Catestatin (chromogranin A344-364) is a novel cardiosuppressive agent: inhibition of isoproterenol and endothelin signaling in the frog heart.
The catecholamine release-inhibitory catestatin [Cts; human chromogranin (Cg) A(352-372), bovine CgA(344-364)] is a vasoreactive and anti-hypertensive peptide derived from CgA. Using the isolated avascular frog heart as a bioassay, in which the interactions between the endocardial endothelium and the subjacent myocardium can be studied without the confounding effects of the vascular endothelium, we tested the direct cardiotropic effects of bovine Cts and its interaction with beta-adrenergic (isoproterenol, ISO) and endothelin-1 (ET-1) signaling. Cts dose-dependently decreased stroke volume and stroke work, with a threshold concentration of 11 nM, approaching the in vivo level of the peptide. Cts reduced contractility by inhibiting phosphorylation of phospholamban (PLN). Furthermore, the Cts effect was abolished by pretreatment with either nitric oxide synthase (N(G)-monomethyl-l-arginine) or guanylate cyclase (ODQ) inhibitors, or an ET(B) receptor (ET(BR)) antagonist (BQ-788). Cts also noncompetitively inhibited the positive inotropic action of ISO. In addition, Cts inhibited the positive inotropic effect of ET-1, mediated by ET(A) receptors, and did not alter the negative inotropic ET-1 influence mediated by ET(BR). Cts action through ET(BR) was further suggested when, in the presence of BQ-788, Cts failed to inhibit the positive inotropism of both ISO and ET-1 stimulation and PLN phosphorylation. We concluded that the cardiotropic actions of Cts, including the beta-adrenergic and ET-1 antagonistic effects, support a novel role of this peptide as an autocrine-paracrine modulator of cardiac function, particularly when the stressed heart becomes a preferential target of both adrenergic and ET-1 stimuli.
Mazza
Rosa
R
Department of Cell Biology, University of Calabria, Arcavacata di Rende, Italy.
Gattuso
Alfonsina
A
Mannarino
Cinzia
C
Brar
Bhawanjit K
BK
Barbieri
Sandra Francesca
SF
Tota
Bruno
B
Mahata
Sushil K
SK
D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002417:Cattle; D053379:Chromogranin A / Q000378:metabolism*; D003864:Depression, Chemical; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism*; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D011893:Rana esculenta; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013318:Stroke Volume / Q000187:drug effects; D019323:omega-N-Methylarginine / Q000494:pharmacology; D000099211:Phospholamban
D002135:Calcium-Binding Proteins; D002316:Cardiotonic Agents; D053379:Chromogranin A; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D006162:Guanylate Cyclase; D007545:Isoproterenol; D019001:Nitric Oxide Synthase; D009842:Oligopeptides; D010069:Oxadiazoles; D010446:Peptide Fragments; D010880:Piperidines; D011810:Quinoxalines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D019323:omega-N-Methylarginine; D000099211:Phospholamban; C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; C109084:chromogranin A (344-364); C086539:BQ 788