In the present study, we investigated whether systemic pretreatment with the AT1 receptor antagonist, candesartan, reduces neuronal injury after cerebral ischaemia in rats.Focal cerebral ischaemia in male, normotensive Wistar rats was induced by 90 min middle cerebral artery occlusion (MCAO) followed by reperfusion. Experiment 1: Candesartan was injected intravenously (i.v.) at doses of 0.1 or 0.3 mg/kg, 4 h prior to ischaemic injury. Experiment 2: Rats were treated with candesartan [0.1 mg/kg, subcutaneously (s.c.) twice daily], on 5 consecutive days prior to ischaemia. The last injection was administered 12 h before MCAO. Mean arterial pressure (MAP) was measured before, during and after ischaemic injury. Twenty-four hours after ischaemia, neurological outcome, infarct volume and brain oedema were evaluated.Acute i.v. pretreatment with candesartan, 0.1 and 0.3 mg/kg, dose-dependently decreased MAP before, during and after ischaemic injury but did not improve recovery from brain ischaemia. Systemic long-term s.c. pretreatment with 0.1 mg/kg candesartan, reduced MAP during and after ischaemia to the same extent as did the i.v. dose of 0.1 mg administered 4 h before MCAO, but significantly improved neurological outcome and reduced infarction size and oedema of the ipsilateral hemisphere when compared with the vehicle-treated group.Long-term blockade of AT1 receptors improves neurological outcome of focal cerebral ischaemia and protects brain tissue against ischaemic injury.
Journal Article Converting enzyme inhibitors in cardiovascular therapy: current status and future potential Get access Thomas Unger, Thomas Unger Department of Pharmacology. University of Heidelberg. Im Neuenheimer Feld 366, 69120 Heidelberg, Germany: T Unger, P Gohlke. Correspondence to Professor Unger. Search for other works by this author on: Oxford Academic PubMed Google Scholar Peter Gohlke Peter Gohlke Department of Pharmacology. University of Heidelberg. Im Neuenheimer Feld 366, 69120 Heidelberg, Germany: T Unger, P Gohlke. Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 28, Issue 2, February 1994, Pages 146–158, https://doi.org/10.1093/cvr/28.2.146 Published: 01 February 1994 Article history Received: 15 April 1993 Accepted: 23 November 1993 Published: 01 February 1994
Rationale: Hypertension is a major risk factor for cerebral small vessel disease, the most prevalent cause of vascular cognitive impairment. As we have shown, hypertension induced by a prolonged Angiotensin II infusion is associated with increased permeability of the blood-brain barrier (BBB), chronic activation of microglia and myelin loss. In this study we therefore aim to determine the contribution of microglia to hypertension-induced cognitive impairment in an experimental hypertension model by a pharmacological depletion approach. Methods: For this study, adult Cx3Cr1gfp/wtxThy1yfp/0 reporter mice were infused for 12 weeks with Angiotensin II or saline and subgroups were treated with PLX5622, a highly selective CSF1R tyrosine kinase inhibitor. Systolic blood pressure (SBP) was measured via tail-cuff. Short- and long-term spatial memory was assessed during an Object Location task and a Morris Water Maze task (MWM). Microglia depletion efficacy was assessed by flow cytometry and immunohistochemistry. BBB leakages, microglia phenotype and myelin integrity were assessed by immunohistochemistry. Results: SBP, heart weight and carotid pulsatility were increased by Ang II and were not affected by PLX5622. Short-term memory was significantly impaired in Ang II hypertensive mice, and partly prevented in Ang II mice treated with PLX5622. Histological and flow cytometry analysis revealed almost complete ablation of microglia and a 60% depletion of brain resident perivascular macrophages upon CSF1R inhibition. Number and size of BBB leakages were increased in Ang II hypertensive mice, but not altered by PLX5622 treatment. Microglia acquired a pro-inflammatory phenotype at the site of BBB leakages in both Saline and Ang II mice and were successfully depleted by PLX5622. There was however no significant change in myelin integrity at the site of leakages. Conclusion: Our results show that depletion of microglia and PVMs, by CSF1R inhibition prevents short-term memory impairment in Ang II induced hypertensive mice. We suggest this beneficial effect is mediated by the major decrease of pro-inflammatory microglia within BBB leakages. This novel finding supports the critical role of brain immune cells in the pathogenesis of hypertension-related cognitive impairment. An adequate modulation of microglia /PVM density and phenotype may constitute a relevant approach to prevent and/or limit the progression of vascular cognitive impairment.
Angiotensin II mediates its haemodynamic effects by binding to specific cell-surface receptors. In humans, two receptor subtypes have been identified, designated AT 1 and AT 2 . Because all major deleterious effects of angiotensin II are produced via binding to AT 1 -receptors, selective blockade of this receptor subtype should confer haemodynamic benefits, while allowing stimulation of the potentially beneficial effects mediated by AT 2 -receptors. Experimental studies using various models have consistently revealed marked differences in the receptor binding properties of different AT 1 -receptor blockers. The relative receptor binding affinities of currently available AT 1 -receptor blockers is candesartan > irbesartan > valsartan/EXP-3174/telmisartan > tasosartan > losartan > eprosartan. Candesartan is also released from the receptor more slowly than other available AT 1 -receptor blockers, with a half-life of approximately 152 min for the receptor-blocker complex, compared with 31 min for EXP-3174, 17 min for irbesartan and 5 min for losartan. Candesartan therefore binds to the AT 1 -receptor more tightly and more persistently than other AT 1 -receptor blockers.
Genetic factors strongly contribute to the pathogenesis of sporadic Alzheimer's disease (AD). Nevertheless, genome-wide association studies only yielded single nucleotide polymorphism loci of moderate importance. In contrast, microsatellite repeats are functionally less characterized structures within our genomes. Previous work has shown that endothelin-converting enzyme-1 (ECE-1) is able to reduce amyloid β content. Here we demonstrate that a CpG-CA repeat within the human ECE-1c promoter is highly polymorphic, harbors transcriptional start sites, is able to recruit the transcription factors poly(ADP-ribose) polymerase-1 and splicing factor proline and glutamine-rich, and is functional regarding haplotype-specific promoter activity. Furthermore, genotyping of 403 AD patients and 444 controls for CpG-CA repeat length indicated shifted allelic frequency distributions. Sequencing of 245 haplotype clones demonstrated that the overall CpG-CA repeat composition of AD patients and controls is distinct. Finally, we show that human and chimpanzee [CpG] m –[CA] n ECE-1c promoter repeats are genetically and functionally distinct. Our data indicate that a short genomic repeat structure constitutes a novel core promoter element, coincides with human evolution, and contributes to the pathogenesis of AD.
Summary: We tested the baroreflex in conscious, strokeprone spontaneously hypertensive rats (SHRSP) and normotensive Wistar-Kyoto controls (WKY) with incremental bolus injections of nitroprusside and methoxamine. The change in heart rate (HR) per change in mean blood pressure (MAP) was greater in WKY than in SHRSP. In contrast, the change in splanchnic nerve activity (SpNA) per change in MAP was greater in SHRSP than in WKY. The sympathetic outflow in SHRSP seems more reactive to blood pressure changes than in WKY. The discordance in HR and SpNA changes suggests that the integration of autonomic function in SHRSP is impaired.
We investigated the chronic effect of bradykinin B2-receptor blockade on the antihypertensive actions of the angiotensin-converting enzyme (ACE) inhibitor ramipril in three different hypertensive rat models, the two-kidney/one-clip (2K1C) hypertensive Wistar rat, the kinin-deficient 2K1C hypertensive Brown Norway Katholieke (BN-K) rat, and the spontaneously hypertensive rat (SHR). Chronic blockade of bradykinin B2 receptors by subcutaneous infusion of the new bradykinin antagonist HOE 140 (500 micrograms/kg/day) attenuated the antihypertensive effect of ramipril only in 2K1C hypertensive Wistar rats, but not in 2K1C BN-K rats and SHR. Our data demonstrate for the first time that potentiation of endogenous kinins contributes to chronic antihypertensive actions of ACE inhibitors in experimental renal hypertension. Whether this holds also true for other forms of hypertension remains to be answered.
