136
human) vertebrates. In all species examined so far, they exhibit a very high
percentage identity and share important common traits such as the sequence 50–62
(unchanged) and the disulfide bridge C17-C38 that appears crucial for their biologi-
cal activity (Helle et al. 2007 ). The main VSs consist of the highly conserved verte-
brate domain vasostatin 2 (VS-2) and the less conserved vasostatin 1 (VS-1), which
correspond to the N-terminal peptides CgA1–113 and CgA1–76, respectively.
Beside these, the shorter VS peptides CgA1–40, CgA4–57, CgA47–66 (chromofun-
gin), and CgA67–76 are also formed within the matrix of chromaffin granules and
are co-released with CAs following chromaffin cell stimulation, for example by
ACh (Metz-Boutigue et al. 1993 ) and also secreted upon stimulation of the isolated
retrogradely perfused bovine adrenal gland (Helle et al. 1993 ). N-terminal frag-
ments containing the VS-1 domain (CgA4–113, CgA1–124, CgA1–135, and
CgA1–199) have been detected in rat heart extracts, together with a larger fragment
presumably corresponding to the intact CgA, suggesting an intracardiac production
of VSs (Glattard et al. 2006 ). VSs act as multifunctional regulatory peptides which,
through autocrine, paracrine and/or endocrine mechanisms depending, among other
factors, on cell and tissue targets as well as on the local concentration of the pep-
tides, modulate several physiological processes (Helle et al. 2001 , 2007 ).
2.1 Cardiac Effects Under Basal and ISO-Stimulated
Conditions
Works performed in the last decade by our research group have indicated that VS-1,
VS-2, and the human CgA7–57 synthetic peptide can act as cardiostatins through
negative modulation of myocardial performance. By using the isolated and perfused
working heart of eel and frog, a preparation suitable for assessing the direct effects
of cardiotropic substances on myocardial performance, we observed that the human
recombinant VS-1, VS-2, and the human CgA7–57 synthetic peptide elicit an inhib-
itory modulation of the basal cardiac performance (Corti et al. 2002 , 2004 ; Imbrogno
et al. 2004 ; Tota et al. 2004 ). VS-1 and CgA7–57 appeared more potent than VS-2
as inhibitory inotropic agents, allowing to hypothesize that the region 7–57 of VS-1
contains the structural determinants for this activity. Interestingly, both in the eel
and frog heart, VSs peptides counteracted the positive inotropism elicited by the
β−adrenergic agonist isoproterenol (ISO) (Corti et al. 2004 ; Imbrogno et al. 2004 ;
Tota et al. 2004 ). Of note, these VSs–dependent cardiosuppressive and antiadrener-
gic effects resulted similar to those reported in the Langendorff perfused rat heart
(Cerra et al. 2006 ), consistent with an ubiquitous cardio-inhibitory role of VSs in
vertebrates which protect the heart by excessive excitatory stimulations. This allows
to consider VSs as components of the “zero steady-state error” counter- regulatory
homeostatic system postulated by Koeslag et al. ( 1999 ) for other CgA- derived
peptides.
A. Gattuso et al.