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Arginine impairs endothelial and executive function in older subjects with cardiovascular risk.

ABSTRACT: Neurovascular coupling, the relationship between cerebral blood flow and neuronal activity, is attenuated in patients with impaired executive function. We tested the hypothesis that peripheral vascular function may associate with executive function in older subjects with cardiovascular risk factors and that treatment with the antioxidant L-arginine would improve both vascular and executive function. Nineteen subjects with type 2 diabetes mellitus and/or controlled hypertension were enrolled. Subjects were treated with L-arginine or placebo for 4 days in a randomized, double-blinded, cross-over study. Brachial artery vascular function, peripheral artery tonometry, and Trail Making Test Part B testing were performed on day 1 and day 4 during each condition. L-arginine significantly reduced the digital reactive hyperemia index, and the comparison of changes against placebo was significant (P = .01). With executive function testing, we observed a significant interaction between treatment and order. Restricting the analysis to the first treatment period, subjects treated with placebo decreased their Trail Making Test Part B times by 57.3 ± 52.5 seconds from day 1 to day 4 (P = .01) while those treated with arginine had no significant change (6.4 ± 18.4 seconds worse, P = .37). In addition, L-arginine was associated with increased mean arterial pressure from 88 ± 9 mm Hg to 92 ± 11 mm Hg, which trended toward significance. L-arginine treatment worsened digital microvascular and executive function in older subjects with cardiovascular risk factors. These data further support a link between vascular and executive function.

SUBMITTER: Beckman JA

PROVIDER: S-EPMC6151275 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Arginine impairs endothelial and executive function in older subjects with cardiovascular risk.

Beckman Joshua A JA Hurwitz Shelley S Fisher Naomi D L NDL

Journal of the American Society of Hypertension : JASH 20180710 10

Neurovascular coupling, the relationship between cerebral blood flow and neuronal activity, is attenuated in patients with impaired executive function. We tested the hypothesis that peripheral vascular function may associate with executive function in older subjects with cardiovascular risk factors and that treatment with the antioxidant L-arginine would improve both vascular and executive function. Nineteen subjects with type 2 diabetes mellitus and/or controlled hypertension were enrolled. Sub ...[more]

PMID: 30057253

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Project description:Discrete calcium signals within the vascular endothelium decrease with age and contribute to impaired endothelial-dependent vasodilation. Calreticulin (Calr), a multifunctional calcium binding protein and endoplasmic reticulum (ER) chaperone, can mediate calcium signals and vascular function within the endothelial cells (ECs) of small resistance arteries. We found Calr protein expression significantly decreases with age in mesenteric arteries and examined the functional role of EC Calr in vasodilation and calcium mobilization in the context of aging. Third-order mesenteric arteries from mice with or without EC Calr knockdown were examined for calcium signals and constriction to phenylephrine (PE) or vasodilation to carbachol (CCh) after 75 wk of age. PE constriction in aged mice with or without EC Calr was unchanged. However, calcium signals and vasodilation to endothelial-dependent agonist carbachol were significantly impaired in aged EC Calr knockdown mice. Ex vivo incubation of arteries with the ER stress inhibitor tauroursodeoxycholic acid (TUDCA) significantly improved vasodilation in mice lacking EC Calr. Our data suggests diminished vascular Calr expression with age can contribute to the detrimental effects of aging on endothelial calcium regulation and vasodilation.NEW & NOTEWORTHY Calreticulin (Calr) is responsible for key physiological processes in endoplasmic reticulum, especially in aging tissue. In particular, endothelial Calr is crucial to vascular function. In this study, we deleted Calr from the endothelium and aged the mice up to 75 wk to examine changes in vascular function. We found two key differences: 1) calcium events in endothelium were severely diminished after muscarinic stimulation, which 2) corresponded with a dramatic decrease in muscarinic vasodilation. Remarkably, we were able to rescue the effect of Calr deletion on endothelial-dependent vasodilatory function using tauroursodeoxycholic acid (TUDCA), an inhibitor of endoplasmic reticulum stress that is currently in clinical trials.

Project description:IntroductionDynamic retinal vessel analysis (DVA) is a new non-invasive method to quantify microvascular endothelial dysfunction by flicker light-induced dilatation (FID). FID has been shown to be impaired in type 2 diabetes as well as heart failure. The aim of the study was to analyze FID in healthy active versus healthy sedentary and cardiovascular (CV) risk patients in addition to corresponding static vessel diameters.MethodsThirty-one healthy active (HA, mean age 60 ± 8 years), 33 healthy sedentary individuals (HS, 59 ± 7 years) and 76 sedentary patients with increased CV risk (SR, 58 ± 6 years) were included in this cross-sectional study. Group differences in CV risk factors and cardiorespiratory fitness, maximal arteriolar (ADmax) and venular (VDmax) dilatation as well as the arteriolar (AFarea) and venular (VFarea) area under the flicker curve were analyzed. The central retinal arteriolar and venular diameters were used to calculate the arteriolar-to-venular diameter ratio (AVR).ResultsHS [ADmax = 3.5 (2.1)%; AFarea = 48.2 (31.9)%∗s] showed higher FID compared to SR [ADmax = 2.7 (1.8)%, p = 0.021; AFarea = 34.5 (26.5)%∗s, p = 0.006] and HA [AFarea = 32.8 (23.1)%∗s, p = 0.029]. HA and SR did not significantly differ. HA had a higher AVR (0.87 ± 0.05) compared to HS (0.83 ± 0.04, p < 0.001) with further deterioration in SR (0.79 ± 0.05, p < 0.001). Interestingly, 28 participants had impaired FID but normal AVR and 43 participants had normal FID but impaired AVR.DiscussionFID can differentiate between sedentary low and high risk individuals. However, FID in healthy active persons (HA) seemed impaired with a concomitant higher AVR. We postulate that lower FID in HA may be explained by predilatated arterioles and a reduced dilatation reserve. We recommend combination of FID with analysis of retinal vessel diameters to differentiate functional non-responders from manifest microvascular endothelial dysfunction and, thereby, improve microvascular risk stratification in a personalized medicine approach.Clinical trial registrationClinicalTrials.gov: NCT02796976 (https://clinicaltrials.gov/ ct2/show/NCT02796976).

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Arginine impairs endothelial and executive function in older subjects with cardiovascular risk.

Publications

Arginine impairs endothelial and executive function in older subjects with cardiovascular risk.

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