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It is already widely known that the different brain areas involved in blood pressure control, are highly vulnerable to the deleterious effects of this condition. Of particular concern are hypertensive and neuroinflammatory-dependent injuries that by modifying blood flow account for artery structural and functional alterations. It was thus our intention to establish if expression changes of some key brain neuroinflammatory factors like caspase-1,3, NF-kB, IL-1β and NLRP3, which are known to control blood pressure, are actively involved with inflammation regulatory events in a highly valuable spontaneously hypertensive rat (SHR) model. Indeed, notably increased (p 0.001) caspase-1, NLRP3 and IL-1β mRNA levels were detected in amygdalar plus hypothalamic areas of SHR. Contextually, similar up-regulated levels of these factors were also reported in brainstem nuclei with respect to the few hippocampal areas. This trend was supported by moderate increases (p 0.05) of NLRP3 in amygdalar and brainstem sites, while notably greater expression differences of NF-kB protein were observed in hippocampal and hypothalamic areas of SHR. At the same time, moderately increased levels of iNOS were typical of all of the above brain areas with the exception of the consistently (p 0.01) increased levels featured in the brainstem. Moreover, even immunohistochemical evaluations supplied notably and moderately increased cleaved caspase-3 cell levels in hippocampus and hypothalamus areas, respectively. Overall, evident hypertensive bouts correlated to neuroinflammatory events, especially in brain areas controlling blood pressure, tend to underlie the value of novel therapeutic approaches designed to improve brain blood flow and subsequently reduce hypertensive-dependent cerebral complications.

Since the discovery of Nesfatin-1 in 2006, intensive research was finalized to further and deeper investigate the precise physiological functions of the peptide at both central and peripheral levels, rapidly enriching the knowledge regarding this intriguing molecule. Nesfatin-1 is a hypothalamic peptide generated via the post-translational processing of its precursor Nucleobindin 2, a protein supposed to play a role in many biological processes thanks to its ability to bind calcium and to interact with different intracellular proteins. Nesfatin-1 is mainly known for its anorexic properties, but it also controls water intake and glucose homeostasis. Recent experimental evidences describe the peptide as a possible direct/indirect orchestrator of central and peripheral cardiovascular control. A specific Nesfatin-1 receptor still remains to be identified although numerous studies suggest that the peptide activates extra- and intracellular regulatory pathways by involving several putative binding sites. The present paper was designed to systematically review the latest findings about Nesfatin-1, focusing on its cardiovascular regulatory properties under normal and physiopathological conditions. The hope is to provide the conceptual basis to consider Nesfatin-1 not only as a pleiotropic neuroendocrine molecule, but also as a homeostatic modulator of the cardiovascular function and with a crucial role in cardiovascular diseases.

The myocardial response to mechanical stretch (Frank-Starling law) is an important physiological cardiac determinant. Modulated by many endogenous substances, it is impaired in the presence of cardiovascular pathologies and during senescence. Catestatin (CST:hCgA352-372), a 21-amino-acid derivate of Chromogranin A (CgA), displays hypotensive/vasodilatory properties and counteracts excessive systemic and/or intra-cardiac excitatory stimuli (e.g., catecholamines and endothelin-1). CST, produced also by the myocardium, affects the heart by modulating inotropy, lusitropy and the coronary tone through a Nitric Oxide (NO)-dependent mechanism. This study evaluated the putative influence elicited by CST on the Frank-Starling response of normotensive Wistar-Kyoto (WKY) and hypertensive (SHR) hearts by using isolated and Langendorff perfused cardiac preparations. Functional changes were evaluated on aged (18-month-old) WKY rats and SHR which mimic human chronic heart failure (HF). Comparison to WKY rats, SHR showed a reduced Frank-Starling response. In both rat strains, CST administration improved myocardial mechanical response to increased end-diastolic pressures. This effect was mediated by EE/IP3K/NOS/NO/cGMP/PKG, as revealed by specific inhibitors. CST-dependent positive Frank-Starling response is paralleled by an increment in protein S-Nitrosylation. Our data suggested CST as a NO-dependent physiological modulator of the stretch-induced intrinsic regulation of the heart. This may be of particular importance in the aged hypertrophic heart, whose function is impaired because of a reduced systolic performance accompanied by delayed relaxation and increased diastolic stiffness.

The length-active tension relation or heterometric regulation (Frank–Starling mechanism) is modulated by nitric oxide (NO) which, released in pulsatile fashion from the beating heart, improves myocardial relaxation and diastolic distensibility. The NO signaling is also implicated in the homeometric regulation exerted by extrinsic factors such as autonomic nervous system, endocrine and humoral agents. In the in vitro working frog heart, the Chromogranin A (CGA)-derived peptide, Catestatin (CTS; bovine CGA344–364), exerts a direct cardio-suppressive action through a NOS–NO–cGMP-mediated mechanism which requires the functional integrity of the endocardial endothelium (EE) and its endothelin-1 B type (ETB) receptor. However, functional interplay between NO and CTS and their role in the Frank–Starling response of the frog heart are lacking. Here we show that CTS improves the sensitivity to preload increases similar to that exerted by NO. This effect is abolished by inhibition of NO synthase (L-NAME), guanylate cyclase (ODQ), protein kinase G (KT5823), PI3K (Wortmannin), as well as by the functional damage of EE (Triton X-100) suggesting that CTS operates through an EE-dependent NO release. On the whole, the use of the avascular frog heart revealed the EE as major sensor–transducer interface between the physical (volume load) and chemical (CTS) stimuli, NO functioning as a connector between heterometric and homeometric regulation.

β3-Adrenergic receptors (ARs) have been recently identified in mammalian hearts where, unlike β1- and β2-ARs, induce cardio-suppressive effects. The aim of this study was to describe β3-AR role in the frog ( Rana esculenta ) heart and to examine its signal transduction pathway. The presence of β3-AR, by using Western blotting analysis, has been also identified. BRL 37344 , a selective β3-AR agonist, induced a dose-dependent negative inotropic effect at concentrations from 10 −12 to 10 −6 M. This effect was not modified by nadolol (β1/β2-AR antagonist) and by phentolamine (α-AR antagonist), but it was suppressed by the β3-AR-specific antagonist SR 59230 and by exposure to the Gi/o proteins inhibitor Pertussis Toxin. In addition, the involvement of EE-NOS-cGMP-PKG/PDE2 pathway in the negative inotropism of BRL 37344 has been assessed. BRL 37344 treatment induced eNOS and Akt phosphorylation as well as an increase of cGMP levels. β3-ARs activation induce a non-competitive antagonism against ISO stimulation which disappeared in presence of PKG and PDE2 inhibition. Taken together our findings provide, for the first time in the frog, a role for β3-ARs in the cardiac performance modulation which involves Gi/o protein and occurs via an EE-NO-cGMP-PKG/PDE2 cascade.