Oral Sapropterin Increases Reflex Vasodilation but Not Cardiac Output During Passive Heating in Older Adults

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Acute Cheese Consumption Reduces Sodium Induced Cutaneous Microvascular Dysfunction by Decreasing Oxidative Stress

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A Novel Method For Assessing Cutaneous Reactive Hyperemia With Laser Speckle Contrast Imagery

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An Investigation of Cardiac Dynamics and Substrate Metabolism in an Animal Heart Failure Model

Heart failure (HF) is a condition in which the working heart is unable to meet the blood flow demands of the body. It is the leading cause of early death in the United States and is a progressive, debilitating disease that presently, can only be detected in late, irreversible stages. The progression of HF is complex and poorly understood, involving a number of molecular mechanisms. It is characterized by a complex of symptoms including cardiac hypertrophy and a shift in myocardial substrate utilization, all leading to reduced pumping efficiency of the heart and decreased systemic blood flow. In HF, the failing myocardium becomes more reliant on glucose as a fuel. In contrast, the healthy heart uses fatty acids almost exclusively to meet its energy requirements. The shift to glucose as a predominant fuel is indicative of many dynamic and molecular changes in the heart as HF progresses and is key toward identifying, characterizing, treating and potentially preventing early stage heart failure. The animal model of HF is a vital research tool, allowing for investigation in systems that are physiologically very similar to that of the human. Despite the research challenges caused by the small heart size, mouse models are particularly desirable because they allow for genetic modification and have a rapid reproductive cycle. In this project an albumin perfused murine model was used to imitate the physiological profile of the human heart. The goal of this project was to identify and characterize, in an albumin and fatty acid perfused working mouse heart, left ventricular end diastolic pressure and volume relationships and corresponding rates of myocardial glycolysis and fatty acid oxidation. The exploration of dynamic measures of cardiac physiology in concert with substrate metabolism in a model that closely mimics the human physiological system shows great promise for future research and development of clinical diagnostic tools and novel therapeutic interventions for the prevention or attenuation of heart failure. This novel project, utilizing the albumin and fatty acid perfused working mouse heart lays the groundwork for future investigations of the dynamic and metabolic aspects of HF

Local angiotensin-(1–7) administration improves microvascular endothelial function in women who have had preeclampsia

Despite remission of clinical symptoms postpartum, women who have had preeclampsia demonstrate microvascular endothelial dysfunction, mediated in part by increased sensitivity to angiotensin II (ANG II). Angiotensin-(1–7) [Ang-(1–7)] is an endogenous inhibitor of the actions of ANG II and plausible druggable target in women who had preeclampsia. We therefore examined the therapeutic potential of Ang-(1–7) in the microvasculature of women with a history of preeclampsia (PrEC; n = 13) and parity-matched healthy control women (HC; n = 13) hypothesizing that administration of Ang-(1–7) would increase endothelium-dependent dilation and nitric oxide (NO)-dependent dilation and decrease ANG II-mediated constriction in PrEC. Using the cutaneous microcirculation, we assessed endothelium-dependent vasodilator function in response to graded infusion of acetylcholine (ACh; 10−7 to 102 mmol/L) in control sites and sites treated with 15 mmol/L NG-nitro-l-arginine methyl ester (l-NAME; NO-synthase inhibitor), 100 µmol/L Ang-(1–7), or 15 mmol/L l-NAME + 100 µmol/L Ang-(1–7). Vasoconstrictor function was measured in response to ANG II (10−20-10−4 mol/L) in control sites and sites treated with 100 µmol/L Ang-(1–7). PrEC had reduced endothelium-dependent dilation ( P &lt; 0.001) and NO-dependent dilation ( P = 0.04 vs. HC). Ang-(1–7) coinfusion augmented endothelium-dependent dilation ( P &lt; 0.01) and NO-dependent dilation ( P = 0.03) in PrEC but had no effect in HC. PrEC demonstrated augmented vasoconstrictor responses to ANG II ( P &lt; 0.01 vs. HC), which was attenuated by coinfusion of Ang-(1–7) ( P &lt; 0.001). Ang-(1–7) increased endothelium-dependent vasodilation via NO synthase-mediated pathways and attenuated ANG II-mediated constriction in women who have had preeclampsia, suggesting that Ang-(1–7) may be a viable therapeutic target for improved microvascular function in women who have had a preeclamptic pregnancy. </jats:p