Cognitive Impairments and Dysexecutive Behavioral Disorders in Chronic Kidney Disease.

The purpose of this study was to characterize cognitive impairments and behavioral disorders in a sample of patients with chronic kidney disease (CKD). A total of 52 patients with CKD were prospectively recruited over a 344-day period. Cognitive functions (memory, action speed, executive function, and language) and behavioral characteristics were assessed with a standardized comprehensive battery. The patients' performances were interpreted with a validated method on the basis of normative data from 1,003 healthy control subjects. Brain MRI and biological data were collected. Multivariable linear regression models and bootstrap analyses were used to identify risk factors for cognitive impairment. Cognitive impairment was observed in 32.5% (95% confidence interval: 17%-48%) of the 40 included patients with full data sets. Action speed and executive functions were the most frequently impaired domains. Dysexecutive behavioral disorders were observed in 27% of patients, and depression was observed in 32.5%. Cognitive impairment was independently associated with stroke volume, high serum parathyroid hormone and uric acid levels, and low serum glucose levels (adjusted R2=0.54, p<0.001 One-third of patients with CKD had cognitive impairments (action speed and executive functions), behavioral dysexecutive disorders (hypoactivity with apathy, irritability, or anosognosia), or depression.

Neurological complications in chronic kidney disease patients.

Chronic kidney disease (CKD) is associated with a high prevalence of cerebrovascular disorders such as stroke, white matter diseases, intracerebral microbleeds and cognitive impairment. This situation has been observed not only in end-stage renal disease patients but also in patients with mild or moderate CKD. The occurrence of cerebrovascular disorders may be linked to the presence of traditional and non-traditional cardiovascular risk factors in CKD. Here, we review current knowledge on the epidemiological aspects of CKD-associated neurological and cognitive disorders and discuss putative causes and potential treatment. CKD is associated with traditional (hypertension, hypercholesterolaemia, diabetes etc.) and non-traditional cardiovascular risk factors such as elevated levels of oxidative stress, chronic inflammation, endothelial dysfunction, vascular calcification, anaemia and uraemic toxins. Clinical and animal studies indicate that these factors may modify the incidence and/or outcomes of stroke and are associated with white matter diseases and cognitive impairment. However, direct evidence in CKD patients is still lacking. A better understanding of the factors responsible for the elevated prevalence of cerebrovascular diseases in CKD patients may facilitate the development of novel treatments. Very few clinical trials have actually been performed in CKD patients, and the impact of certain treatments is subject to debate. Treatments that lower LDL cholesterol or blood pressure may reduce the incidence of cerebrovascular diseases in CKD patients, whereas treatment with erythropoiesis-stimulating agents may be associated with an increased risk of stroke but a decreased risk of cognitive disorders. The impact of therapeutic approaches that reduce levels of uraemic toxins has yet to be evaluated.

Possible involvement of microRNAs in vascular damage in experimental chronic kidney disease.

Chronic kidney disease (CKD) is associated with vascular calcifications and atherosclerosis. There is a need for novel predictors to allow earlier diagnosis of these disorders, predict disease progression, and improve assessment of treatment response. We focused on microRNAs since they are implicated in a variety of cellular functions in cardiovascular pathology. We examined changes of microRNA expression in aortas of CKD and non-CKD wild type mice and apolipoprotein E knock-out mice, respectively. Both vascular smooth muscle-specific miR-143 and miR-145 expressions were decreased in states of atherosclerosis and/or CKD or both, and the expression level of protein target Myocardin was increased. The inflammatory miR-223 was increased in more advanced stages of CKD, and specific protein targets NFI-A and GLUT-4 were dramatically decreased. Expression of miR-126 was markedly increased and expression of protein targets VCAM-1 and SDF-1 was altered during the course of CKD. The drug sevelamer, commonly used in CKD, corrected partially these changes in microRNA expression, suggesting a direct link between the observed microRNA alterations and uremic vascular toxicity. Finally, miR-126, -143 and -223 expression levels were deregulated in murine serum during the course of experimental CKD. In conclusion, these miRNAs could have role(s) in CKD vascular remodeling and may therefore represent useful targets to prevent or treat complications of CKD.

Cognitive disorders and dementia in CKD: the neglected kidney-brain axis.

Epidemiologic data suggest that individuals at all stages of CKD have a higher risk of developing cognitive disorders and dementia. This risk is generally explained by the high prevalence of both symptomatic and subclinical ischemic cerebrovascular lesions. However, other potential mechanisms, including direct neuronal injury by uremic toxins, could also be involved, especially in the absence of obvious cerebrovascular disease. We discuss the prevalence and characteristics of cognitive disorders and dementia in patients with CKD, brain imaging findings, and traditional and nontraditional risk factors. Understanding the pathophysiologic interactions between renal impairment and brain function is important in order to minimize the risk for future cognitive impairment.

Prolonged acute migraine with aura and reversible brain MRI abnormalities after liquid sclerotherapy.

Transient visual disturbances constitute the most commonly reported neurological side effect during and immediately after sclerotherapy. A few studies, based on clinical and diffusion-weighted MRI assessments, have suggested that these transient neurological symptoms correspond to migraine with aura. Recently, it has been reported that brain magnetic resonance imaging can reveal transient T2*-weighted abnormalities during the acute phase of migraine with aura. We reported a 36-year-old man who presented with transient neurological symptoms and concomitant T2*-weighted abnormalities on brain magnetic resonance imaging immediately after liquid sclerotherapy. We hypothesize that the reversible nature of the patient's T2*-weighted abnormalities may indicate a relationship with the post-sclerotherapy migraine with aura attack.

Presence of intracranial artery calcification is associated with mortality and vascular events in patients with ischemic stroke after hospital discharge: a cohort study.

BACKGROUND AND PURPOSE: Although intracranial artery calcification (IAC) has been reported to be a risk factor for ischemic stroke, the prognostic implications of IAC in stroke outcome are unknown. The purpose of this study was to determine the association between IAC and risk of vascular events and death in patients with stroke after hospital discharge. METHODS: All patients with ischemic stroke over a 1-year period were included (n=302). IAC, assessed by multidetector CT, was defined as hyperdense foci (peak density>130 Hounsfield units) and assessed in the 7 major cerebral arteries. The IAC scores ranged from 0 (no calcification) to 7. Follow-up information on major clinical events (including fatal or nonfatal ischemic stroke, cardiac and peripheral artery events, and all-cause death) was obtained by means of a structured phone interview. RESULTS: IAC was present in 260 patients (83%). With a mean follow-up of 773±223 days, 88 major clinical events occurred in 67 patients (22%): 45 new ischemic vascular events (ischemic stroke: n=22; cardiac event: n=15; peripheral artery event: n=8) and 43 deaths from any cause. Patients with the highest IAC scores had significantly higher rates of death and vascular events than those with the lowest IAC scores (log rank test, P=0.029). In the Cox proportional hazards regression model, the IAC score was significantly associated with major clinical events (hazard ratio, 1.34; 95% CI, 1.11-1.61; P=0.002). CONCLUSIONS: In patients with ischemic stroke, IAC detection may constitute a simple marker of a high risk of future major clinical events.

Chronic renal failure alters endothelial function in cerebral circulation in mice.

We examined structure, composition, and endothelial function in cerebral arterioles after 4 wk of chronic renal failure (CRF) in a well-defined murine model (C57BL/6J and apolipoprotein E knockout female mice). We also determined quantitative expression of endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (on serine 1177 and threonine 495), and caveolin-1; quantitative expression of markers of vascular inflammation or oxidative stress [Rock-1, Rock-2, VCAM-1, and peroxisome proliferator-activated receptor-γ (PPARγ)]; and the plasma concentration of L-arginine and asymmetric dimethylarginine (ADMA). Our hypothesis was that endothelial function would be impaired in cerebral arterioles during CRF following either a decrease in NO production (through alteration of eNOS expression or regulation) or an increase in NO degradation (due to oxidative stress or vascular inflammation). Endothelium-dependent relaxation was impaired during CRF, but endothelium-independent relaxation was not. CRF had no effect on cerebral arteriolar structure and composition. Quantitative expressions of eNOS, eNOS phosphorylated on serine 1177, caveolin-1, Rock-1, Rock-2, and VCAM-1 were similar in CRF and non-CRF mice. In contrast, quantitative expression of PPARγ (which exercises a protective role on blood vessels) was significantly lower in CRF mice, whereas quantitative expression of eNOS phosphorylated on the threonine 495 (the inactive form of eNOS) was significantly higher. Lastly, the plasma concentration of ADMA (a uremic toxin and an endogenous inhibitor of eNOS) was elevated and plasma concentration of L-arginine was low in CRF. In conclusion, endothelial function is impaired in a mouse model of early stage CRF. These alterations may be related (at least in part) to a decrease in NO production.

Intestinal Chelators, Sorbants, and Gut-Derived Uremic Toxins.

Chronic kidney disease (CKD) is a highly prevalent condition and is associated with a high comorbidity burden, polymedication, and a high mortality rate. A number of conventional and nonconventional risk factors for comorbidities and mortality in CKD have been identified. Among the nonconventional risk factors, uremic toxins are valuable therapeutic targets. The fact that some uremic toxins are gut-derived suggests that intestinal chelators might have a therapeutic effect. The phosphate binders used to prevent hyperphosphatemia in hemodialysis patients act by complexing inorganic phosphate in the gastrointestinal tract but might conceivably have a nonspecific action on gut-derived uremic toxins. Since phosphorous is a major nutrient for the survival and reproduction of bacteria, changes in its intestinal concentration may impact the gut microbiota's activity and composition. Furthermore, AST-120 is an orally administered activated charcoal adsorbent that is widely used in Asian countries to specifically decrease uremic toxin levels. In this narrative review, we examine the latest data on the use of oral nonspecific and specific intestinal chelators to reduce levels of gut-derived uremic toxins.

Metformin prevents stroke damage in non-diabetic female mice with chronic kidney disease.

Chronic kidney disease (CKD) worsens ischemic stroke severity in both patients and animals. In mice, these poorer functional outcomes are associated with decreased brain activity of AMP-activated protein kinase (AMPK), a molecule that recently emerged as a potential therapeutic target for ischemic stroke. The antidiabetic drug metformin, a well-known activator of AMPK, has improved stroke outcomes in diabetic patients with normal renal function. We investigated whether chronic metformin pre-conditioning can rescue AMPK activity and prevent stroke damage in non-diabetic mice with CKD. Eight-week-old female C57BL/6J mice were assigned to CKD or SHAM groups. CKD was induced through right kidney cortical electrocautery, followed by left total nephrectomy. Mice were then allocated to receive metformin (200 mg/kg/day) or vehicle for 5 weeks until stroke induction by transient middle cerebral artery occlusion (tMCAO). The infarct volumes were lower in CKD mice exposed to metformin than in vehicle-treated CKD mice 24 h after tMCAO. Metformin pre-conditioning of CKD mice improved their neurological score, grip strength, and prehensile abilities. It also enhanced AMPK activation, reduced apoptosis, increased neuron survival and decreased microglia/macrophage M1 signature gene expression as well as CKD-induced activation of the canonical NF-κB pathway in the ischemic lesions of CKD mice.

Cellular and molecular mechanisms associated with ischemic stroke severity in female mice with chronic kidney disease.

Ischemic stroke is highly prevalent in chronic kidney disease (CKD) patients and has been associated with a higher risk of neurological deterioration and in-hospital mortality. To date, little is known about the processes by which CKD worsens ischemic stroke. This work aimed to investigate the cellular and molecular mechanism associated with ischemic stroke severity in an in vivo model of CKD. CKD was induced through right kidney cortical electrocautery in 8-week-old female C57BL/6 J mice followed by left total nephrectomy. Transient middle cerebral artery occlusion (tMCAO) was performed 6 weeks after left nephrectomy. Twenty-four hours after tMCAO, the infarct volumes were significantly wider in CKD than in SHAM mice. CKD mice displayed decreased neuroscore, impaired ability to remain on rotarod device, weaker muscular strength and decreased prehensile score. Apoptosis, neuronal loss, glial cells recruitment and microglia/macrophages M1 signature genes CD32, CD86, IL-1ß, IL-6, MCP1 and iNOS were significantly increased within ischemic lesions of CKD mice. This effect was associated with decreased AMP kinase phosphorylation and increased activation of the NFΚB pathway. Pharmacological targeting of AMP kinase activity, which is known to block microglia/macrophages M1 polarization, appears promising to improve stroke recovery in CKD.

Potentially Common Therapeutic Targets for Multiple Sclerosis and Ischemic Stroke.

Ischemic stroke (IS) and multiple sclerosis (MS) are two pathologies of the central nervous system (CNS). At the first look, this appears to be the only similarity between the two diseases, as they seem quite different. Indeed IS has an acute onset compared to MS which develops chronically; IS is consecutive to blood clot migrating to cerebral blood vessels or decrease in cerebral blood flow following atherosclerosis or decreases in cardiac output, whereas MS is an immune disease associated with neurodegeneration. However, both pathologies share similar pathologic pathways and treatments used in MS have been the object of studies in IS. In this mini-review we will discuss similarities between IS and MS on astrocytes and neuroinflammation hallmarks emphasizing the potential for treatments.

The Impact of Uremic Toxins on Vascular Smooth Muscle Cell Function.

Chronic kidney disease (CKD) is associated with profound vascular remodeling, which accelerates the progression of cardiovascular disease. This remodeling is characterized by intimal hyperplasia, accelerated atherosclerosis, excessive vascular calcification, and vascular stiffness. Vascular smooth muscle cell (VSMC) dysfunction has a key role in the remodeling process. Under uremic conditions, VSMCs can switch from a contractile phenotype to a synthetic phenotype, and undergo abnormal proliferation, migration, senescence, apoptosis, and calcification. A growing body of data from experiments in vitro and animal models suggests that uremic toxins (such as inorganic phosphate, indoxyl sulfate and advanced-glycation end products) may directly impact the VSMCs' physiological functions. Chronic, low-grade inflammation and oxidative stress-hallmarks of CKD-are also strong inducers of VSMC dysfunction. Here, we review current knowledge about the impact of uremic toxins on VSMC function in CKD, and the consequences for pathological vascular remodeling.

Updates on the Mechanisms and the Care of Cardiovascular Calcification in Chronic Kidney Disease.

In chronic kidney disease (CKD), the progressive decrease in renal function leads to disturbances of mineral metabolism that generally cause secondary hyperparathyroidism. The increase in serum parathyroid hormone is associated with reduced serum calcium and calcitriol levels and/or increased serum fibroblast growth factor-23 and phosphate levels. The resulting CKD-associated disorder of mineral and bone metabolism is associated with various other metabolic dysregulations such as acidosis, malnutrition, inflammation, and accumulation of uremic toxins. It favors the occurrence of vascular calcification, which results from an imbalance between numerous inhibitors and promoters of soft-tissue mineralization. This review provides an overview of the most recent state of knowledge concerning the mechanisms that lead to the development of vascular calcification in the CKD setting. It further proposes directions for potential new therapeutic targets.

The Impact of Uremic Toxins on Cerebrovascular and Cognitive Disorders.

Individuals at all stages of chronic kidney disease (CKD) have a higher risk of developing cognitive disorders and dementia. Stroke is also highly prevalent in this population and is associated with a higher risk of neurological deterioration, in-hospital mortality, and poor functional outcomes. Evidence from in vitro studies and in vivo animal experiments suggests that accumulation of uremic toxins may contribute to the pathogenesis of stroke and amplify vascular damage, leading to cognitive disorders and dementia. This review summarizes current evidence on the mechanisms by which uremic toxins may favour the occurrence of cerebrovascular diseases and neurological complications in CKD.

Constrictor and dilator effects of angiotensin II on cerebral arterioles.

BACKGROUND AND PURPOSE: In light of the equivocal data on the cerebral vasoconstrictor and vasodilator actions of angiotensin II (Ang II) and the potential clinical importance of this, we investigated the effects of Ang II on rat pial arterioles. METHODS: We determined the effect of Ang I (3.10(-6) mol/L) in the absence and presence of the converting enzyme inhibitor, captopril (10(-5) mol/L) in cerebral arterioles of male Wistar rats (open-skull preparation), and those of Ang II (3.10(-12) to 3.10(-6) mol/L) in the absence and presence of the Ang II receptor (AT1) antagonist, telmisartan (10(-5) mol/L) or the AT2 antagonist, PD123319 (10(-5) mol/L). We examined the effect of PD123319 (10(-5) mol/L) and the Ca2+-activated K+ (BKCa) channel blocker, tetraethylammonium (10(-4) mol/L) on the Ang II responses in the presence of telmisartan (10(-5) mol/L). RESULTS: Ang II-induced dose-dependent constriction with a maximum decrease of -20.1+/-1.0% at 10(-6) mol/L. Captopril significantly decreased Ang I-induced vasoconstriction (-4.0+/-0.9 versus -21.3+/-2.5%; n=4). Telmisartan reversed Ang II-induced vasoconstriction (9.5+/-2.5 versus -20.1+/-1% at 10(-6) mol/L; n=5). PD123319 significantly increased Ang II-induced vasoconstriction (-12.9+/-0.8 versus -10.2+/-0.4% at 10(-6) mol/L; n=5). PD123319 abolished (-2.6+/-0.7 versus 9.3+/-1.1% at 10(-6) mol/L; n=5) whereas tetraethylammonium reversed (-12.1+/-1.6 versus 9.9+/-1.0% at 10(-6) mol/L; n=4) Ang II-induced vasodilatation in the presence of telmisartan. CONCLUSIONS: Angiotensin is converted locally into Ang II; the overall effect of Ang II is vasoconstrictor following stimulation of the AT1 receptor, but a vasodilator response can be evoked following stimulation of the AT2 receptor and activation of BKCa.

Comparative effects of the angiotensin II receptor blocker, telmisartan, and the angiotensin-converting enzyme inhibitor, ramipril, on cerebrovascular structure in spontaneously hypertensive rats.

OBJECTIVE: Antihypertensive treatment with angiotensin-converting enzyme inhibitors (ACEIs) reverses cerebral arteriolar remodeling, thus restoring dilatation and hence the lower limit of cerebral blood flow (CBF) autoregulation (LLCBF). The objective of this study was to determine whether angiotensin II receptor AT1 blockers (ARBs) produce the same effect. DESIGN: We examined the effects of treatment with an ARB [telmisartan (TEL), 1.93 +/- 0.04 mg/kg per day] or an ACEI [ramipril (RAM), 1.00 +/- 0.02 mg/kg per day] on the cerebral circulation in spontaneously hypertensive rats (SHR). METHODS: Arteriolar pressure and diameter (cranial window) and CBF (laser Doppler) were measured during stepwise hypotensive hemorrhage, before and after deactivation (ethylenediamine tetraacetic acid), in untreated Wistar-Kyoto (WKY) rats and SHR untreated or treated for 3 months with TEL or RAM in the drinking water. RESULTS: Treatment normalized arteriolar internal diameter (SHR, 38 +/- 3 microm; TEL, 52 +/- 2 microm; RAM, 50 +/- 2 microm; WKY, 58 +/- 4 microm), essentially by reversing eutrophic inward remodeling, and the LLCBF (SHR, 80 +/- 11 mmHg; TEL, 60 +/- 4 mmHg; RAM, 71 +/- 6 mmHg; WKY, 57 +/- 5 mmHg). CONCLUSION: The fact that the ARB (TEL) is as effective as an ACEI (RAM) in reversing cerebral arteriolar remodeling suggests that the cerebrovascular AT1 receptor is an underlying mechanism that promotes hypertensive eutrophic inward remodeling.

Captopril improves cerebrovascular structure and function in old hypertensive rats.

We examined the effects of an angiotensin-converting enzyme inhibitor (ACEI), captopril, on cerebral arterioles in young and old spontaneously hypertensive rats (SHR). Animals were anesthetized with sodium pentobarbitone (60 mg kg(-1) day(-1)). We measured cerebral blood flow (CBF, arbitrary units) and cerebral arteriolar internal diameter (ID, mum) prior to and during stepwise hypotension (SH) in 6- (WKY-6) and 15-month-old (WKY-15) Wistar Kyoto rats and in age-matched SHR that were untreated (SHR-6 and SHR-15) or treated for 3 months with captopril (SHR-6C, 105+/-2 mg kg(-1) day(-1) and SHR-15C, 94+/-1 mg kg(-1) day(-1)). ID and cross-sectional area of the vessel wall (CSA) were measured in deactivated (EDTA) cerebral arterioles during a second SH. Captopril decreased the lower limit of CBF autoregulation (61+/-6 in SHR-6C and 51+/-2 in SHR-15C vs 52+/-6 in WKY-6 and 62+/-7 in WKY-15 and 83+/-14 mmHg in SHR-6 and 120+/-19 mmHg in SHR-15; P<0.05) and CSA (510+/-21 in SHR-6C and 585+/-25 in SHR-15C vs 529+/-12 in WKY-6 and 549+/-20 in WKY-15 and 644+/-38 mmHg in SHR-6 and 704+/-38 mmHg in SHR-15; P<0.05). Captopril increased cerebral arteriolar external diameter of SHR (105+/-5 in SHR-6C and 94+/-4 in SHR-15C vs 125+/-8 in WKY-6 and 108+/-3 in WKY-15 and 83+/-2 mmHg in SHR-6 and 80+/-2 mmHg in SHR-15 for a pial arteriolar pressure step of 35-39 mmHg; P<0.05). Captopril attenuated increases in cerebral arteriolar distensibility in young SHR. Thus, ACEIs attenuate eutrophic and hypertrophic inward remodeling of cerebral arterioles in young and old SHR, thus decreasing the lower limit of CBF autoregulation.

Deleterious vascular effects of indoxyl sulfate and reversal by oral adsorbent AST-120.

BACKGROUND: In chronic kidney disease (CKD), blood vessels are permanently exposed to uremic toxins such as indoxyl sulfate (IS). We hypothesized that IS could alter vascular tone and that reducing its serum concentration could be beneficial. DESIGN: We studied acute and longer-term effects of IS and AST-120, an oral charcoal adsorbent, on vascular reactivity, endothelium integrity and expression of adhesion molecules VCAM-1 and ICAM-1 in aortic rings of normal and uremic wild type (WT) mice in vitro, and the cardiovascular effects of AST-120 in both WT and apoE-/- mice with CKD in vivo. RESULTS: In vitro, 1.0 mM IS acutely reduced vascular relaxation (64% for IS 1.0 mM vs. 80% for control, p < 0.05). The effect was more marked after 4 days exposure (39% for IS 1.0 mM 4 days; p < 0.001, prolonged vs. acute exposure), and was associated with endothelial cell loss and upregulation of ICAM-1/VCAM-1 expression. In vitro, AST-120 restored normal vascular function and prevented IS induced endothelial cell loss and ICAM-1/VCAM-1 upregulation. In vivo, AST-120 treatment of CKD mice (1) improved vascular relaxation (72% vs. 48% maximal relaxation in treated vs. untreated mice, p < 0.001), (2) reduced aortic VCAM-1 and ICAM-1 expression, (3) decreased aorta systolic expansion rate (9 ± 3% CKD vs. 14 ± 3% CKD + AST-120, p < 0.02), and (4) prevented the increase in pulse wave velocity (3.56 ± 0.17 m/s CKD vs. 3.10 ± 0.08 m/s CKD + AST-120, p < 0.006). Similar changes were observed in apoE-/- mice. CONCLUSION: IS appears to be an important contributor to the vascular dysfunction associated with CKD. AST-120 treatment ameliorates this dysfunction, possibly via a decrease in serum IS concentration.

Effects of chronic nitric oxide synthase inhibition on cerebral arterioles in Wistar-Kyoto rats.

OBJECTIVE: Cerebral arterioles in stroke-prone spontaneously hypertensive rats (SHRSP), but not in Sprague-Dawley rats with hypertension induced by nitric oxide (NO) synthase inhibition, undergo inward remodeling. The goal of this study was to determine whether development of vascular inward remodeling may depend on genetic factors. DESIGN: We examined effects of NO synthase inhibition on the structure of cerebral arterioles in Wistar-Kyoto rats (WKY), a rat strain genetically distinct from Sprague-Dawley. METHODS: Pressure (servonull), diameter (cranial window) and cross-sectional area of the vessel wall (CSA, histologically) were measured in maximally dilated (EDTA) cerebral arterioles in WKY, untreated (n = 8) or treated for 3 months with the NO synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) (10 mg/kg per day, n = 10) in the drinking water, and in untreated SHRSP (n = 7). RESULTS: Treatment with L-NAME in WKY increased mean cerebral arteriolar pressure (69 +/- 7 versus 47 +/- 7 mmHg, P < 0.05) and pulse pressure (30 +/- 3 versus 17 +/- 1 mmHg, P < 0.05) to levels significantly lower than in SHRSP (98 +/- 5 and 35 +/- 1 mmHg respectively, P < 0.05). CSA was significantly greater in L-NAME-treated WKY and SHRSP than in untreated WKY (1692 +/- 50 and 1525 +/- 98 microm respectively, versus 1224 +/- 85, P < 0.05). External diameter was significantly less in L-NAME-treated WKY than in untreated WKY (119 +/- 5 versus 135 +/- 4 microm, P < 0.05) but significantly greater than in SHRSP (98 +/- 1 microm, P < 0.05). CONCLUSION: Cerebral arterioles undergo hypertrophy and remodeling in WKY with L-NAME-induced hypertension. These findings suggest that genetic factors present in WKY and SHRSP may play a role in the development of vascular inward remodeling during chronic hypertension in rats.

Impact of treatment with melatonin on cerebral circulation in old rats.

Melatonin deprival in young rats induces alterations in cerebral arteriolar wall similar to those observed during aging: atrophy and a decrease in distensibility. In this study, we examined the effects of melatonin treatment on cerebral arteriolar structure and distensibility and on the lower limit of cerebral blood flow autoregulation (LLCBF) in old rats. We measured cerebral blood flow (arbitrary unit, laser Doppler, open skull preparation) prior to and during stepwise hypotension (SH) in adult (12/13 months) and old (24/25 months) IcoWI and WAG/Rij male rats. Old rats were untreated or treated for 3 months with melatonin (0.39 (IcoWi) and 0.44 (Wag/Rij) mg kg-1 day-1, drinking water). Stress-strain relationships were determined using cross-sectional area (CSA, microm2, histometry) and values of arteriolar internal diameter (microm) obtained during a second SH following arteriolar deactivation (EDTA, 67 mmol l(-1)). Aging induced (a) atrophy of the arteriolar wall in IcoWI (616+/-20 vs 500+/-27 microm2, P<0.05) but not in WAG/Rij rats (328+/-25 vs 341+/-20 microm2), (b) a decrease in arteriolar wall distensibility and (c) an increase in the LLCBF in both strains (67+/-10 mmHg in 12-month-old vs 95+/-6 mmHg in 24-month-old IcoWi, P<0.05 and 53+/-2 mmHg in 13-month-old vs 67+/-6 mmHg in 25-month-old WAG/Rij). Melatonin treatment induced in IcoWI and WAG/Rij rats (a) hypertrophy of the arteriolar wall (643+/-34 and 435+/-25 microm2, respectively), (b) an increase in arteriolar wall distensibility and (c) a decrease in the LLCBF (64+/-6 and 45+/-4 mmHg, respectively). Melatonin treatment of old rats induced hypertrophy of the arteriolar wall, prevented the age-linked decrease in cerebral arteriolar distensibility and decreased the LLCBF. British Journal of Pharmacology (2004) 141, 399-406. doi:10.1038/sj.bjp.0705629