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      Early Exercise Training After Renal Transplantation and Asymmetric Dimethylarginine: The Effect of Obesity

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          Background/Aims : To assess, in a prospective cohort study of 238 renal transplant patients, our hypothesis that elevated ADMA levels may be influenced by physical exercise and obesity. Methods : Blood samples before and after six months were obtained from 116 transplant patients participating in an aerobic exercise (Group I). A control group consisted of 122 matched transplant patients who did not exercise regularly (Group II). Results : There were no significant differences in ADMA levels between both groups before the training program (Group I<sub>B</sub> vs Group II<sub>B</sub>). After six months of exercise, ADMA levels in Group I decreased (Group I<sub>B</sub> vs Group I<sub>A</sub> : 3.50 ± 0.45 vs 2.11 ± 0.35μmol/L; p< 0.01) and were lower compared to those in Group II (Group I<sub>A</sub> vs Group II<sub>A</sub> : 2 11 ± 0 23 vs 3 25 ± 0 34μmol/L; p< 0 01) Analysis of our results in obese renal transplant recipients (BMI B 30 kg/m<sup>2</sup>) confirmed a smaller effect of exercise training (Group I<sub>BO</sub> vs Group I<sub>AO</sub> : 3 75 ± 0 52 vs 3 45 ± 0 45; p< 0 05 and Group I<sub>AO</sub> vs Group II<sub>AO</sub> : 3.45 ± 0.45 vs 3.74 ± 0.62; p<0.05). Blood lipids, HbA<sub>1C</sub>, insulin, and systolic BP were also affected by the training program. Conclusion : Elevated ADMA levels were significantly decreased by early exercise after renal transplantation. The effect of exercise was smaller in obese patients.

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          Asymmetric dimethylarginine causes hypertension and cardiac dysfunction in humans and is actively metabolized by dimethylarginine dimethylaminohydrolase.

          Plasma levels of an endogenous nitric oxide (NO) synthase inhibitor, asymmetric dimethylarginine (ADMA), are elevated in chronic renal failure, hypertension, and chronic heart failure. In patients with renal failure, plasma ADMA levels are an independent correlate of left ventricular ejection fraction. However, the cardiovascular effects of a systemic increase in ADMA in humans are not known. In a randomized, double-blind, placebo-controlled study in 12 healthy male volunteers, we compared the effects of intravenous low-dose ADMA and placebo on heart rate, blood pressure, cardiac output, and systemic vascular resistance at rest and during exercise. We also tested the hypothesis that ADMA is metabolized in humans in vivo by dimethylarginine dimethylaminohydrolase (DDAH) enzymes. Low-dose ADMA reduced heart rate by 9.2+/-1.4% from 58.9+/-2.0 bpm (P<0.001) and cardiac output by 14.8+/-1.2% from 4.4+/-0.3 L/min (P<0.001). ADMA also increased mean blood pressure by 6.0+/-1.2% from 88.6+/-3.4 mm Hg (P<0.005) and SVR by 23.7+/-2.1% from 1639.0+/-91.6 dyne. s. cm-5 (P<0.001). Handgrip exercise increased cardiac output in control subjects by 96.8+/-23.3%, but in subjects given ADMA, cardiac output increased by only 35.3+/-10.6% (P<0.05). DDAHs metabolize ADMA to citrulline and dimethylamine. Urinary dimethylamine to creatinine ratios significantly increased from 1.26+/-0.32 to 2.73+/-0.59 after ADMA injection (P<0.01). We estimate that humans generate approximately 300 micromol of ADMA per day, of which approximately 250 micromol is metabolized by DDAHs. This study defines the cardiovascular effects of a systemic increase in ADMA in humans. These are similar to changes seen in diseases associated with ADMA accumulation. Finally, our data also indicate that ADMA is metabolized by DDAHs extensively in humans in vivo.
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            Elevated plasma asymmetric dimethylarginine as a marker of cardiovascular morbidity in early diabetic nephropathy in type 1 diabetes.

            Increased plasma concentration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, has been associated with endothelial dysfunction, insulin resistance, and atherosclerosis in nondiabetic populations. In end-stage renal failure, circulating ADMA is elevated and a strong predictor of cardiovascular outcome. This study investigated the relation between ADMA and diabetic micro- and macrovascular complications in a large cohort of type 1 diabetic patients with and without early diabetic nephropathy. ADMA concentrations in plasma were determined by a high-performance liquid chromatography method in 408 type 1 diabetic patients with overt diabetic nephropathy (252 men; mean age 42.7 years [SD 11.0], mean duration of diabetes 28 years [SD 9], median serum creatinine level 102 micromol/l [range 52-684]). A group of 192 patients with longstanding type 1 diabetes and persistent normoalbuminuria served as control subjects (118 men; mean age 42.6 years [SD 10.2], mean duration of diabetes 27 years [SD 9]). In patients with diabetic nephropathy, mean +/- SD plasma ADMA concentration was elevated 0.46 +/- 0.08 vs. 0.40 +/- 0.08 micromol/l in normoalbuminuric patients (P 0.2). However, in 44 patients with nephropathy and history of myocardial infarction and/or stroke, ADMA was significantly elevated at 0.48 +/- 0.08 micromol/l compared with 0.46 +/- 0.08 micromol/l in patients without major cardiovascular events (P=0.05). Elevated circulating ADMA may contribute to the excess cardiovascular morbidity and mortality in early diabetic nephropathy.
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              Weight loss in combination with physical activity improves endothelial dysfunction in human obesity.

              To test whether weight loss may improve endothelial dysfunction in human obesity, we recruited 28 healthy obese subjects, aged 30-46 years, with BMI 30-43 kg/m(2). Endothelium-dependent and -independent vasodilation were investigated by intra-arterial infusion of increasing doses of acetylcholine (ACh; 7.5, 15, and 30 microg x ml(-1) x min(-1)) and sodium nitroprusside (0.8, 1.6, and 3.2 microg x ml(-1) x min(-1)). Insulin resistance was estimated by homeostasis model assessment (HOMA). Weight loss was obtained by caloric restriction and physical activity. We observed a significant reduction in BMI (from 33.1 +/- 4.2 to 27.5 +/- 4.5 kg/m(2), -16.9%, P < 0.0001) and in waist circumference (from 108.2 +/- 12.1 to 96.8 +/- 12.9 cm, -10.5%, P < 0.0001). Weight loss was also associated with a significant increase in ACh-stimulated forearm blood flow (FBF), from 7.4 +/- 2.8 to 12.9 +/- 3.4 ml. 100 ml(-1) of tissue x min(-1) kg/m(2) (P < 0.0001). Multivariate regression analysis demonstrated that the only independent predictor of FBF was HOMA, accounting for 44.5% of the variation, whereas the addition of BMI explained another 2.3% of the variation. Our data demonstrate that energy-restricted diet associated with physical activity induce a significant and clinically relevant improvement in ACh-stimulated vasodilation in obese healthy subjects.

                Author and article information

                Kidney Blood Press Res
                Kidney and Blood Pressure Research
                S. Karger AG
                November 2014
                27 August 2014
                : 39
                : 4
                : 289-298
                aDepartment of Nephrology, Transplant Centre, Institute for Clinical and Experimental Medicine and Institute for Postgraduate Education; bFaculty of Physical Education and Sport, Charles University; cCardiovascular Research Centre, Institute for Clinical and Experimental Medicine, Prague; dInstitute of Clinical Biochemistry and Hematology, Medical Faculty, Charles University, Pilsen; eDepartment of Surgery, 3 rd Medical Faculty, Charles University, Prague; fDepartment of Internal Medicine, Medical Faculty, Ostrava University, Ostrava, Czech Republic
                Author notes
                *Prof. Vladimir Teplan, MD, PhD, DSc, Department of Nephrology, Transplant Centre, Institute for Clinical and Experimental, Medicine, Videnska 1958/9, 140 21 Prague 4 (Czech Republic), Tel. +420-2-261363121, Fax +420-2-261363168, E-Mail
                355806 Kidney Blood Press Res 2014;39:289-298
                © 2014 S. Karger AG, Basel

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                Page count
                Pages: 10
                Original Paper

                Cardiovascular Medicine, Nephrology

                Physical Exercise, Renal Transplantation, ADMA, Obesity


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