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that all the CST effects are mediated by ETBR, but not by ETAR, reinforces the
hypothesis that the peptide actions involve the ET-1 subtype receptors mainly
located on the EE. Of note, also in the rat heart, the CST cardio-suppressive action
requires the functional integrity of the EE, sustaining the EE-myocardial interaction
in the CST action (Mazza et al. 2008 ).
In the eel heart, the CST-induced cardio-depressive effects are achieved through
a pertussis toxin-sensitive (PTX) activation, independent from receptor, of Gi/o pro-
teins. In the same way, atropine pretreatment does not affect the CST response in the
eel heart, pointing to a muscarinic receptor independent effect (Imbrogno et al.
2010 ). Being CST a cationic and hydrophobic peptide, it is improbable that it
directly modulates receptors. A PTX-sensitive mechanism has been also reported by
Krüger et al. ( 2003 ) in rat mast cells where the active domain of bovine cateslytin
(CgA344–358) induced histamine release through aggregation on negatively
charged membranes (Jean-François et al. 2008 ). This alternative aggregation mech-
anism may be also hypothesized for CST even if further research is needed to
deepen this issue. In addition, in the eel heart, the CST negative inotropic action is
also mediated by β1/β2/β3-adrenergic receptors and involves a NO-cGMP-
dependent mechanism (Table 1 ). Of note, in the rat, the negative inotropic and lusi-
tropic effects induced by CST involve both β2/β3-ARs, with a higher affinity for the
first one, but not β1-AR, while they are reduced by α-AR and unaffected by cholin-
ergic receptors inhibition also recruiting a PI3K/Akt/eNOS/NO/cGMP-dependent
mechanism (Angelone et al. 2008 ).
3.3 Effects Under Loading Stimulated Conditions
The Frank–Starling’s law (intrinsic regulation) operates in all classes of vertebrates.
It varies among vertebrates particularly between mammalian and amphibian/fish
species, the latter showing an elevated sensitivity to the heterometric response in
part ascribed to a greater extensibility of the thin myocardial trabeculum (Shiels and
White 2008 ). While cardiac output in fish and amphibians is increased, to a large
extent, by changing the volume of blood pumped by the heart, in mammals it is
modulated by increasing the heart rate rather than volume. As largely shown, the
Frank-Starling response is modulated by many endogenous and exogenous sub-
stances. Haemodynamic forces, such as stretch, can activate major cardiac homeo-
metric autoregulatory mechanisms that include autocrine and paracrine molecules
released from endothelial/endocardial cells and cardiac myocytes that modulate
myocytes contractility. The importance of this control has been firstly emphasized
by the discovery that the cardiac natriuretic peptides adapt myocardial contractility
and relaxation in a stretch-dependent manner (de Bold et al. 1981 ). This scenario
was further expanded by the role that the stretch-induced release of Nitric Oxide
from cardiomyocytes, vascular, and endocardial cells, exerts on pumping perfor-
mance enhancing the Frank–Starling response (Prendergast et al. 1997 ; Imbrogno
et al. 2001 ; Garofalo et al. 2009 ; Mazza et al. 2012 ). More recently, studies both in
A. Gattuso et al.