Browsing by Subject "Nitrite"
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Item Dose–Response Effect of Dietary Nitrate on Muscle Contractility and Blood Pressure in Older Subjects: A Pilot Study(Oxford University Press, 2021) Gallardo, Edgar J.; Gray, Derrick A.; Hoffman, Richard L.; Yates, Brandon A.; Moorthi, Ranjani N.; Coggan, Andrew R; Kinesiology, School of Health and Human SciencesWe have recently demonstrated that dietary nitrate, a source of nitric oxide (NO) via the nitrate → nitrite → NO enterosalivary pathway, can improve muscle contractility in healthy older men and women. Nitrate ingestion has also been shown to reduce blood pressure in some, but not all, studies of older individuals. However, the optimal dose for eliciting these beneficial effects is unknown. A pilot randomized, double-blind, placebo-controlled crossover study was therefore performed to determine the effects of ingesting 3.3 mL/kg of concentrated beetroot juice containing 0, 200, or 400 µmol/kg of nitrate in 9 healthy older subjects (mean age 70 ± 1 years). Maximal knee extensor power (Pmax) and speed (Vmax) were measured ~2.5 hours after nitrate ingestion using isokinetic dynamometry. Blood pressure was monitored periodically throughout each study. Pmax (in W/kg) was higher (p < .05) after the lower dose (3.9 ± 0.4) compared to the placebo (3.7 ± 0.4) or higher dose (3.7 ± 0.4). Vmax (in rad/s) also tended to be higher (p = .08) after the lower dose (11.9 ± 0.7) compared to the placebo (10.8 ± 0.8) or higher dose (11.2 ± 0.8). Eight out of 9 subjects achieved a higher Pmax and Vmax after the lower versus the higher dose. These dose-related changes in muscle contractility generally paralleled changes in breath NO levels. No significant changes were found in systolic, diastolic, or mean arterial blood pressure. A lower dose of nitrate increases muscle speed and power in healthy older individuals, but these improvements are lost at a higher dose. Blood pressure, on the other hand, is not reduced even with a higher dose.Item Measurement of nitrate and nitrite in biopsy-sized muscle samples using HPLC(American Physiological Society, 2018-11) Troutman, Ashley D.; Gallardo, Edgar J.; Brown, Mary Beth; Coggan, Andrew R.; Kinesiology, School of Physical Education and Tourism ManagementStudies of rats have indicated that skeletal muscle plays a central role in whole-body nitrate ( NO−3 )/nitrite ( NO−2 )/nitric oxide (NO) metabolism. Extending these results to humans, however, is challenging due to the small size of needle biopsy samples. We therefore developed a method to precisely and accurately quantify NO−3 and NO−2 in biopsy-sized muscle samples. NO−3 and NO−2 were extracted from rat soleus samples using methanol combined with mechanical homogenization + ultrasound, bead beating, pulverization at liquid N2 temperature or pulverization + 0.5% Triton X-100. After centrifugation to remove proteins, NO−3 and NO−2 were measured using HPLC. Mechanical homogenization + ultrasound resulted in the lowest NO−3 content (62 ± 20 pmol/mg), with high variability [coefficient of variation (CV) >50%] across samples from the same muscle. The NO−2 / NO−3 ratio (0.019 ± 0.006) was also elevated, suggestive of NO−3 reduction during tissue processing. Bead beating or pulverization yielded lower NO−2 and slightly higher NO−3 levels, but reproducibility was still poor. Pulverization + 0.5% Triton X-100 provided the highest NO−3 content (124 ± 12 pmol/mg) and lowest NO−2 / NO−3 ratio (0.008 ± 0.001), with the least variability between duplicate samples (CV ~15%). These values are consistent with literature data from larger rat muscle samples analyzed using chemiluminescence. Samples were stable for at least 5 wk at -80°C, provided residual xanthine oxidoreductase activity was blocked using 0.1 mmol/l oxypurinol. We have developed a method capable of measuring NO−3 and NO−2 in <1 mg of muscle. This method should prove highly useful in investigating the role of skeletal muscle in NO−3 / NO−2 /NO metabolism in human health and disease. NEW & NOTEWORTHY Measurement of nitrate and especially nitrite in small, i.e., biopsy-sized, muscle samples is analytically challenging. We have developed a precise, accurate, and convenient method for doing so using an affordable commercial HPLC system.Item Simultaneous Pharmacokinetic Analysis of Nitrate and its Reduced Metabolite, Nitrite, Following Ingestion of Inorganic Nitrate in a Mixed Patient Population(SpringerLink, 2020-11) Coggan, Andrew R.; Racette, Susan B.; Thies, Dakkota; Peterson, Linda R.; Stratford, Robert E., Jr.; Kinesiology, School of Health and Human SciencesPurpose: The pharmacokinetic properties of plasma NO3- and its reduced metabolite, NO2-, have been separately described, but there has been no reported attempt to simultaneously model their pharmacokinetics following NO3- ingestion. This report describes development of such a model from retrospective analyses of concentrations largely obtained from primary endpoint efficacy trials. Methods: Linear and non-linear mixed effects analyses were used to statistically define concentration dependency on time, dose, as well as patient and study variables, and to integrate NO3- and NO2- concentrations from studies conducted at different times, locations, patient groups, and several studies in which sample range was limited to a few hours. Published pharmacokinetic studies for both substances were used to supplement model development. Results: A population pharmacokinetic model relating NO3- and NO2- concentrations was developed. The model incorporated endogenous levels of the two entities, and determined these were not influenced by exogenous NO3- delivery. Covariate analysis revealed intersubject variability in NO3- exposure was partially described by body weight differences influencing volume of distribution. The model was applied to visualize exposure versus response (muscle contraction performance) in individual patients. Conclusions: Extension of the present first-generation model, to ultimately optimize NO3- dose versus pharmacological effects, is warranted.Item A Single Dose of Dietary Nitrate Increases Maximal Knee Extensor Angular Velocity and Power in Healthy Older Men and Women(Oxford, 2019-07-22) Coggan, Andrew R; Hoffman, Richard L; Gray, Derrick A; Moorthi, Ranjani N; Thomas, Deepak P; Leibowitz, Joshua L; Thies, Dakkota; Peterson, Linda R; Kinesiology, School of Physical Education and Tourism ManagementBackground Aging results in reductions in maximal muscular strength, speed, and power, which often lead to functional limitations highly predictive of disability, institutionalization, and mortality in elderly adults. This may be partially due to reduced nitric oxide (NO) bioavailability. We, therefore, hypothesized that dietary nitrate (NO3−), a source of NO via the NO3− → nitrite (NO2−) → NO enterosalivary pathway, could increase muscle contractile function in older subjects. Methods Twelve healthy older (age 71 ± 5 years) men and women were studied using a randomized, double-blind, placebo-controlled, crossover design. After fasting overnight, subjects were tested 2 hours after ingesting beetroot juice containing or devoid of 13.4 ± 1.6 mmol NO3−. Plasma NO3− and NO2− and breath NO were measured periodically, and muscle function was determined using isokinetic dynamometry. Results NO3− ingestion increased (p < .001) plasma NO3−, plasma NO2−, and breath NO by 1,051% ± 433%, 138% ± 149%, and 111% ± 115%, respectively. Maximal velocity of knee extension increased (p < .01) by 10.9% ± 12.1%. Maximal knee extensor power increased (p < .05) by 4.4% ± 7.8%. Conclusions Acute dietary NO3− intake improves maximal knee extensor angular velocity and power in older individuals. These findings may have important implications for this population, in whom diminished muscle function can lead to functional limitations, dependence, and even premature death.Item Skeletal Muscle Contractile Function in Heart Failure With Reduced Ejection Fraction—A Focus on Nitric Oxide(Frontiers Media, 2022-06-01) Park, Lauren K.; Coggan, Andrew R.; Peterson, Linda R.; Exercise & Kinesiology, School of Health and Human SciencesDespite advances over the past few decades, heart failure with reduced ejection fraction (HFrEF) remains not only a mortal but a disabling disease. Indeed, the New York Heart Association classification of HFrEF severity is based on how much exercise a patient can perform. Moreover, exercise capacity—both aerobic exercise performance and muscle power—are intimately linked with survival in patients with HFrEF. This review will highlight the pathologic changes in skeletal muscle in HFrEF that are related to impaired exercise performance. Next, it will discuss the key role that impaired nitric oxide (NO) bioavailability plays in HFrEF skeletal muscle pathology. Lastly, it will discuss intriguing new data suggesting that the inorganic nitrate ‘enterosalivary pathway’ may be leveraged to increase NO bioavailability via ingestion of inorganic nitrate. This ingestion of inorganic nitrate has several advantages over organic nitrate (e.g., nitroglycerin) and the endogenous nitric oxide synthase pathway. Moreover, inorganic nitrate has been shown to improve exercise performance: both muscle power and aerobic capacity, in some recent small but well-controlled, cross-over studies in patients with HFrEF. Given the critical importance of better exercise performance for the amelioration of disability as well as its links with improved outcomes in patients with HFrEF, further studies of inorganic nitrate as a potential novel treatment is critical.