PATHOGENESIS OF SOLUTE-FREE WATER RETENTION IN EXPERIMENTAL ASCITIC CIRRHOSIS: IS VASOPRESSIN THE ONLY CULPRIT?

ABSTRACT Background. Catecholamines trigger proximal tubular fluid retention and reduce renal excretion of solute-free water. In advanced cirrhosis, non-osmotic hypersecretion of vasopressin (ADH) is considered the cause of dilutional hyponatremia, but ADH V 2 receptor antagonists are not beneficial in long-term treatment of ascites. Aim. To test the hypothesis that water retention in experimental ascitic cirrhosis might depend primarily on adrenergic hyperfunction. Methods. Hormonal status, renal function and tubular free-water reabsorption (TFWR) were assessed in six groups of rats with ascitic cirrhosis: rats with cirrhosis due to 13-week CCl 4 administration (group G1); cirrhotic rats receiving daily diuretics (0.5 mg/kg furosemide plus 2 mg/kg K + -canrenoate) from 11 th to 13 th week of CCl 4 (G2), diuretics associated with guanfacine oral prodrug ( 2A adrenergic receptor agonist and sympatholytic agent) 2 (G3), 7 (G4), or 10 mg/kg (G5), or with SSP-004240F1 (V 2 receptor antagonist) 1 mg/kg (G6). Results. Natriuresis was lower in G1 than in G2, G4 and G6 (all P<0.05). Guanfacine, added to diuretics (i.e. G3 vs. G2), reduced serum norepinephrine from 423 ± 22 to 211 ± 41 ng/L (P<0.05), plasma renin activity from 35 ± 8 to 9 ± 2 ng/mL/h (P<0.05), and TFWR from 45 ± 8 to 20 ± 6 microL/min (P<0.01). TFWR correlated with plasma aldosterone (r=0.51, P<0.01) and urinary potassium excretion (r=0.90, P<0.001). Conclusion. In ascitic cirrhosis, reduced volaemia, use of diuretics (especially furosemide), and adrenergic hyperfunction cause tubular retention of water. Suitable doses of sympatholytic agents are effective aquaretics. Catecholamines and water retention in cirrhosis. 3 SUMMARY STATEMENT Adrenergic hyperfunction reduces renal excretion of water. In advanced cirrhosis, hypersecretion of vasopressin is considered the cause of dilutional hyponatremia. We show that in experimental cirrhosis sympatholytic agents ( 2A -adrenoceptor agonists) are as effective as V 2 -antagonists to blunt water retention. Short title. Catecholamines and water retention in cirrhosis. Keywords. 2 -adrenoceptor agonists; experimental cirrhosis; ascites; cirrhosis complications; dilutional hyponatremia. Abbreviations used in this paper: A, aldosterone; ADH, vasopressin; CCl 4 , carbon tetrachloride; CIN, steady-state plasma clearance of inulin; CK, potassium clearance; CNa, sodium clearance; Cosm, osmolar clearance; CPAH, steady-state plasma clearance of para-aminohippurate; E, epinephrine; EABV, effective arterial blood volume; FEK, fractional excretion of potassium; FENa, fractional sodium excretion; FF, filtration fraction; FlNa, filtered sodium load; GFR, glomerular filtration rate; HRS, hepatorenal syndrome; IN, inulin; MAP, mean arterial pressure; N, norepinephrine; PAH, para-aminohippurate; Posm, plasma osmolality; PRA, plasma renin activity; RPF, renal plasma flow; SD, standard deviation; TFWR, tubular free-water reabsorption; Uosm, urine osmolality. Catecholamines and water retention in cirrhosis. 4 INTRODUCTION Impairment in body water homeostasis is common in patients with advanced cirrhosis and ascites. A higher rate of renal retention of water in relation to sodium, due to a reduction in solute-free water clearance, leads to a positive balance between water ingestion and excretion and to dilutional hyponatremia The inability of ascitic cirrhotic patients to excrete an adequate amount of solutefree water in the urine is related to the following mechanisms: i) baroreceptor-mediated non-osmotic stimulation of vasopressin (ADH) release due to arterial splanchnic vasodilatation and reduction of effective arterial blood volume (EABV) Significant reduction of effective arterial blood volume (EABV) triggers both excess isosmotic proximal tubular sodium retention (with reduced delivery of fluid to the Henle's loop) and non-osmotic hyper-secretion of ADH. These two homeostatic mechanisms, which aim at preserving the size of functional volaemia by means of tubular solute-free water retention This assumption seems even more convincing when the behavior of tubular reabsorption of sodium and water in patients with liver cirrhosis is pondered. Lithium clearance (an established index of delivery of tubular fluid to the loop of Henle) is already significantly reduced in standing pre-ascitic cirrhotic patients Despite the above considerations, in recent literature and clinical practice, the use of vasopressin V 2 receptor antagonists has become the standard of care in order to try and treat dilutional hyponatremia in ascitic cirrhosi

FR010: Use of FeRAM Devices in a Small Satellite

This paper describes how a ferroelectric RAM from Ramtron has been used to increase the reliability of PiCPoT, a small satellite developed at Politecnico di Torino for educational purposes. It compares the FeRAM solution with respect to a FLASH one. The memories are used for saving housekeeping telemetry data while the satellite is far from the ground station. Due to the intrinsic radiation tolerance and the lower power consumption, FeRAM are very suitable for the applicatio

New Viral Diseases and New Possible Remedies by Means of the Pharmacology of the Renin-Angiotensin System

All strains of SARS-CoV-2, as well as previously described SARS-CoV and MERS-CoV, bind to ACE2, the cell membrane receptor of β-coronaviruses. Monocarboxypeptidase ACE2 activity stops upon viral entry into cells, leading to inadequate tissue production of angiotensin 1-7 (Ang1-7). Acute lung injury due to the human respiratory syncytial virus (hRSV) or avian influenza A H7N9 and H5N1 viruses is also characterized by significant downregulation of lung ACE2 and increased systemic levels of angiotensin II (Ang II). Restoration of Ang1-7 anti-inflammatory, antifibrotic, vasodilating, and natriuretic properties was attempted at least in some COVID-19 patients through i.v. infusion of recombinant human ACE2 or intranasal administration of the modified ACE2 protein, with inconsistent clinical results. Conversely, use of ACE inhibitors (ACEis), which increase ACE2 cell expression, seemed to improve the prognosis of hypertensive patients with COVID-19. To restore Ang1-7 tissue levels in all these viral diseases and avoid the untoward effects frequently seen with ACE2 systemic administration, a different strategy may be hypothesized. Experimentally, when metallopeptidase inhibitors block ACE2, neprilysin (NEP), highly expressed in higher and lower airways, starts cleaving angiotensin I (Ang I) into Ang1-7. We suggest a discerning use of ACEis in normohypertensive patients with β-coronavirus disease as well as in atypical pneumonia caused by avian influenza viruses or hRSV to block the main ACE-dependent effects: Ang II synthesis and Ang1-7 degradation into angiotensin 1-5. At the same time, i.v.-infused Ang I, which is not hypertensive provided ACE is inhibited, may become the primary substrate for local Ang1-7 synthesis via ubiquitous NEP; i.e., NEP could replace inadequate ACE2 function if Ang I was freely available. Moreover, inhibitors of chymase, a serine endopeptidase responsible for 80% of Ang II-forming activity in tissues and vessel walls, could protect patients with atypical pneumonia from Ang II-mediated microvascular damage without reducing arterial blood pressure