1614.1 Histamine
The potent vasodilator action of CST in rats has been explained as due to the release
of the vasodilator histamine from mast cells and H 1 receptors stimulation (Kennedy
et al. 1998 ). The most active N-terminal domain of CST (bCgA344–358:
RSMRLSFRARGYGFR) caused a concentration-dependent (0.01–5 μM) release
of histamine from peritoneal and pleural mast cells. CST is a very potent activator
of histamine release, more active even than the wasp venom mastoparan and the
neuropeptide substance P. Interestingly, CST stimulation of histamine release from
rat mast cell appears to be due to the same mechanism shared by mastoparan and
other cationic charged neuropeptides. The blocking effect of PTX suggested the
involvement of a Gi subunit in CST- evoked histamine release (Kruger et al. 2003 ).
To investigate the mechanism involved in the early positive inotropic effect of CST,
we performed experiments in which rat papillary muscles were pretreated with
mepyramine, a pharmacological blocker of H 1 histamine receptors. Indeed, it has
been shown that the positive inotropic effect of histamine on rat ventricular myocar-
dium (Hattori 1999 ) is due to the activation of H 1 histamine receptors, which are
abundantly expressed in this tissue (Matsuda et al. 2004 ). The fact that H 1 histamine
receptors blockade with mepyramine completely abrogated the early transient
increase of contractile force induced by CST, strongly suggests that this effect is due
to histamine release, possibly from mast cells present within cardiac tissue and car-
diac H 1 receptors activation (Bassino et al. 2011 ).
4.2 ANP, BNP and TNFα
In the rat heart, immunohistochemical evidences showed the co-localization of CgA
and atrial natriuretic peptide (ANP) in nonadrenergic myoendocrine atrial cells
(Steiner et al. 1990 ). In patients with chronic heart failure, while CgA plasma level
does not correlate with hormones such as catecholamines, vasopressin, endothelins
and components of the renin–angiotensin system (Nicholls et al. 1996 ), it correlates
with the levels of tumour necrosis factor (TNF)α and TNFα receptors (Corti et al.
2000 ), and with the levels of brain natriuretic peptide (BNP) (Pieroni et al. 2007 ). It
has been shown that CgA colocalizes with BNP in biopsies from patients with
dilated cardiomyopathy and hypertrophic myopathy (Pieroni et al. 2007 ). It seems
therefore that CgA circulating levels in chronic heart failure reflect myocardial
inflammation and distension, more than neuroendocrine autonomic activation.
The fact that CgA-derived peptides, natriuretic peptides (Costa et al. 2000 ) and
TNFα (Alloatti et al. 1999 ) can stimulate endothelial cells to produce NO, which in
turn diffuses to cardiac cells, reinforces the hypothesis that NO represents a key
signal molecule on which CgA-derived and other peptide mediators converge, and
Signalling Pathways of CgA-Derived Peptides in Cardiac and endothelial cells