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Salt Lake City, UT, United States

Kohan D.E.,University of Utah | Kohan D.E.,Salt Lake Veterans Affairs Medical Center
Current Opinion in Nephrology and Hypertension | Year: 2010

Purpose of Review: Endothelin is important in the development of cardiorenal disease. This review discusses recent developments in understanding endothelin's role in hypertension and chronic kidney disease (CKD). Recent Findings: Endothelin-1 production is increased in hypertension and CKD. Endothelin-1 stimulates vasoconstriction, inflammation and fibrosis, thereby promoting hypertension, atherosclerosis and CKD. These effects are closely linked to angiotensin II and reactive oxygen species. In preclinical studies, endothelin receptor antagonists were effective in treating hypertension (particularly with endothelial dysfunction) and CKD. In preclinical studies, endothelin A-selective, as opposed to combined endothelin A and B, receptor blockers have generally been more efficacious. Few clinical trials have been conducted in hypertension and/or kidney disease, partly due to concerns over side effects of testicular toxicity and fluid retention. Endothelin blockade reduces blood pressure in patients with resistant hypertension, with additional beneficial metabolic effects. Endothelin antagonism improves proteinuria in CKD (diabetic or not), particularly in patients taking inhibitors of angiotensin II action. Summary: Endothelin is a promising target in the treatment of resistant hypertension and CKD, with additional potential benefits on atherosclerosis and the metabolic syndrome. The nature and mechanisms of drug side effects require elucidation before the potential of this new class of drugs can be fully realized. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source


Addison O.,University of Maryland Baltimore County | Addison O.,Geriatric Research | Addison O.,Bt Inc. | Drummond M.J.,University of Utah | And 6 more authors.
Journal of Nutrition, Health and Aging | Year: 2014

Objectives: Intramuscular adipose tissue (IMAT) is recognized as a negative predictor of both muscle and mobility function in older adults, however the mechanism by which IMAT may negatively influence muscle and mobility function is currently unknown. The release of pro-inflammatory cytokines from IMAT provides a potential reason for these negative associations. To explore this hypothesis we compared IMAT and muscular inflammation in age-and BMI-matched older non-obese frail and non-frail adults. We also sought to examine the relationship between IMAT and inflammation, and muscle and mobility function in this group of older adults. Design: A case-control sampling was used for this study. Age-and BMI-matched non-obese frail and non-frail individuals (<65 years) were recruited. Measurements: MRI was used to quantify thigh IMAT and lean tissue. Unilateral muscle biopsies were used to quantify muscular inflammation as represented by interleukin-6 (IL-6) and tumor-necrosis factor alpha (TNF-α). Muscle and mobility function was also measured using a maximal voluntary isometric contraction, six-minute walk, and self-selected gait speed. Participants: 26 older (80.7 +/− 5.4 years) individuals (8 frail and 18 non-frail) were enrolled. Results: The frail-group had increased IMAT (p<0.01) and decreased lean tissue (p<0.01), and elevated IL-6 muscle mRNA (p=0.02) and IL-6 protein content (p=0.02) compared to the non-frail group. IMAT was significantly associated with IL-6 mRNA (r=0.43, p=.04) and protein expression within the muscle (r=0.41, p= 0.045). IL-6 mRNA was significantly associated with six-minute walk (r=−0.63, p<0.01), and gait speed (r=−0.60, p <0.01) and IL-6 protein was significantly associated with muscle force (r=−0.54, p=0.01), six-minute walk (r=−0.66, p<0.01), and gait speed (r=−0.76, p<0.01). No significant relationships were found for any variables with TNF-α. Conclusion: Non-obese, older, frail individuals have increased IMAT and muscular inflammation when compared to their non-frail, age- and BMI-matched peers. A significant relationship exists between IMAT and muscle IL-6 expression as well as between IL-6 and muscle and mobility function of these older adults. This IMAT-inflammatory pathway provides a potential link between IMATs and decreased muscle and mobility function. © 2014, Serdi and Springer-Verlag France. Source


Addison O.,University of Maryland Baltimore County | Addison O.,Geriatric Research | Drummond M.J.,University of Utah | Lastayo P.C.,University of Utah | And 5 more authors.
Journal of Nutrition, Health and Aging | Year: 2014

Objectives: Intramuscular adipose tissue (IMAT) is recognized as a negative predictor of both muscle and mobility function in older adults, however the mechanism by which IMAT may negatively influence muscle and mobility function is currently unknown. The release of pro-inflammatory cytokines from IMAT provides a potential reason for these negative associations. To explore this hypothesis we compared IMAT and muscular inflammation in age-and BMI-matched older non-obese frail and non-frail adults. We also sought to examine the relationship between IMAT and inflammation, and muscle and mobility function in this group of older adults. Design: A case-control sampling was used for this study. Age-and BMI-matched non-obese frail and non-frail individuals (<65 years) were recruited. Measurements: MRI was used to quantify thigh IMAT and lean tissue. Unilateral muscle biopsies were used to quantify muscular inflammation as represented by interleukin-6 (IL-6) and tumor-necrosis factor alpha (TNF-α). Muscle and mobility function was also measured using a maximal voluntary isometric contraction, six-minute walk, and self-selected gait speed. Participants: 26 older (80.7 +/- 5.4 years) individuals (8 frail and 18 non-frail) were enrolled. Results: The frail-group had increased IMAT (p<0.01) and decreased lean tissue (p<0.01), and elevated IL-6 muscle mRNA (p=0.02) and IL-6 protein content (p=0.02) compared to the non-frail group. IMAT was significantly associated with IL-6 mRNA (r=0.43, p=.04) and protein expression within the muscle (r=0.41, p= 0.045). IL-6 mRNA was significantly associated with six-minute walk (r=-0.63, p<0.01), and gait speed (r=-0.60, p <0.01) and IL-6 protein was significantly associated with muscle force (r=-0.54, p=0.01), six-minute walk (r=-0.66, p<0.01), and gait speed (r=-0.76, p<0.01). No significant relationships were found for any variables with TNF-a. Conclusion: Non-obese, older, frail individuals have increased IMAT and muscular inflammation when compared to their non-frail, age- and BMI-matched peers. A significant relationship exists between IMAT and muscle IL-6 expression as well as between IL-6 and muscle and mobility function of these older adults. This IMAT-inflammatory pathway provides a potential link between IMATs and decreased muscle and mobility function. Source


Marcus R.L.,University of Utah | Addison O.,University of Utah | Lastayo P.C.,University of Utah | Hungerford R.,University of Utah | And 5 more authors.
Journal of Endocrinological Investigation | Year: 2013

Background: Aging is associated with a decline in skeletal muscle size.Muscle is critical both for mobility and glucose disposal. While resistance exercise (RE) increases muscle mass and function in the elderly, its role in improving glucose utilization is less clear. Aims: To investigate whether muscle size was linked with insulin sensitivity (IS) in elders with diabetes following RE and if regional muscle glucose uptake differed from systemic glucose utilization. Methods: Seven (68.4±5.9 yr) adults with diabetes participated. After 16 weeks of RE, within 24 h (post 1) and after 1 week of no exercise (post 2), lean tissue cross-sectional area (CSA) and IS via glucose infusion rate (GIR) were assessed along with a standardized 18-F fluorodeoxyglucose (FDG)-positron emission tomography uptake value (SUV). Results: CSA increased between pre-test (108.5±35.3 cm2) and post 1 (116.8±40.9 cm2), p=0.02 and did not differ at post 2 (116.0±39.3 cm2). GIR during the 40 mU/m2/min insulin clamp differed between pretest (22.0±15.8 mg/kg/min) and post 1 (67.9±72.8 mg/kg/min), and post 1 and post 2 (25.0±27.2 mg/kg/min) but not between pre-test and post 2. GIR results during the 200 mU/m2/min insulin clamps also differed between pre-test and post 1, and post 1 and post 2 but not between pre-test and post 2. FDG-SUV increased between pre-test (1.1±0.2) and post 1 (1.4±0.3), and remained stable between post 1 and post 2 (1.4±0.4). Conclusion: RE that increased muscle size and FDG-SUV improved IS 24 h but not 1 week after exercise training. Source


Pandit M.M.,University of Utah | Strait K.A.,University of Utah | Strait K.A.,Salt Lake Veterans Affairs Medical Center | Matsuda T.,Osaka University | And 2 more authors.
American Journal of Physiology - Renal Physiology | Year: 2012

Collecting duct (CD) endothelin-1 (ET-1) is an important autocrine inhibitor of Na and water transport. CD ET-1 production is stimulated by extracellular fluid volume expansion and tubule fluid flow, suggesting a mechanism coupling CD Na delivery and ET-1 synthesis. A mouse cortical CD cell line, mpkCCDc14, was subjected to static or flow conditions for 2 h at 2 dyn/cm 2, followed by determination of ET-1 mRNA content. Flow with 300 mosmol/l NaCl increased ET-1 mRNA to 65% above that observed under static conditions. Increasing perfusate osmolarity to 450 mosmol/l with NaCl or Na acetate increased ET-1 mRNA to ~184% compared with no flow, which was not observed when osmolarity was increased using mannitol or urea. Reducing Na concentration to 150 mosmol/l while maintaining total osmolarity at 300 mosmol/l with urea or mannitol decreased the flow response. Inhibition of epithelial Na channel (ENaC) with amiloride or benzamil abolished the flow response, suggesting involvement of ENaC in flow-regulated ET-1 synthesis. Aldosterone almost doubled the flow response. Since Ca 2+ enhances CD ET-1 production, the involvement of plasma membrane and mitochondrial Na/Ca 2+ exchangers (NCX) was assessed. SEA0400 and KB-R7943, plasma membrane NCX inhibitors, did not affect the flow response. However, CGP37157, a mitochondrial NCX inhibitor, abolished the response. In summary, the current study indicates that increased Na delivery, leading to ENaC-mediated Na entry and mitochondrial NCX activity, is involved in flow-stimulated CD ET-1 synthesis. This constitutes the first report of either ENaC or mitochondrial NCX regulation of an autocrine factor in any biologic system. © 2012 the American Physiological Society. Source

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