Effects of Aliskiren on Stroke in Rats Expressing Human Renin and Angiotensinogen Genes

OBJECTIVE: Pre-treatment with angiotensin receptor blockers is known to improve neurological outcome after stroke. This study investigated for the first time, whether the renin inhibitor aliskiren has similar neuroprotective effects. METHODS: Since aliskiren specifically blocks human renin, double transgenic rats expressing human renin and angiotensinogen genes were used. To achieve a systolic blood pressure of 150 or 130 mmHg animals were treated with aliskiren (7.5 or 12.5 mg/kg*d) or candesartan (1.5 or 10 mg/kg*d) via osmotic minipump starting five days before middle cerebral artery occlusion with reperfusion. Infarct size was determined by magnetic resonance imaging. mRNA of inflammatory marker genes was studied in different brain regions. RESULTS: The mortality of 33.3% (7 of 21 animals) in the vehicle group was reduced to below 10% by treatment with candesartan or aliskiren (p<0.05). Aliskiren-treated animals had a better neurological outcome 7 days post-ischemia, compared to candesartan (Garcia scale: 9.9±0.7 vs. 7.3±0.7; p<0.05). The reduction of infarct size in the aliskiren group did not reach statistical significance compared to candesartan and vehicle (24 h post-ischemia: 314±81 vs. 377±70 and 403±70 mm(3) respectively). Only aliskiren was able to significantly reduce stroke-induced gene expression of CXC chemokine ligand 1, interleukin-6 and tumor necrosis factor-alpha in the ischemic core. CONCLUSIONS: Head-to-head comparison suggests that treatment with aliskiren before and during cerebral ischemia is at least as effective as candesartan in double transgenic rats. The improved neurological outcome in the aliskiren group was blood pressure independent. Whether this effect is due to primary anti-inflammatory mechanisms has to be investigated further

Temporary losartan or captopril in young SHR induces malignant hypertension despite initial normotension

Temporary losartan or captopril in young SHR induces malignant hypertension despite initial normotension.BackgroundExposure of normotensive rats to angiotensin-converting enzyme (ACE) inhibitors in early life causes hypertrophy of intrarenal arteries. Similar defects have been found in knockout mice lacking angiotensinogen, ACE, or angiotensin II type 1 (AT1) receptors. On the other hand, transient inhibition of the renin-angiotensin system from 2weeks of age in spontaneously hypertensive rats (SHR), either with ACE inhibitors or with AT1 receptor antagonists partially prevents the increase in blood pressure. However, permanent treatment of SHR from conception onwards with ACE inhibitors completely prevents hypertension. Although these studies demonstrated protection from hypertension-induced changes in the heart and large arteries, renal arteries were not studied and follow-up did not extend beyond 6months of age. We postulated that while brief exposure to ACE inhibitors or AT1 receptor antagonists in young SHR would temporarily decrease blood pressure, it would also be associated with development of intrarenal arterial malformation, and ultimately have deleterious effects.MethodsDirect effects on intrarenal arterial morphology of an ACE inhibitor (captopril, 100mg/kg/day) and an AT1 receptor antagonist (losartan, 50mg/kg/day), administered from the last week of gestation until 8weeks of age were examined in SHR. After stopping treatment at 8weeks, we continued to monitor blood pressure until spontaneous death.ResultsSystolic blood pressure at 8weeks was normalized by captopril and losartan (SHR control 187 ± 8mm Hg; captopril 118 ± 5mm Hg; and losartan 120 ± 9mm Hg). However, by 30weeks, blood pressure had increased to control SHR levels. At 4weeks, the media of renal arteries and arterioles was hypertrophied. Marked smooth muscle cell hyperplasia of cortical arteries resulted in significantly increased wall thickness by 8weeks, despite similar external diameter. Arterial wall structure was disrupted, with fragmentation of elastic fibers and irregular distribution of collagen type I fibers. After stopping treatment, the rats gradually began to show poor health and all had died by 1year of age, while all 1-year-old control SHR females were in good health. The cause of morbidity and mortality in the rats treated in early life was clearly malignant hypertension. Severe hypertrophy of renal arterioles was found, as well as cerebral hemorrhage.ConclusionDespite initial normalization of blood pressure interference with the renin-angiotensin system during a crucial stage of development in SHR can initiate marked smooth muscle cell hyperplasia and disruption of the wall structure of the intrarenal arteries. Subsequent progression of this intrarenal process after cessation of treatment suggests an independent process that eventually results in malignant hypertension and early death

Maintenance of Hypertensive Hemodynamics Does Not Depend on ROS in Established Experimental Chronic Kidney Disease

While the presence of oxidative stress in chronic kidney disease (CKD) is well established, its relation to hypertensive renal hemodynamics remains unclear. We hypothesized that once CKD is established blood pressure and renal vascular resistance (RVR) no longer depend on reactive oxygen species. CKD was induced by bilateral ablation of 2/3 of each kidney. Compared to age-matched, sham-operated controls all ablated rats showed proteinuria, decreased glomerular filtration rate (GFR), more renal damage, higher mean arterial pressure (MAP), RVR and excretion of oxidative stress markers and hydrogen peroxide, while excretion of stable nitric oxide (NO) metabolites tended to decrease. We compared MAP, RVR, GFR and fractional excretion of sodium under baseline and during acute Tempol, PEG-catalase or vehicle infusion in rats with established CKD vs. controls. Tempol caused marked reduction in MAP in controls (96±5 vs.79±4 mmHg, P<0.05) but not in CKD (130±5 vs. 127±6 mmHg). PEG-catalase reduced MAP in both groups (controls: 102±2 vs. 94±4 mmHg, P<0.05; CKD: 118±4 vs. 110±4 mmHg, P<0.05), but did not normalize MAP in CKD rats. Tempol and PEG-catalase slightly decreased RVR in both groups. Fractional excretion of sodium was increased by both Tempol and PEG-catalase in both groups. PEG-catalase decreased TBARS excretion in both groups. In sum, although oxidative stress markers were increased, MAP and RVR did not depend more on oxidative stress in CKD than in controls. Therefore reactive oxygen species appear not to be important direct determinants of hypertensive renal hemodynamics in this model of established CKD

An open resource for non-human primate imaging

Non-human primate neuroimaging is a rapidly growing area of research that promises to transform and scale translational and cross-species comparative neuroscience. Unfortunately, the technological and methodological advances of the past two decades have outpaced the accrual of data, which is particularly challenging given the relatively few centers that have the necessary facilities and capabilities. The PRIMatE Data Exchange (PRIME-DE) addresses this challenge by aggregating independently acquired non-human primate magnetic resonance imaging (MRI) datasets and openly sharing them via the International Neuroimaging Data-sharing Initiative (INDI). Here, we present the rationale, design, and procedures for the PRIME-DE consortium, as well as the initial release, consisting of 25 independent data collections aggregated across 22 sites (total = 217 non-human primates). We also outline the unique pitfalls and challenges that should be considered in the analysis of non-human primate MRI datasets, including providing automated quality assessment of the contributed datasets

Experimental Autoimmune Encephalomyelitis in the Common Marmoset, a Bridge Between Rodent EAE and Multiple Sclerosis for Immunotherapy Development

The attrition rate of new drugs for central nervous system diseases including multiple sclerosis (MS) is very high. A widely recognized bottleneck in the selection of promising central nervous system drug candidates from the development pipeline is the lack of sufficiently predictive animal models. Here, we review how the experimental autoimmune encephalomyelitis (EAE) model in the Neotropical primate "common marmoset" can help to bridge the gap between rodent EAE models and MS. The EAE model in the marmoset closely resembles MS in the clinical as well as pathological presentation and can be used for fundamental research into immunopathogenic mechanisms and for therapy development. We discuss recent insights arising from this model, both on novel therapeutics and immunopathogenesis

Accelerating the Evolution of Nonhuman Primate Neuroimaging

© 2019 Elsevier Inc. Nonhuman primate neuroimaging is on the cusp of a transformation, much in the same way its human counterpart was in 2010, when the Human Connectome Project was launched to accelerate progress. Inspired by an open data-sharing initiative, the global community recently met and, in this article, breaks through obstacles to define its ambitions