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This Article Full Text Full Text (PDF) All Versions of this Article: 295/1/H113    most recent 00172.2008v2 00172.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Mazza, R. Articles by Mahata, S. K. PubMed PubMed Citation Articles by Mazza, R. Articles by Mahata, S. K.

Catestatin (chromogranin A_344-364) is a novel cardiosuppressive agent: inhibition of isoproterenol and endothelin signaling in the frog heart

¹Department of Cell Biology, University of Calabria, Arcavacata di Rende, Italy; and ²Department of Medicine, University of California and Veterans Affairs San Diego Healthcare System, San Diego, California

Submitted 18 February 2008 ; accepted in final form 2 May 2008

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 β-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 β-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.

chromogranin A; myocardial contractility; inotropic agents; avascular heart; endocardial endothelium