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The intraorgan renin-angiotensin system (RAS) plays an important role in the pathophysiology of a variety of diseases and has been implicated in fibrogenesis. The role of RAS in the development of chronic pancreatitis is not well established. The blockade of RAS in rat models with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor 1 (AT1) blockers (ARBs) mostly have reduced pancreatic inflammation and fibrosis with a few exceptions. At the same time, the use of ACEi and ARBs in humans is associated with a modest risk of acute pancreatitis. The aim of this study was to elucidate the effect of the AT1 signaling pathway in the development of pancreatitis using AT1a- and AT1b-deficient mice as well as the ARB losartan. Chronic pancreatitis was induced by repetitive cerulein administration in C57BL/6J wild-type (WT) and AT1a- and AT1b-deficient mice ([AT1a.sup.-/-] and [AT1b.sup.-/-]), and pancreatic injury was assessed at day 10. Pancreatic weight of cerulein treated groups was significantly reduced. There was severe parenchymal atrophy and fibrosis assessed by histological examination. Fibrosis was accompanied by activation of pancreatic stellate cells (PSC) evaluated by Western blot analysis for a-smooth muscle actin. No differences were seen between cernlein-treated WT, [AT1a.sup.-/-], [AT1b.sup.-/-] mice, or losartan treated-WT mice with regards to morphological or molecular alterations induced by cerulein. Our results demonstrate that AT1a and AT1b receptor pathways do not seem to be essential for the development of pancreatitis in the mouse model of pancreatitis induced by repetitive cerulein injury. renin-angiotensin system; losartan; angiotensin receptor 1 doi: 10.1152/ajpgi.00006.2010.

Angiotensin II promotes liver fibrogenesis by stimulating nonphagocytic NADPH oxidase (NOX)-induced oxidative stress. Angiotensin II type 1 (AT1) receptor blockers attenuate experimental liver fibrosis, yet their effects in human liver fibrosis are unknown. We investigated the effects of losartan on hepatic expression of fibrogenic, inflammatory, and NOX genes in patients with chronic hepatitis C (CHC). Fourteen patients with CHC and liver fibrosis received oral losartan (50 mg/ day) for 18 mo. Liver biopsies were performed at baseline and after treatment. The degree of inflammation and fibrosis was evaluated by histological analysis (METAVIR). Collagen content was measured by morphometric quantification of Sirius red staining. Overall collagen content and fibrosis stage remained stable in the whole series, yet the fibrosis stage decreased in seven patients. Inflammatory activity improved in seven patients. The effect of losartan on hepatic expression of 31 profibrogenic and inflammatory genes and components of the NOX complex was assessed by quantitative PCR. Losartan treatment was associated with a significant decrease in the expression of several profibrogenic and NOX genes including procollagen [alpha]1(I) and [alpha]1(IV), urokinase-type plasminogen activator, metalloproteinase type 2, NOX activator 1 (NOXA-1) and organizer 1 (NOXO-I), and Rac-1. Losartan was well tolerated in all patients and was effective in attenuating the activity of the systemic renin-angiotensin system. No effects on serum liver tests or viral load were observed. We conclude that prolonged administration of losartan, an oral AT1 receptor blocker, is associated with downregulation of NOX components and fibrogenic genes in patients with CHC. Controlled studies are warranted to assess the effect of AT1 receptor blockers in chronic liver injury. angiotensin; liver fibrosis; antifibrogenic doi: 10.1152/ajpgi.00162.2009

In rats, both central and systemic ANG II type 1 ([AT.sub.1]) receptor blockade attenuate sympathetic hyperactivity, but central blockade more effectively attenuates left ventricular (LV) dysfunction post-myocardial infarction (MI). In protocol 1, we examined whether functional effects on cardiac load may play a role and different cardiac effects disappear after withdrawal of the blockade. Wistar rats were infused for 4 wk post-MI intracerebroventricularly (1 mg x [kg.sup.-1] x [day.sup.-1]) or injected subcutaneously daily (100 mg x [kg.sup.-1] x [day.sup.-1]) with losartan. LV dimensions and function were assessed at 4 wk and at 6 wk post-MI, i.e., 2 wk after discontinuing treatments. At 4 and 6 wk post-MI, LV dimensions were increased and ejection fraction was decreased. Intracerebroventricular but not subcutaneous losartan significantly improved these parameters. At 6 wk, LV peak systolic pressure (LVPSP) and maximal or minimal first derivative of change in pressure over time (dP/[dt.sub.max/min]) were decreased and LV end-diastolic pressure (LVEDP) was increased. All four indexes were improved by previous intracerebroventricular losartan, whereas subcutaneous losartan improved LVEDP only. In protocol H, we evaluated effects of oral instead of subcutaneous administration of losartan for 4 wk post-MI. Losartan (~200 mg x [kg.sup.-1] x [day.sup.-1]) either via drinking water or by gavage similarly decreased [AT.sub.1] receptor binding densities in brain nuclei and improved LVEDP but further decreased LVPSP and dP/[dt.sub.max]. These results indicate that effects on cardiac load by peripheral [AT.sub.1] receptor blockade or the pharmacokinetic profile of subcutaneous versus oral dosing do not contribute to the different cardiac effects of central versus systemic [AT.sub.1] receptor blockade post-MI. losartan; cardiac remodeling; echocardiography; Millar catheter; brain; ANG II type 1

Angioten-sin II accelerates and renin-angiotensin system blockade halts progression; blockade with high doses even reverses established glomerulosclerosis. Aldosterone also accelerates progression of glomerulosclerosis, partially independently of angiotensin 1I. The purpose of this study was to assess the relative ability of an angiotensin receptor type I (A[T.sub.1]) blocker, a mineralocorticoid receptor blocker, and their combination to reverse glomerulosclerosis. Sprague-Dawley rats were subjected to subtotal renal ablation (SNX) or sham operation. Eight weeks after surgery, they were either euthanized or allocated to treatment with vehicle, losartan, spironolactone, their combination, or unspecific antihypertensive treatment (dihydralazine) for 4 wk. Renal morphology was evaluated by stereology in tissues obtained using pressure-controlled perfusion fixation. Systolic blood pressure was significantly higher in SNX compared with sham-operated animals and decreased in all treatment groups. Compared with wk 8 after SNX, the glomerulosclerosis index (GSI) had increased further by week 12 in the vehicle- and dihydralazine-treated groups but was significantly lowered in the SNX+losartan as well as in the SNX+losartan+spironolactone groups and had not progressed further in the SNX+spironolactone group. The study confirms the partial regression of established glomerulosclerosis in subtotally nephrectomized rats alter high-dose A[T.sub.1] receptor blockade. Nonhyperkalemic doses of spironotactone prevented the increase but failed to decrease the GSI below the 8-wk level and preserved podocyte numbers. Combining the A[T.sub.1] blocker with mineralocorticoid receptor blockade failed to further increase the regression of glomerulosclerosis. aldosterone escape: renin-angiotensin system

Atrial fibrillation (AF) is the most frequent arrhythmia found in clinical practice. In recent studies, a decrease in the development or recurrence of AF was found in hypertensive patients treated with angiotensin-converting enzyme inhibitors or angiotensin receptor-blocking agents. Hypertension is related to an increased wall tension in the atria, resulting in increased stretch of the individual myocyte, which is one of the major stimuli for the remodeling process. In the present study, we used a model of cultured atrial neonatal rat cardiomyocytes under conditions of stretch to provide insight into the mechanisms of the preventive effect of the angiotensin receptor-blocking agent losartan against AF on a molecular level. Stretch significantly increased protein-to-DNA ratio and atrial natriuretic factor mRNA expression, indicating hypertrophy. Expression of genes encoding for the inward rectifier K+ current (IKI), Kir2.1, and Kir2.3, as well as the gene encoding for the ultrarapid delayed rectifier [K.sup.+] current ([I.sub.Kur]), Kv1.5, was significantly increased. In contrast, mRNA expression of Kv4.2 was significantly reduced in stretched myocytes. Alterations of gene expression correlated with the corresponding current densities: [I.sub.K1] and [I.sub.Kur] densities were significantly increased in stretched myocytes, whereas transient outward [K.sup.+] current ([I.sub.to]) density was reduced. These alterations resulted in a significant abbreviation of the action potential duration. Losartan (1 [micro]M) prevented stretch-induced increases in the protein-to-DNA ratio and atrial natriuretic peptide mRNA expression in stretched myocytes. Concomitantly, losartan attenuated stretch-induced alterations in [I.sub.K1], [I.sub.Kur], and [I.sub.to] density and gene expression. This prevented the stretch-induced abbreviation of action potential duration. Prevention of stretch-induced electrical remodeling might contribute to the clinical effects of losartan against AF. atrial fibrillation; mechanical stretch; hypertrophy; ion channels doi:10.1152/ajpheart.00546.2006

Byline: P. Pandi, A. Nagappa Antinociception is termed as a reduction in the response of pain sensory system to noxious stimuli. Repeated treatments of losartan (10 mg/kg) orally has been [...]

Proc. Natl Acad. Sci. USA doi:10.1073/ pnas.0900351106 (2009). The blood-pressure drug losartan could fight some breast cancers, studies in mice suggest. Arul Chinnaiyan of the University of Michigan in Ann [...]