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The influence exerted by CST on the Frank-Starling response of both normotensive
Wistar Kyoto and hypertensive rat hearts was evaluated in a recent study (Angelone
et al. 2015 ). In both rat strains, CST administration improved myocardial mechani-
cal response to increased end-diastolic pressures, shifting to left the Frank–Starling
curve. This effect of CST involved the vascular endothelium and required the activa-
tion of the AKT/NOS/NO/cGMP/PKG cascade. As suggested by the Authors of this
study, the parallel increase of myocardial protein S-Nitrosylation may explain the
apparent contradiction of this finding with the previously described negative inotro-
pic effect of CST. Indeed, it has been shown that, in the mammalian heart, among
several targets, S-Nitrosylation modulates RyR channels in the sarcoplasmic reticu-
lum, as well as potassium channels and L-type calcium channels at the plasma
membrane level (Hess et al. 2005 ), thus importantly influencing calcium cycling
and contractility. The finding that CST is able to modulate the stretch- induced
intrinsic regulation of the heart, suggests that this peptide may play an important
role in the aged hypertrophic heart, whose function is impaired because of a reduced
systolic performance accompanied by delayed relaxation and increased diastolic
stiffness.
Further studies showed that, besides mammalian heart, CST also functions as an
important negative modulator of heart performance in frog (Mazza et al. 2008 ) and
eel heart (Imbrogno et al. 2010 ). In the frog heart, CST dose-dependently decreased
stroke volume and stroke work, and reduced the positive inotropic effect induced by
Iso or ET-1; the threshold concentration was 11 nM, a value comparable to the cir-
culating levels of this peptide (∼2–4 nM). By using pharmacological blockers,
Mazza et al. ( 2008 ) showed that CST effects were due to NOS, guanylate cyclase
(GC) and ET(B) receptor activation, as well as phospholamban (PLN)
phosphorylation.
In the eel heart, CST was able to reduce both basal contractility and the positive
inotropic response induced by β-adrenergic stimulation. In addition, CST induced a
significant increase of the Frank–Starling response, which was blocked by L-NMMA
and thapsigargin, but independent from GC (Imbrogno et al. 2010 ). Taken together,
these reports indicated that in both frog and fish, CST is able to modulate myocardial
performance under basal, as well as under increased preload, conditions, and counter-
acts the adrenergic-mediated positive inotropism, thus strikingly supporting the evo-
lutionary significance and establishing the cardiomodulatory role of this peptide.
2.3 Chromofungin
Chromofungin (CgA47–66) is a CgA-derived peptide implicated in inflammation
and innate immunity, displaying antimicrobial activities and activating neutrophils.
The effects of Chr have been recently tested on the isolated Langendorff perfused
rat heart (Filice et al. 2015 ). Under basal conditions, Chr induced dose-dependent
G. Alloatti and M.P. Gallo