Myocardial and coronary modulation of the homologous rat Chromogranin A1-64 (rCGA1-64) in the rat heart

Aim: 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 sequence (rCGA1-64), corresponding to human N-terminal CGA-derived vasostatin1. The rCGA1-64 cardiotropic activity has been explored on rat cardiac preparations.Methods: We used the Langendorff-perfused rat heart to test rCGA1-64 actions under both basal conditions (inotropism and lusitropism) and in the presence of Isoproterenol (Iso)- and Endothelin1(ET)-dependent stimulation. The effects of modified peptides were also evaluated for structure-function analyses.Results: rCGA1-64 (from 33nM) induced negative inotropism and lusitropism and coronary dilation, counteracting Iso- and ET-1-induced positive inotropic effects and ET-1-dependent coronary constriction. Structure-function analysis using three modified peptides, revealed the requirement of the di-sulfide bridge for the cardiotropic action. All peptides non-competitively antagonized adrenergic stimulation.Conclusions: 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.