Angiotensin II-induced vasodilation: role of bradykinin, NO and endothelium-derived hyperpolarizing factors

Interactie tussen AT1 en a1-adrenerge receptoren (Hoofdstuk 6) Carvedilol, de selectieve ß1-adrenoceptor antagonist metoprolol, de niet-selectieve ßadrenoceptor antagonist propranolol, en de a1-adrenoceptor antagonist prazosin beïnvloedden geen van allen de constrictoire respons van HCMA’s op Ang II. Ang II, na toevoeging aan het orgaan bad in een lage (non-constrictoire) concentratie, versterkte de respons op de a1-adrenoceptor agonist fenylefrine enorm. Zowel carvedilol als de AT1 receptor antagonist irbesartan remden deze door Ang II geïnduceerde potentiatie. Carvedilol remde eveneens de door Ang II versterkte ophoping van inositolfosfaten onder invloed van fenylefrine in hartspiercellen. Samenvattend kan gesteld worden dat AT1-a1-receptor ‘crosstalk’, mogelijk via inositolfosfaten, HCMA’s gevoeliger maakt voor a1-adrenoceptor agonisten. De a1-adrenoceptor blokkerende effecten van carvedilol zorgen er voor dat carvedilol dit potentiërende effect van Ang II tegen kan gaan. Dit verklaart waarom het bloeddrukverhogende effect van Ang II bij patiënten met hartfalen die behandeld worden met carvedilol kleiner is dan bij patiënten die behandeld worden met metoprolol

Modelling judicial dialogue in the European community : the quantitative basis of preliminary references to the ECJ

Digitised version produced by the EUI Library and made available online in 2020.While it has traditionally been viewed as the mechanism for constructing a remarkable supranational legal order, as well as the primary indication of judicial support for European integration, the intensity of "dialogue" established by preliminary references from national courts to the European Court of Justice varies considerably and unexpectedly amongst member states. By focusing attention on what generates litigation involving EC law, the model presented here identifies transnational economic interaction and transnational movement of people as factors which account almost entirely for cross-national variation in reference rates. These findings are contrasted with the inability of other factors to account for variation, including population size, implementation of EC law, reception of supremacy and direct effect, judicial empowerment, legal education, and various aspects of national legal culture

Combined renin inhibition/(Pro)renin receptor blockade in diabetic retinopathy- a study in transgenic (mREN2)27 rats

Dysfunction of renin-angiotensin system (RAS) contributes to the pathogenesis of diabetic retinopathy (DR). Prorenin, the precursor of renin is highly elevated in ocular fluid of diabetic patients with proliferative retinopathy. Prorenin may exert local effects in the eye by binding to the so-called (pro)renin receptor ((P)RR). Here we investigated the combined effects of the renin inhibitor aliskiren and the putative (P)RR blocker handle-region peptide (HRP) on diabetic retinopathy in streptozotocin (STZ)-induced diabetic transgenic (mRen2)27 rats (a model with high plasma prorenin levels) as well as prorenin stimulated cytokine expression in cultured Müller cells. Adult (mRen2)27 rats were randomly divided into the following groups: (1) non-diabetic; (2) diabetic treated with vehicle; (3) diabetic treated with aliskiren (10 mg/kg per day); and (4) diabetic treated with aliskiren+HRP (1 mg/kg per day). Age-matched non-diabetic wildtype Sprague-Dawley rats were used as control. Drugs were administered by osmotic minipumps for three weeks. Transgenic (mRen2)27 rat retinas showed increased apoptotic cell death of both inner retinal neurons and photoreceptors, increased loss of capillaries, as well as increased expression of inflammatory cytokines. These pathological changes were further exacerbated by diabetes. Aliskiren treatment of diabetic (mRen2)27 rats prevented retinal gliosis, and reduced retinal apoptotic cell death, acellular capillaries and the expression of inflammatory cytokines. HRP on top of aliskiren did not provide additional protection. In cultured Müller cells, prorenin significantly increased the expression levels of IL-1α and TNF-α, and this was completely blocked by aliskiren or HRP, their combination, (P)RR siRNA and the AT1R blocker losartan, suggesting that these effects entirely depended on Ang II generation by (P)RR-bound prorenin. In conclusion, the lack of effect of HRP on top of aliskiren, and the Ang II-dependency of t

Beneficial effects of combined AT1 receptor/neprilysin inhibition (ARNI) versus AT1 receptor blockade alone in the diabetic eye

PURPOSE. Dysfunction of the renin-angiotensin system (RAS) contributes to pathogenesis of diabetic retinopathy (DR). Yet RAS blockers have only limited beneficial effects on progression of DR in clinical trials. The natriuretic peptide system offsets RAS, so that enhancing the activity of this system on top of RAS blockade might be beneficial. Neprilysin has an important role in the degradation of natriuretic peptides. Therefore, we hypothesize that dual angiotensin receptor-neprilysin inhibition (ARNI) may outperform angiotensin receptor blocker (ARB) in protection against DR. We tested this hypothesis in streptozotocininduced diabetic transgenic (mRen2)27 rats. METHODS. Adult male diabetic (mRen2)27 rats were followed for 5 or 12 weeks. Treatment with vehicle, irbesartan (ARB), or ARB combined with the neprilysin inhibitor thiorphan (irbesartan+thiorphan [ARNI]) occurred during the final 3 weeks. Retinal cell death, gliosis, and capillary loss were evaluated. Real-time polymerase chain reaction (RT-PCR) analyses were performed to quantify the retinal level of inflammatory cell markers. RESULTS. Both ARB-and ARNI-treated groups showed similarly reduced retinal apoptotic cell death, gliosis, and capillary loss compared to the vehicle-treated group in the 5-week study. Treatment with ARNI reduced the expression of inflammatory markers more than ARB treatment in the 5-week study. In the 12-week study, ARNI treatment showed significantly more reduction in apoptotic cell death (51% vs. 25% reduction), and capillary loss (68% vs. 43% reduction) than ARB treatment. CONCLUSIONS. Treatment with ARNI provides better protection against DR in diabetic (mRen2)27 transgenic rats, compared to ARB alone. This approach may be a promising treatment option for patients with DR

Prorenin anno 2008

For many years, prorenin has been considered to be nothing more than the inactive precursor of renin. Yet, its elevated levels in diabetic subjects with microvascular complications and its extrarenal production at various sites in the body suggest otherwise. This review discusses the origin, regulation, and enzymatic activity of prorenin, its role during renin inhibition, and the angiotensin-dependent and angiotensin-independent consequences of its binding to the recently discovered (pro)renin receptor. The review ends with the concept that prorenin rather than renin determines tissue angiotensin generation

(Pro)renin and its receptors: pathophysiological implications

Tissue angiotensin generation depends on the uptake of circulating (kidney-derived) renin and/or its precursor prorenin [together denoted as (pro)renin]. Since tissue renin levels are usually somewhat higher than expected based upon the amount of (renin-containing) blood in tissue, an active uptake mechanism has been proposed. Several candidates have been evaluated in the past three decades, including a renin-binding protein, the mannose 6-phosphate/insulin-like growth factor II receptor and the (pro)renin receptor. Although the latter seemed the most promising, its nanomolar affinity for renin and prorenin is several orders of magnitude above their actual (picomolar) levels in blood, raising doubt on whether (pro)renin-(pro)renin receptor interaction will ever occur in vivo. A wide range of in vitro studies have now demonstrated (pro)renin-receptor-induced effects at nanomolar renin and prorenin concentrations, resulting in a profibrotic phenotype. In addition, beneficial in vivo effects of the putative (pro)renin receptor blocker HRP (handle region peptide) have been observed, particularly in diabetic animal models. Despite these encouraging results, many other studies have reported either no or even contrasting effects of HRP, and (pro)renin-receptor-knockout studies revealed lethal consequences that are (pro)renin-independent, most probably due to the fact that the (pro)renin receptor co-localizes with vacuolar H+-ATPase and possibly determines the stability of this vital enzyme. The present review summarizes all of the recent findings on the (pro)renin receptor and its blockade, and critically compares it with the other candidates that have been proposed to mediate (pro)renin uptake from blood. It ends with the conclusion that the (pro)renin-(pro)renin receptor interaction, if it occurs in vivo, is limited to (pro)renin-synthesizing organs such as the kidney

Het wensenlijstje van de eikenprocessierups

De afgelopen jaren is er hard gewerkt om erachter te komen wat de voorkeuren zijn van de eikenprocessierups. Dit is gedaan in het kader van het TOP-sectoronderzoek naar de maatschappelijke impact en de beheersing van de eikenprocessierups. Want als je weet wat deze rups het liefste op het menu heeft staan, kun je daarop inspelen met een bepaalde beheerstrategie, om de eikenprocessierupspopulatie te onderdrukken op een zeer gerichte manier. Mede op basis van de resultaten van dit onderzoek is de Leidraad Beheersing Eikenprocessierups verbeterd en uitgebreid tot de update van 2022