Catestatin (Cts) is a Chromogranin A-derived peptide with three identified human variants (G364S/P370L/R374Q-Cts) with different anti-hypertensive potential. Cts inhibits catecholamine release and reduces cardiac contractility.

Aims: 

Study the action of WT-Cts and its variants on rat ventricular myocardium.

Methods: 

Contractile force and Ca2+ transients were measured on papillary muscles or isolated cardiac cells (CC) in basal conditions and in the presence of b-adrenergic stimulation (ISO). NO production and eNOS phosphorylation were studied on BAE1 (Bovine Aortic Endothelial) cells. Specific blockers were used to study the role of PI3K-NO-cGMP pathway.

Results: 

In basal conditions, while ineffective at 5 nM, WT-Cts transiently enhanced myocardial contractility and Ca²⁺ transients at higher concentrations (10–50 nM). WT-Cts (5–50 nM) reduced the effect of ISO. The anti-adrenergic effect was not due to a direct action on CC, but mediated by a PI3K-dependent NO release from endocardial endothelial cells. Indeed, Cts induced Wortmannin-sensitive, Ca²⁺-independent increase of NO production and phospho-eNOS on BAE1 cells. The variant P370L-Cts, but not G364S-Cts, exerted an anti-adrenergic effect comparable to that induced by WT-Cts. Both variants, however, increased developed tension in basal conditions.

Conclusions: 

Our results suggest that the anti-adrenergic effect of Cts depends on PI3K-Akt-PeNOS pathway and that its structural alterations may cause variation in potency.