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.
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.
Cerra
M C
MC
B.T., Department of Cell Biology, University of Calabria, 87030 Arcavacata di Rende (CS), Calabria, Italy.
Gallo
M P
MP
Angelone
T
T
Quintieri
A M
AM
Pulerà
E
E
Filice
E
E
Guérold
B
B
Shooshtarizadeh
P
P
Levi
R
R
Ramella
R
R
Brero
A
A
Boero
O
O
Metz-Boutigue
M H
MH
Tota
B
B
Alloatti
G
G
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*
D002316:Cardiotonic Agents; D053379:Chromogranin A; D019332:Endothelin-1; D009569:Nitric Oxide; D019869:Phosphatidylinositol 3-Kinases; D007545:Isoproterenol; D002118:Calcium