14 4
cardiac counter-regulators under intense excitatory stimuli (e.g. CA-induced myo-
cardial stress).
In particular, while in the eel the VS-1-elicited negative inotropism implicates
the functional involvement of β-ARs receptors, as well as a PTX sensitive
G-protein-NO–cGMP–PKG pathway, in the frog heart its cardio-inhibition is unaf-
fected by both adrenergic receptor and G proteins inhibition and recruits a
NO-independent pathway. Furthermore, in both species, the structure-function rela-
tionships analysis of several sequences of VS-1 reveals the importance of highly
conserved domains and functionally important regions.
In both fish and frog hearts, the heterometric regulation of cardiac function
(Frank-Starling response) was positively affected by CST through an EE-induced
NO release. Moreover, the evidence that CST-induced effect on the Frank-Starling
response is of the same magnitude of that induced by NO, strongly supports the idea
that CST contributes to the intrinsic regulation of the vertebrate heart by functioning
as an endogenous NOS activator. In this context, the comparative analysis of CgA-
derived peptides cardioactivity in fish and frog, characterized by different ventricu-
lar myoangioarchitecture (avascular heart: frog; poorly vascularized heart: eel), has
been helpful to identify the EE-myocardial interactions underpinning VSs and CST
actions.
Furthermore, in addition to its antiadrenergic action, in the frog heart CST acts
as a direct cardiac modulator under ET-1 stimulation, suggesting a role in the
homeostatic counteraction not only against excessive SAN activation, but also
against hypertensive cardiomyopathy, as established in mammalian counterpart
(Angelone et al. 2008 ).
Looking toward mammalian vertebrates, CST dose-dependently increases coro-
nary pressure and abolishes the ISO-dependent vasodilation under basal conditions,
while it potently vasodilates the ET-1 preconstricted coronaries (Angelone et al.
2008 ), thus reinforcing previous evidence of vasodilation promoted by both endog-
enous and exogenous CST in human subjects (O’Connor et al. 2002 ; Fung et al.
2010 ). Of note, also the native (rat) CgA 1–64 (rCgA1–64), corresponding to human
VS-1 (Metz-Boutigue et al. 1993 ) is able to counteract ET-1-elicited positive con-
tractility in rat, as well as the ET-1-induced coronary constriction (Cerra et al. 2006 ).
Finally, VS-1 and CST are able to mediate cardioprotective effects, primarily
through a direct action on the myocardium, rather than endothelium-mediated
effects. The comparison of the cardioprotective effects of VS-1 and CST in ischemic
conditioning highlights, at the same time, a remarkable similarity and subtle differ-
ence, VS-1 appearing as a pre-conditioning inducer while CST emerging as a post-
conditioning agent (Penna et al. 2012 ).
In conclusion, the experimental evidence regarding VS-1 and CST as cardio-
circulatory homeostatic stabilizers makes wider the view of the neurovisceral con-
trol of the heart, particularly in relation to the concept of counter-regulatory
hormones in “zero steady-state error” homeostasis elaborated by Koeslag et al.
( 1999 ). At the same time, the use of fish and amphibian paradigms adds a new piece
to the expanding puzzle of neuroendocrine control of cardiac function both under
basal and stress conditions, allowing to illustrate how these neuro-endocrine agents
A. Gattuso et al.