141counteraction against excessive SAN activation, e.g., prolonged stress, HF, hyper-
tensive cardiomyopathy (Angelone et al. 2008 ).
The CST-induced cardiosuppressive and anti-adrenergic effects observed in eel
and frog resulted comparable to those elicited by VSs both in mammalian and non
mammalian vertebrates (Tota et al. 2004 ). The biological significance of such appar-
ently redundant molecular strategy remains to be clarified. Conceivably, processing
more than one cardioactive peptide from the same prohormone might be advanta-
geous in maintaining homeostasis. It can be hypothesized that, by acting on overlap-
ping or different sites, VS-1 and CST may achieve selective intracardiac actions in
a spatiotemporal and tissue-specific manner (e.g. summation and synergism or
potentiation of the target cell responses). A similar cardiovascular case is repre-
sented by the proteolytic cleavage of proANF precursor that in mammals gives rise
to the major form of circulating ANP (ANP1–28) and several biologically active
peptides (proANF1–30, long-acting sodium stimulator; proANF31–67, vessel dila-
tor; and proANF79–98, kaliuretic stimulator) (Vesely et al. 1994 ). At least two of
them, i.e. vessel dilator and ANP, show almost overlapping properties, being vaso-
dilatory, diuretic, and natriuretic (Vesely 2006 ). The examples provided by both
CgA and proANF illustrate the striking cardiac potential for multilevel interactions
between endocrine precursors and their derived peptides.
3.2 Mechanism of Action
In the frog heart, the CST cardiosuppressive action appears EE-NOS/NO/cGMP-
dependent, being abolished by functional EE damage with Triton X-100 and pre-
treatment with NOS or guanylate cyclase inhibitors. Of note, this contrasts with the
VS-1-induced negative inotropism in the frog heart, which, unlike the pattern dem-
onstrated in eel and rat hearts (Imbrogno et al. 2004 ; Cappello et al. 2007 ), involved
neither the EE nor the G protein nor the NO-cGMP-protein kinase G mechanism
(Corti et al. 2004 ). The question as to how and why the two peptides, representing
NH 2 -and COOH-terminal domains of CgA, respectively, utilize divergent signaling
pathways to converge on similar cardiotropic actions, remains open.
Moreover, in the frog heart, the CST negative inotropism is mediated by ETB
receptor (ETBR) subtype, mainly expressed in endothelial cells and linked to eNOS
phosphorylation and NO synthesis, but not by ETAR (mostly expressed in cardio-
myocytes), thus emphasizing the paracrine role of EE in regulating the contractility
of the subjacent myocardium (Mazza et al. 2008 ). This role appears of particular
importance in the frog heart, where the EE lining the very extensive lacunae of the
avascular spongy ventricle represents a relevant source of bioactive NO (Sys et al.
1997 ; Gattuso et al. 1999 ; Mazza et al. 2010 , 2012 , 2013 ). The crucial role of ETBR
in the CST signaling is further supported by the evidence that, in the presence of its
selective inhibition, CST fails to inhibit both the ISO-and ET-1-elicited positive
inotropic effects as well as its inhibitory and stimulatory effects on phospholamban
(PLN) and ERK1/2 phosphorilation, respectively (Mazza et al. 2008 ). The finding
Comparative Aspects of CgA-Derived Peptides in Cardiac Homeostasis