Cirrhosis is associated with cardiovascular abnormalities. Scanty information is available as to whether these include left ventricle diastolic dysfunction and wall thickness increase. To this aim in 27 cirrhotic patients with tense ascites, 17 cirrhotic patients with previous episodes of ascites (not actual), and 11 controls we investigated by echocardiography and echocolor Doppler left ventricle diastolic function (E wave, A wave, E/A ratio, deceleration time of E wave), systolic function (ejection fraction), and wall thickness (left ventricle posterior wall thickness + interventricular septum thickness) along with neurohumoral variables. All measurements (supine position) were repeated after total paracentesis (10.7 +/- 0.6 L of ascites) in ascitic patients. Both in patients with and without ascites E/A ratio was reduced as compared with controls (0.93 +/- 0.07 and 0.97 +/- 0.06 vs. 1.18 +/- 0.08, P < .05) while left ventricle wall thickness was increased (18.6 +/- 0.6 and 20.1 +/- 0.8 vs. 17.2 +/- 0.7, P < .05 and P < .01, respectively), irrespective of the postviral or alcoholic cause of liver disease. In all cirrhotics both right and left atrial and right ventricle diameters were significantly greater. Ejection fraction was slightly but significantly (P < .01) reduced in ascitic patients. Paracentesis induced a reduction of the highly increased basal plasma renin activity, aldosterone, norepinephrine (P < .01), and epinephrine (P < .05) and improved diastolic function (E/A, P < .05). Systolic function was unaffected. Thus, irrespective of ascites and cause, advanced cirrhosis is associated with left ventricle diastolic dysfunction and wall thickness increase. We can speculate that neurohumoral overactivity, known to stimulate cardiac tissue growth, may challenge the heart, promoting fibrosis and exerting a further hindrance to ventricular relaxation in patients with cirrhosis experiencing episodes of ascites.

In males, hypertension is characterized by a higher prevalence of increased iron stores and metabolic abnormalities that are part of the IRHIO syndrome. This finding may have clinical implications due to the increased risk of IRHIO patients to develop hepatic cirrhosis and also for the role of iron in early atherogenesis.

The urokinase‐type plasminogen activator (uPA) receptor (uPAR) participates to the mechanisms causing renal damage in response to hyperglycaemia. The main function of uPAR in podocytes (as well as soluble uPAR ‐(s)uPAR‐ from circulation) is to regulate podocyte function through αvβ3 integrin/Rac‐1. We addressed the question of whether blocking the uPAR pathway with the small peptide UPARANT, which inhibits uPAR binding to the formyl peptide receptors (FPRs) can improve kidney lesions in a rat model of streptozotocin (STZ)‐induced diabetes. The concentration of systemically administered UPARANT was measured in the plasma, in kidney and liver extracts and UPARANT effects on dysregulated uPAR pathway, αvβ3 integrin/Rac‐1 activity, renal fibrosis and kidney morphology were determined. UPARANT was found to revert STZ‐induced up‐regulation of uPA levels and activity, while uPAR on podocytes and (s)uPAR were unaffected. In glomeruli, UPARANT inhibited FPR2 expression suggesting that the drug may act downstream uPAR, and recovered the increased activity of the αvβ3 integrin/Rac‐1 pathway indicating a major role of uPAR in regulating podocyte function. At the functional level, UPARANT was shown to ameliorate: (a) the standard renal parameters, (b) the vascular permeability, (c) the renal inflammation, (d) the renal fibrosis including dysregulated plasminogen‐plasmin system, extracellular matrix accumulation and glomerular fibrotic areas and (e) morphological alterations of the glomerulus including diseased filtration barrier. These results provide the first demonstration that blocking the uPAR pathway can improve diabetic kidney lesion in the STZ model, thus suggesting the uPA/uPAR system as a promising target for the development of novel uPAR‐targeting approaches.

Histaminergic neurons are exclusively located in the hypothalamic tuberomammillary nucleus, from where they project to many brain areas including the nucleus accumbens (NAc), a brain area that integrates diverse monoaminergic inputs to coordinate motivated behaviours. While the NAc expresses various histamine receptor subtypes, the mechanisms by which histamine modulates NAc activity are still poorly understood. Using whole‐cell patch‐clamp recordings, we found that pharmacological activation of histamine 2 (H2) receptors elevates the excitability of NAc medium spiny neurons (MSNs), while activation of H1 receptors failed to significantly affect MSN excitability. The evoked firing of MSNs increased after seconds of local H2 agonist administration and remained elevated for minutes. H2 receptor (H2R) activation accelerated subthreshold depolarization in response to current injection, reduced the latency to fire, diminished action potential afterhyperpolarization and increased the action potential half‐width. The increased excitability was protein kinase A‐dependent and associated with decreased A‐type K+ currents. In addition, selective pharmacological inhibition of the Kv4.2 channel, the main molecular determinant of A‐type K+ currents in MSNs, mimicked and occluded the increased excitability induced by H2R activation. Our results indicate that histaminergic transmission in the NAc increases MSN intrinsic excitability through H2R‐dependent modulation of Kv4.2 channels. Activation of H2R will significantly alter spike firing in MSNs in vivo, and this effect could be an important mechanism by which these receptors mediate certain aspects of goal‐induced behaviours. Key points Histamine is synthesized and released by hypothalamic neurons of the tuberomammillary nucleus and serves as a general modulator for whole‐brain activity including the nucleus accumbens. Histamine receptors type 2 (HR2), which are expressed in the nucleus accumbens, couple to Gαs/off proteins which elevate cyclic adenosine monophosphate levels and activate protein kinase A. Whole‐cell patch‐clamp recordings revealed that H2R activation increased the evoked firing in medium spiny neurons of the nucleus accumbens via protein kinase A‐dependent mechanisms. HR2 activation accelerated subthreshold depolarization in response to current injection, reduced the latency to fire, diminished action potential medium after‐hyperpolarization and increased the action potential half‐width. HR2 activation also reduced A‐type potassium current. Selective pharmacological inhibition of the Kv4.2 channel mimicked and occluded the increased excitability induced by H2R activation.

Retinitis pigmentosa (RP) is characterized by progressive loss of vision due to photoreceptor degeneration leading to secondary inflammation. The urokinase‐type plasminogen activator (uPA) system contributes to retinal inflammation, but its role in RP is unknown. In the rd10 mouse model of RP, we addressed this question with the use of the peptide UPARANT designed to interact with the uPA system. UPARANT was systemically administered from post‐natal day (PD) 10 to PD30 when its efficacy in RP rescue was investigated using electroretinographic recordings, Western blot and immunocytochemistry. Temporal profile of protein expression in the uPA system was also investigated. UPARANT reduced both Müller cell gliosis and up‐regulated levels of inflammatory markers and exerted major anti‐apoptotic effects without influencing the autophagy cascade. Rescue from retinal cell degeneration was accompanied by improved retinal function. No scotopic phototransduction was rescued in the UPARANT‐treated animals as determined by the kinetic analysis of rod‐mediated a‐waves and confirmed by rod photoreceptor markers. In contrast, the cone photopic b‐wave was recovered and its rescue was confirmed in the whole mounts using cone arrestin antibody. Investigation of the uPA system regulation over RP progression revealed extremely low levels of uPA and its receptor uPAR both of which were recovered by HIF‐1α stabilization indicating that HIF‐1 regulates the expression of the uPA/uPAR gene in the retina. Ameliorative effects of UPARANT were likely to occur through an inhibitory action on up‐regulated activity of the αvβ3 integrin/Rac1 pathway that was suggested as a novel target for the development of therapeutic approaches against RP.

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