143mammalian and non-mammalian vertebrates have provided evidence that CST, by
functioning as an endogenous NOS activator, also contributes to the humoral regu-
lation of the heterometric response (Imbrogno et al. 2010 ; Mazza et al. 2012 ;
Angelone et al. 2015 ).
In the frog heart, Mazza and co-workers ( 2012 ) demonstrated that CST posi-
tively modulates the heterometric response through an EE-dependent NO release
which involved a PI3K–NOS–cGMP pathway confirming, also under stretch condi-
tions, CST as a paracrine stimulus for NO release from EE. This effect appears
mediated by ETBR since it is blocked by BQ788 but not by BQ123. The evidence
that CST-induced effect on the Frank-Starling response was of the same magnitude
of that induced by NO, strongly supports the idea that CST contributes to the endo-
crine/paracrine regulation of the heterometric response of the vertebrate heart by
functioning as an endogenous NOS activator. This view is also reinforced by the
evidence obtained in the eel heart in which, mimicking the NO modulation, CST
improves the Frank–Starling response (Imbrogno et al. 2010 ; Garofalo et al. 2009 ),
as supported by the increased p-eNOS expression in CST-treated hearts (Table 1 ). A
reduction of the cardiac response to preload was observed after NOS, but not gua-
nylate cyclase, inhibition suggesting an action mechanism dependent on NO but
independent on its classical cGMP signaling. Of note, the CST-induced increase of
the heterometric response was significantly reduced by inhibition of SERCA2a
pumps (Imbrogno et al. 2010 ), indicating that CST-induced NO release directly
regulates SR Ca2+ reuptake.
On the basis of these data it appears that exogenous CST, acting as a paracrine
stimulus for NO release, is able to modulate cardiac function under both basal and
stretch hemodynamic conditions.
4 Cardiac CST and VSs Profiles
Summarizing work from the last decade, here we have documented in a compara-
tive context, the cardiotropic features of CgA-derived peptides (VS and CST) on eel
and frog hearts used as bioassays of non mammalian vertebrates, also highlighting
aspects of uniformity and species-specific diversity in the cardiotropism of VSs and
CST. Apart from the antihypertensive profile of CST, all peptides induce intrinsic
negative inotropy and counteract the β-adrenergic-mediated positive inotropism
exerted by isoproterenol, which might be important under sympathetic
overstimulation conditions (Table 1 ).
It is of relevance that both in eel and frog heart the minimally effective peptide
concentrations match with the nanomolar range corresponding to the circulating
level of CgA normally found in man. In an integrated perspective, this points to VSs
and CST as components of a wider orchestration of their precursor CgA in regulat-
ing circulatory homeostasis. In this context, CgA and its derived peptides, VSs and
CST, appear as new players in the scenario of the endocrine heart, functioning as
Comparative Aspects of CgA-Derived Peptides in Cardiac Homeostasis