123of a sophisticated double switched counter regulation induced by CST against
cardiac beta-adrenergic effects.
In the heart, PLN controls sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) by
a phosphorylation/dephosphorylation mechanism. Dephosphorylated PLN inhibits
SR Ca2+ sequestration via SERCA2a (Reddy et al. 1999 ), while PLN, phosphory-
lated at Ser16 by PKA, relieves its inhibition on SERCA2a (Schmidt et al. 2001 ). In
addition to phosphorylation, PLN may be S-nitrosylated. This influences stretch-
induced contractile effects on the myocardium (see Garofalo et al. 2009 ).
Accordingly, S-nitrosylated PLN represents a selective downstream target of the
NO release induced by CST, which contributes to the modulation of inotropy and
lusitropy by regulating SR Ca2+ fluxes and Ca2+ availability for the contractile
apparatus.
Another trait of the signal-transduction mechanism activated by CST and its
variants was described by Bassino et al. ( 2011 ) by measuring Ca2+ transients and
myocardial contractility on isolated cardiomyocytes and papillary muscles,
respectively. On BAE-1 cells they also evaluated, the effects of CST NO produc-
tion and eNOS phosphorylation at Ser 1179 (PSer1179eNOS) showing that CST
(5–50 nM) reduces in a dose-dependent manner the effects of beta-adrenergic
stimulation. Since CST induces a Wortmannin-sensitive, Ca2+-independent
increase of NO production and PSer1179eNOS, it is presumable that the effects of the
peptide are due to a NO release from endocardial endothelial cells, rather than to
a direct myocardial action.
Similar to the wild-type peptide, P370L-CST, but not G364S-CST, induces an
anti-adrenergic action and stimulates NO release (Angelone et al. 2008 ).
Interestingly, the Ca2+-independent, caveolae-dependent activation of the Akt-PI3K-
eNOS pathway elicited by CST is similar to that suggested for the negative ino-
trope, anti-adrenergic N-terminal VS-1 (Ramella et al. 2010 and references therein),
highlighting common features in the cellular mechanisms regulated by these CgA
fragments.
As shown on the rat heart, CST induces a coronary modulation. This coronary
activity is non-univocal. Under basal conditions, the peptide dose-dependently
increases CP (maximum response at 200 nM) and abolishes the ISO-dependent
vasodilation. Contrarily, but in line with the vasodilation observed in humans after
CST administration (Fung et al. 2010 ), it potently dilates coronary vessels pre-
constricted by ET-1 (Angelone et al. 2008 ). The cross-talk ET-1/CST, corroborated
also by studies carried out on the frog heart (Mazza et al. 2012 ), together with the
interaction with β adrenoceptors, is consistent with a CST signalling mechanism
which starts at the plasma membrane before to converge on the sympatho-inhibitory
NO pathway (Fig. 3 ).
The data here illustrated, together with those reported on other chapters of this
volume, propose the negative effects induced by CST on myocardial contractility
and relaxation, as well as its coronary vasomotion, as relevant components of the
mechanisms that sustain the homeostatic counteraction against sympathetic
over- activation. This is a peculiar trait of conditions (e.g., prolonged stress, HF,
hypertensive cardiomyopathy, etc.) which are characterized by a potentially harmful
Cardiac Physio-Pharmacological Aspects of Three Chromogranin A-Derived Peptides...