paracrine modulation of myocardial and coronaryperformance acting as stabilizer against intenseexcitatory stimuli.—I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
