Intermittent parathyroid hormone administration attenuates endothelial dysfunction in old rats.

Aging is an independent risk factor for cardiovascular disease and is characterized by a decline in endothelial function. Parathyroid hormone (PTH) administration has been shown to increase endothelial nitric oxide synthase (eNOS) expression. The purpose of this investigation was to determine the effect of intermittent PTH administration on aortic endothelial function in old rodents. We hypothesized that intermittent PTH administration would improve endothelial function in older rodents. Old (24-mo-old) and young (4-mo-old) Fischer-344 rats were given 10 injections of PTH 1-34 (43 µg·kg-1·day-1) or phosphate-buffered saline (100 µl/day) over 15 days. Endothelium-dependent relaxation of aortic rings in response to acetylcholine (10-9 to 10-5 M) was significantly impaired in old control (OC) compared with young control (YC) as indicated by a reduced area under the curve (AUC, 100 ± 6.28 vs. 54.08 ± 8.3%; P < 0.05) and impaired maximal relaxation (Emax, 70.1 ± 4.48 vs. 92.9 ± 4.38%; P < 0.05). Emax was improved in old animals treated with PTH (OPTH) (OC, 70.1 ± 4.48 vs. OPTH, 85 ± 7.48%; P < 0.05) as well as AUC (OC, 54.08 ± 8.3 vs. OPTH, 82.5 ± 5.7%; P < 0.05) while logEC50 was not different. Endothelial-independent relaxation in response to sodium nitroprusside was not different among groups. Aortic eNOS protein expression was significantly decreased in OC compared with YC (P < 0.05). PTH treatment restored eNOS expression in OPTH animals (P < 0.05). These data suggest that PTH may play a role in attenuating age-related impairments in aortic endothelial function. NEW & NOTEWORTHY: We have demonstrated that intermittent parathyroid hormone administration can rescue age-related vascular dysfunction by improving endothelial-dependent dilation in the aorta of older rodents. This demonstrates a novel potential benefit of parathyroid hormone administration in aging.

High dietary sodium reduces brachial artery flow-mediated dilation in humans with salt-sensitive and salt-resistant blood pressure.

Recent studies demonstrate that high dietary sodium (HS) impairs endothelial function in those with salt-resistant (SR) blood pressure (BP). The effect of HS on endothelial function in those with salt-sensitive (SS) BP is not currently known. We hypothesized that HS would impair brachial artery flow-mediated dilation (FMD) to a greater extent in SS compared with SR adults. Ten SR (age 42 ± 5 yr, 5 men, 5 women) and 10 SS (age 39 ± 5 yr, 5 men, 5 women) healthy, normotensive participants were enrolled in a controlled feeding study consisting of a run-in diet followed by a 7-day low dietary sodium (LS) (20 mmol/day) and a 7-day HS (300 mmol/day) diet in random order. Brachial artery FMD and 24-h BP were assessed on the last day of each diet. SS BP was individually assessed and defined as a change in 24-h mean arterial pressure (MAP) of >5 mmHg between the LS and HS diets (ΔMAP: SR -0.6 ± 1.2, SS 7.7 ± 0.4 mmHg). Brachial artery FMD was lower in both SS and SR individuals during the HS diet (P < 0.001), and did not differ between groups (P > 0.05) (FMD: SR LS 10.6 ± 1.3%, SR HS 7.2 ± 1.5%, SS LS 12.5 ± 1.7%, SS HS 7.8 ± 1.4%). These data indicate that an HS diet impairs brachial artery FMD to a similar extent in adults with SS BP and SR BP.

Cardiac function is preserved following 4 weeks of voluntary wheel running in a rodent model of chronic kidney disease.

The purpose of this investigation was to determine the effect of 4 wk of voluntary wheel running on cardiac performance in the 5/6 ablation-infarction (AI) rat model of chronic kidney disease (CKD). We hypothesized that voluntary wheel running would be effective in preserving cardiac function in AI. Male Sprague-Dawley rats were divided into three study groups: 1) sham, sedentary nondiseased control; 2) AI-SED, sedentary AI; and 3) AI-WR, wheel-running AI. Animals were maintained over a total period of 8 wk following AI and sham surgery. The 8-wk period included 4 wk of disease development followed by a 4-wk voluntary wheel-running intervention/sedentary control period. Cardiac performance was assessed using an isolated working heart preparation. Left ventricular (LV) tissue was used for biochemical tissue analysis. In addition, soleus muscle citrate synthase activity was measured. AI-WR rats performed a low volume of exercise, running an average of 13 ± 2 km, which resulted in citrate synthase activity not different from that in sham animals. Isolated AI-SED hearts demonstrated impaired cardiac performance at baseline and in response to preload/afterload manipulations. Conversely, cardiac function was preserved in AI-WR vs. sham hearts. LV nitrite + nitrate and expression of LV nitric oxide (NO) synthase isoforms 2 and 3 in AI-WR were not different from those of sham rats. In addition, LV H2O2 in AI-WR was similar to that of sham and associated with increased expression of LV superoxide-dismutase-2 and glutathione peroxidase-1/2. The findings of the current study suggest that a low-volume exercise intervention is sufficient to maintain cardiac performance in rats with CKD, potentially through a mechanism related to improved redox homeostasis and increased NO.

Voluntary wheel running augments aortic l-arginine transport and endothelial function in rats with chronic kidney disease.

Reduced nitric oxide (NO) synthesis contributes to risk for cardiovascular disease in chronic kidney disease (CKD). Vascular uptake of the NO precursor l-arginine (ARG) is attenuated in rodents with CKD, resulting in reduced substrate availability for NO synthesis and impaired vascular function. We tested the effect of 4 wk of voluntary wheel running (RUN) and/or ARG supplementation on endothelium-dependent relaxation (EDR) in rats with CKD. Twelve-week-old male Sprague-Dawley rats underwent ⅚ ablation infarction surgery to induce CKD, or SHAM surgery as a control. Beginning 4 wk following surgery, CKD animals either remained sedentary (SED) or received one of the following interventions: supplemental ARG, RUN, or combined RUN+ARG. Animals were euthanized 8 wk after surgery, and EDR was assessed. EDR was significantly impaired in SED vs. SHAM animals after 8 wk, in response to ACh (10(-9)-10(-5) M) as indicated by a reduced area under the curve (AUC; 44.56 ± 9.01 vs 100 ± 4.58, P < 0.05) and reduced maximal response (Emax; 59.9 ± 9.67 vs. 94.31 ± 1.27%, P < 0.05). AUC was not improved by ARG treatment but was significantly improved above SED animals in both RUN and RUN+ARG-treated animals. Maximal relaxation was elevated above SED in RUN+ARG animals only. l-[(3)H]arginine uptake was impaired in both SED and ARG animals and was improved in RUN and RUN+ARG animals. The results suggest that voluntary wheel running is an effective therapy to improve vascular function in CKD and may be more beneficial when combined with l-arginine.

Lower potassium intake is associated with increased wave reflection in young healthy adults.

BACKGROUND: Increased potassium intake has been shown to lower blood pressure (BP) even in the presence of high sodium consumption however the role of dietary potassium on vascular function has received less attention. The aim of this study was to evaluate the relationship between habitual intake of sodium (Na) and potassium (K) and measures of arterial stiffness and wave reflection. METHODS: Thirty-six young healthy adults (21 M, 15 F; 24 ± 0.6 yrs; systolic BP 117 ± 2; diastolic BP 63 ± 1 mmHg) recorded their dietary intake for 3 days and collected their urine for 24 hours on the 3rd day. Carotid-femoral pulse wave velocity (PWV) and the synthesis of a central aortic pressure waveform (by radial artery applanation tonometry and generalized transfer function) were performed. Aortic augmentation index (AI), an index of wave reflection, was calculated from the aortic pressure waveform. RESULTS: Subjects consumed an average of 2244 kcals, 3763 mg Na, and 2876 mg of K. Average urinary K excretion was 67 ± 5.3 mmol/24 hr, Na excretion was 157 ± 11 mmol/24 hr and the average Na/K excretion ratio was 2.7 ± 0.2. An inverse relationship between AI and K excretion was found (r = -0.323; p < 0.05). A positive relationship between AI and the Na/K excretion ratio was seen (r = 0.318; p < 0.05) while no relationship was noted with Na excretion alone (r = 0.071; p > 0.05). Reflection magnitude, the ratio of reflected and forward waves, was significantly associated with the Na/K excretion ratio (r = 0.365; p <0.05) but not Na or K alone. PWV did not correlate with Na or the Na/K excretion ratio (p > 0.05) but showed an inverse relationship with K excretion (r = -0.308; p < 0.05). CONCLUSIONS: These data suggest that lower potassium intakes are associated with greater wave reflection and stiffer arteries in young healthy adults.

Impaired L-arginine uptake but not arginase contributes to endothelial dysfunction in rats with chronic kidney disease.

Reduced nitric oxide bioavailability contributes to increased cardiovascular disease risk in patients with chronic kidney disease (CKD). Arginase has been implicated as a potential therapeutic target to treat vascular dysfunction by improving substrate availability for endothelial nitric oxide synthase. The purpose of this study was to determine if arginase contributes to endothelial dysfunction in the 5/6 ablation infarction (AI) rat model of CKD. Endothelium-dependent relaxation of aortic rings to acetylcholine was significantly impaired in AI animals versus sham after 8 weeks and was not improved by arginase inhibition (S-(2-Boronoethyl)-L-cysteine hydrochloride) alone or in combination with L-arginine. Additionally, scavenging of superoxide (Tempol, Tempol + L-arginine, Tempol + L-arginine + S-(2-Boronoethyl)-L-cysteine hydrochloride) was not effective, suggesting that a mechanism independent of oxidative stress contributes to endothelium-dependent relaxation in moderate to severe CKD. Aortic uptake of radiolabeled L-arginine was attenuated in AI animals and was associated with a reduced expression of the L-arginine transporter CAT-1. These data suggest that arginase does not contribute to endothelial dysfunction in CKD; however, impaired L-arginine transport may play an important role in diminishing substrate availability for nitric oxide production leading to endothelial dysfunction.

Cardiac function and tolerance to ischemia-reperfusion injury in chronic kidney disease.

BACKGROUND: Cardiac dysfunction is an independent risk factor of ischemic heart disease and mortality in chronic kidney disease (CKD) patients, yet the relationship between impaired cardiac function and tolerance to ischemia-reperfusion (IR) injury in experimental CKD remains unclear. METHODS: Cardiac function was assessed in 5/6 ablation-infarction (AI) and sham male Sprague-Dawley rats at 20 weeks of age, 8 weeks post-surgery using an isolated working heart system. This included measures taken during manipulation of preload and afterload to produce left ventricular (LV) function curves as well as during reperfusion following a 15-min ischemic bout. In addition, LV tissue was used for biochemical tissue analysis. RESULTS: Cardiac function was impaired in AI animals during preload and afterload manipulations. Cardiac functional impairments persisted post-ischemia in the AI animals, and 36% of AI animals did not recover sufficiently to achieve aortic overflow following ischemia (versus 0% of sham animals). However, for those animals able to withstand the ischemic perturbation, no difference was observed in percent recovery of post-ischemic cardiac function between groups. Urinary NOx (nitrite + nitrate) excretion was lower in AI animals and accompanied by reduced LV endothelial nitric oxide synthase and NOx. LV antioxidants superoxide dismutase-1 and -2 were reduced in AI animals, whereas glutathione peroxidase-1/2 as well as NADPH-oxidase-4 and H(2)O(2) were increased in these animals. CONCLUSIONS: Impaired cardiac function appears to predispose AI rats to poor outcomes following short-duration ischemic insult. These findings could be, in part, mediated by increased oxidative stress via nitric oxide-dependent and -independent mechanisms.

Exercise as an Adjunct Therapy In Chronic Kidney Disease.

Physical activity levels are low in patients with chronic kidney disease (CKD). Evidence indicates that a sedentary lifestyle contributes to increased morbidity and mortality risk; thus, increasing physical activity is an undeniable aspect of a healthy lifestyle. Despite the myriad of health benefits associated with exercise, as well as clinical guidelines in its favor, exercise is still not prescribed as part of routine care in the CKD patient population. This article briefly discusses the benefits of regular exercise implemented across all stages of CKD on independent predictors of survival such as cardiorespiratory fitness, cardiovascular health and protein-energy wasting. Health care providers of the multidisciplinary nephrology team play a pivotal role in the encouragement and implementation of increasing physical activity levels. In order to increase physical activity counseling and enhance healthcare providers' confidence in prescribing exercise for CKD patients, general recommendations for physical activity in these patients are provided.

High dietary sodium intake impairs endothelium-dependent dilation in healthy salt-resistant humans.

BACKGROUND: Excess dietary sodium has been linked to the development of hypertension and other cardiovascular diseases. In humans, the effects of sodium consumption on endothelial function have not been separated from the effects on blood pressure. The present study was designed to determine if dietary sodium intake affected endothelium-dependent dilation (EDD) independently of changes in blood pressure. METHOD: Fourteen healthy salt-resistant adults were studied (9M, 5F; age 33 ±â€Š2.4 years) in a controlled feeding study. After a baseline run-in diet, participants were randomized to a 7-day high-sodium (300-350 mmol/day) and 7-day low-sodium (20 mmol/day) diet. Salt resistance, defined as a 5 mmHg or less change in a 24-h mean arterial pressure, was individually assessed while on the low-sodium and high-sodium diets and confirmed in the participants undergoing study (low-sodium: 85 ±â€Š1 mmHg; high-sodium: 85 ±â€Š2 mmHg). EDD was determined in each participant via brachial artery flow-mediated dilation on the last day of each diet. RESULTS: Sodium excretion increased during the high-sodium diet (P < 0.01). EDD was reduced on the high-sodium diet (low: 10.3 ±â€Š0.9%, high: 7.3 ±â€Š0.7%; P < 0.05). The high-sodium diet significantly suppressed plasma renin activity (PRA), plasma angiotensin II, and aldosterone (P < 0.05). CONCLUSION: These data demonstrate that excess salt intake in humans impairs endothelium-dependent dilation independently of changes in blood pressure.

Dietary sodium loading impairs microvascular function independent of blood pressure in humans: role of oxidative stress.

Animal studies have reported dietary salt-induced reductions in vascular function independent of increases in blood pressure (BP). The purpose of this study was to determine if short-term dietary sodium loading impairs cutaneous microvascular function in normotensive adults with salt resistance. Following a control run-in diet, 12 normotensive adults (31 ± 2 years) were randomized to a 7 day low-sodium (LS; 20 mmol day(-1)) and 7 day high-sodium (HS; 350 mmol day(-1)) diet (controlled feeding study). Salt resistance, defined as a 5 mmHg change in 24 h mean BP determined while on the LS and HS diets, was confirmed in all subjects undergoing study (LS: 84 ± 1 mmHg vs. HS: 85 ± 2 mmHg; P > 0.05). On the last day of each diet, subjects were instrumented with two microdialysis fibres for the local delivery of Ringer solution and 20 mm ascorbic acid (AA). Laser Doppler flowmetry was used to measure red blood cell flux during local heating-induced vasodilatation (42°C). After the established plateau, 10 mm l-NAME was perfused to quantify NO-dependent vasodilatation. All data were expressed as a percentage of maximal cutaneous vascular conductance (CVC) at each site (28 mm sodium nitroprusside; 43°C). Sodium excretion increased during the HS diet (P < 0.05). The plateau % CVCmax was reduced during HS (LS: 93 ± 1 % CVCmax vs. HS: 80 ± 2 % CVCmax; P < 0.05). During the HS diet, AA improved the plateau % CVCmax (Ringer: 80 ± 2 % CVCmax vs. AA: 89 ± 3 % CVCmax; P < 0.05) and restored the NO contribution (Ringer: 44 ± 3 % CVCmax vs. AA: 59 ± 6 % CVCmax; P < 0.05). These data demonstrate that dietary sodium loading impairs cutaneous microvascular function independent of BP in normotensive adults and suggest a role for oxidative stress.

Cellular and molecular mechanisms of apoptosis in age-related muscle atrophy.

Age-related muscle atrophy is due to loss of muscle fibers as well as atrophy of the remaining fibers. Evidence shows that loss of myofibers may be, in part, due to apoptosis. Two major apoptotic pathways have been extensively studied which are the mitochondrion-mediated and receptor-mediated pathways. However, other pathways exist, such as the p53 pathway. To date, it is not completely clear what pathways are responsible for loss of fibers in age-related muscle atrophy. Evidence suggests that multiple pathways may play a role. In this review article the effects of aging on the mitochondrion-, receptor-, and p53-mediated apoptotic pathways in skeletal muscle are discussed.

The effects of vitamin D on skeletal muscle function and cellular signaling.

It is thought that every cell in the body expresses the vitamin D receptor, and therefore vitamin D may play a role in health and homeostasis of every organ system, including skeletal muscle. Human, animal, and cell culture studies have collectively shown that vitamin D affects muscle strength and function. Vitamin D functions in a plethora of cellular processes in skeletal muscle including calcium homeostasis, cell proliferation, cell differentiation, fiber size, prevention of fatty degeneration, protection against insulin resistance and arachidonic acid mobilization. These processes appear to be mediated by several signaling pathways affected by vitamin D. This review aims to explore the effects of vitamin D on skeletal muscle in each model system and to delineate potential cell signaling pathways affected by vitamin D.

Cardiac-specific overexpression of catalase identifies hydrogen peroxide-dependent and -independent phases of myocardial remodeling and prevents the progression to overt heart failure in G(alpha)q-overexpressing transgenic mice.

BACKGROUND: Although it seems that reactive oxygen species contribute to chronic myocardial remodeling, questions remain about (1) the specific types of reactive oxygen species involved, (2) the role of reactive oxygen species in mediating specific cellular events, and (3) the cause-and-effect relationship between myocardial reactive oxygen species and the progression to heart failure. Transgenic mice with myocyte-specific overexpression of G(alpha)q develop a dilated cardiomyopathy that progresses to heart failure. We used this model to examine the role of H(2)O(2) in mediating myocardial remodeling and the progression to failure. METHODS AND RESULTS: In G(alpha)q myocardium, markers of oxidative stress were increased at 4 weeks and increased further at 20 weeks. G(alpha)q mice were crossbred with transgenic mice having myocyte-specific overexpression of catalase. At 4 weeks of age, left ventricular end-diastolic dimension was increased and left ventricular fractional shortening decreased in G(alpha)q mice and deteriorated further through 20 weeks. In G(alpha)q mice, myocardial catalase overexpression had no effect on left ventricular end-diastolic dimension or fractional shortening at 4 weeks but prevented the subsequent deterioration in both. In G(alpha)q mice, myocyte hypertrophy; myocyte apoptosis; interstitial fibrosis; and the progression to overt heart failure, as reflected by lung congestion and exercise intolerance, were prevented by catalase overexpression. CONCLUSIONS: In G(alpha)q mice, myocyte-specific overexpression of catalase had no effect on the initial phenotype of left ventricular dilation and contractile dysfunction but prevented the subsequent progressive remodeling phase leading to heart failure. Catalase prevented the cellular hallmarks of adverse remodeling (myocyte hypertrophy, myocyte apoptosis, and interstitial fibrosis) and the progression to overt heart failure. Thus, H(2)O(2), associated oxidant pathways, or both play a critical role in adverse myocardial remodeling and the progression to failure.