139cytoskeleton as an important determinant of the signal-transduction cascade which
underlies the inhibitory influence exerted by VSs on the contractile myocardial
machinery (Mazza et al. 2007 ). In both eel and frog heart preparations, the treat-
ment with pertussis toxin (PTx), a toxin which uncouples signal transduction
between several families of receptors and Gi or Go proteins (Ai et al. 1998 ), did not
modify basal cardiac performance; however, it abolished the inotropic effect of VSs
in the eel heart (Imbrogno et al. 2004 ), without influencing it in the frog heart (Corti
et al. 2004 ). So far, except for CST, which is known to interact with nicotinic recep-
tors, functioning as a non-competitive antagonist (Mahata et al. 1997 ; Kraszewski
et al. 2015 ), no conclusive evidence is available concerning the presence of specific
receptors for CgA fragments, including VS peptides. Therefore, whether VSs act on
the heart via classic receptor-ligand interactions still remains to be elucidated. Apart
from specific receptor interactions, in the eel heart VSs could activate G proteins
through spatially localized cell membrane perturbation caused by the interaction of
the lipophylic portion of the peptide with a lipidic bilayer domain. Indeed, such a
mechanism was suggested to explain the antimicrobic action of some VS-derived
fragments (Lugardon et al. 2002 ; Maget-Dana et al. 2002 ). Conceivable, VS pep-
tides might exert their action, including the myocardial inotropic effects, by modu-
lating the activities of signalling principles, regulatory proteins, such as ion channels,
and cell membrane elements, implicated in the regulation of intercellular communi-
cation. Aspects of diversity have been also reported in relation to the involvement of
cholinergic and adrenergic systems in the determinism of VSs induced cardiosup-
pression. In fact, in the eel heart, pretreatments with either atropine (a non-specific
muscarinic antagonist) or phentolamine and propanolol (α and β adrenergic antago-
nists, respectively), which per se do not modify basal cardiac parameters, abolish
the VSs-mediated inotropism (Imbrogno et al. 2004 ); in contrast, in the frog heart
the VS-induced negative inotropism is unchanged by these treatments (Corti et al.
2004 ). This different response pattern between teleost and amphibian hearts is also
revealed by the involvement of the endocardial endothelium (EE) and the Nitric
Oxide (NO)-cGMP signal-transduction pathway. While in the eel heart both the EE
and the NO-cGMP signaling transduce the intracavitary VSs signal to the beating
myocardium (Imbrogno et al. 2004 ), in the frog heart, neither the EE nor the
NO-cGMP mechanism appear relevant for eliciting the VSs negative effect (Corti
et al. 2004 ). These differences in the transduction pathways in frog vs eel heart may
be explained by species-specific differences (from ultrastructural to biochemical
and molecular levels), which may affect peptide binding, internalization, trans-
endocardial transport, etc. For example, scavenger receptors have been character-
ized in the EE of the teleost heart (Seternes et al. 2001 ). Thus, it can be hypothesized
that in teleost blood-borne endoluminal VS peptides interact with scavenger recep-
tors, thereby triggering an EE-mediated mechanism, which in turn affects myocar-
dial inotropy (Table 1 ).
Comparative Aspects of CgA-Derived Peptides in Cardiac Homeostasis