116
(Cerra et al. 2008 ), Catestatin (CST), a catecholamine (CA) release inhibitor with
antihypertensive and cardioprotective properties (Angelone et al. 2008 ; Penna
et al. 2010 ), and Serp, a sympathomimetic cardiostimulating peptide (Tota et al.
2012 ). With reference to the focus of this chapter, we will illustrate the physio-
pharmacologic cardiovascular properties of these CgA-derived peptides, as well
as the molecular cascades that they recruit to modulate the mammalian heart per-
formance under basal conditions and in relation to other endocrines, such as CA
and Endothelin-1 (ET-1).
2 Vasostatin-1 as Cardiac Stabilizer
CgA cleavage of at the N- terminus generates fragments of different length, collec-
tively known as Vasostatins (VSs) because of their ability to relax vascular smooth
muscle pre-contracted by Endothelin-1 (Aardal et al. 1993 ). Studies from our
research group showed on several animal models (rat, frog and eel) that VSs [VS-1:
human recombinant (hr) CgA1-78 (hrVS-1), rat CgA1-64; Vasostatin-2 (hrCgA1-
115: hrVS-2)] influence heart performance. The isolated and Langendorff perfused
rat heart was also used to better describe the influence of VSs on myocardial con-
tractility and relaxation. It was found that hrVS-1 (containing the rat CgA1-76
sequence) acts as a negative inotrope which reduces contractility and cardiac work
in a dose (11–165 nM)-dependent manner (Cerra et al. 2006 ). These effects are
shown by the decreased left ventricular pressure (LVP) and rate pressure product
(RPP: HR × LVP), indexes of contractility and work, respectively. In addition, the
peptide depresses myocardial relaxation (negative lusitropic effects), by dose-
dependently decreasing the maximal rate of the left ventricular pressure decline
[(LVdP/dt)min], the half time relaxation (HTR), and T/-t ratio obtained by (LVdP/
dt)max/(LVdP/dt)min (Pieroni et al. 2007 ). Of note, cardiodepression is indepen-
dent from coronary vasomotility, since the administration of the CgA fragment
unaffected Coronary Pressure (CP). Comparable, although less potent, myocardial
effects are induced by hrVS-2 that, however, increased CP at 110 and 165 nM (Cerra
et al. 2006 ).
In parallel with the basal negative inotropic and lusitropic effects, VSs counter-
act the positive inotropism induced by activation of β-adrenergic receptors (β-ARs)
by Isoproterenol (ISO) without modifying the β-AR-dependent coronary dilation.
This counterbalancing action occurs via a non-competitive type of antagonism, as
shown by the percentage of RPP variations evaluated in terms of EC50 values of
ISO alone and in presence of hrVS-1 (Cerra et al. 2006 ). The role of VSs as car-
diodepressive peptides in the presence also of adrenergic stimulation is corrobo-
rated by evidence obtained by exposing the ex vivo perfused rat heart and papillary
muscles to the highly conserved (Metz-Boutigue et al. 1993 ; Helle et al. 2007 )
N-terminal native (rat) CgA1-64 (rCgA1-64) fragment (Cerra et al. 2008 ). The pep-
tide, at concentrations from 33 to 165 nM, similar to those of the precursor CgA in
human serum (normal levels: 0.5–4 nM, neuroendocrine tumors and last stages of
T. Angelone et al.