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spill-over of CAs, ET-1 and other humoral effectors. Accordingly, the cardiac,
vascular and antihypertensive properties of CST, suggest the peptide as an autocrine-
paracrine modulator that cooperates with full-length CgA and its derived VS-1 in
the multilevel processes required for cardio-circulatory homeostasis under healthy
and diseased conditions. This is opening to researches of applicative interest, as
those aimed to generate CST analogues able to mimic the cardiovascular actions of
the peptide, as in the case of the pharmacophore synthesized by Tsigelny et al.
( 2013 ). This may be of relevance to enhance the possibilities for clinical treatment
of diseases in which an altered Sympatho-Adrenal Neuroendocrine equilibrium is
accompanied by a deterioration of the cardiovascular function.
3.1 Myocardial Stretch
Recently, the cardiac actions of CST were extended to the regulation of the myocar-
dial response to stretch (i.e. the Frank-Starling mechanism) (Angelone et al. 2015 ).
It was observed that, on the isolated and Langendorff perfused heart of the normo-
tensive Wistar Kyoto (WKY) rat, CST significantly enhances the preload-induced
increases of LVP and (LVdP/dt)max. It potentiates the diastolic response, as shown
by the incremented (LVdP/dt) min. Notably, CST improves the myocardial response
to stretch (i.e. increased end-diastolic pressures). This occurs not only in normoten-
sive heart, but also in 18-months old Spontaneously Hypertensive Rats (SHR). This
is relevant since at 18 months, the SHR heart shows traits that are characteristic of
the developing HF, including depressed contractility, ventricular myocardial fibro-
sis, and reduced Frank-Starling response (Bing et al. 1995 ). In this context, the
potentiation induced by CST on the myocardial response to stretch may be advanta-
geous for the failing heart since it alleviates the functional damage, being also of
benefit against HF progression.
The mechanism of action recruited by CST in both normotensive and hyperten-
sive rat to potentiate the Frank-Starling relationship involves the Vascular
Endothelium (VE), the AkT/NOSs/NO/cGMP/PKG cascade and is accompanied by
an increment in protein S-Nitrosylation. In both WKY and SHR rats the positive
effect elicited by CST on the Frank-Starling response was abolished by the func-
tional impairment of the VE induced by perfusion with Triton X-100. Also the expo-
sure to the eNOS inhibitor, L-NAME, and the NO scavenger, PTIO, abolished CST
effects on the Frank-Starling response of normotensive WKY and hypertensive
SHR. In addition, the effect induced by CST was abolished by specific inhibition of
sGC by ODQ and was accompanied by an increase of intracellular cGMP levels.
Together with the Endocardial Endothelium, the VE is an important source of
paracrine NO produced by eNOS, while myocytes generates autocrine NO through
eNOS and nNOS located within membrane caveole, and in proximity of the SR,
respectively (Petroff et al. 2010 ; Perrelli et al. 2013 ; Hammond and Balligand
2012 ). The result is the optimization of LV systolic and diastolic functions, not only
under basal conditions, but also in response to stretch (Prendergast et al. 1997 ).
T. Angelone et al.