A. Nicotinic Acid Effects on Fuel Utilization at Rest
Numerous investigators have demonstrated changes in FFA mobilization as a result of ingesting or infusing nicotinic acid. The articles that were reviewed all indicated that plasma or serum FFA levels were lowered by the presence of nicotinic acid.
Havel, Carlson, Ekelund and Holmgren37 investigated the effects of norepinephrine and nicotinic acid on energy metabolism in seven 21-26-year-olds. They ingested 1-3 g of nicotinic acid daily for 3 days before the testing to become accustomed to the flushing response caused by nicotinic acid, and then reported to the laboratory at 0800 h after a 12-15 h fast. During the entire procedure (just over 4 h) the participants were supine, with a catheter in an antecubital vein and a brachial artery, while expired air was collected intermittently. Norepinephrine was infused between minutes 45 and 60, and plasma concentrations of FFA, glycerol and glucose rose rapidly. At minute 120, nicotinic acid (100 or 200 mg) infusion started at 15 min intervals up to minute 225, when another infusion of norepinephrine started. The plasma concentration of FFA, glycerol and glucose decreased after the first infusion of nicotinic acid and stabilized in 30 min. The RER was increased after administration of nicotinic acid. The effect of norepinephrine on FFA and glycerol levels was almost completely blocked by nicotinic acid.
Two groups of investigators took advantage of the decreasing plasma levels of FFA caused by administration of nicotinic acid to investigate cold exposure in man. Hanson et al.22 used four males (aged 21-25 years) to examine the effects of nicotinic acid ingestion on plasma FFA in acute cold exposure in a fasted state. A 200-mg dose of nicotinic acid was taken 10 min before the start of the cold exposure. The plasma FFA level was significantly lower in the conditions of the experiment that involved ingestion of nicotinic acid. More recently, Martineau and Jacobs23 also investigated plasma FFA levels using nicotinic acid, although the cold exposure was in water. Eight males (aged 19-32 years) performed two cold-water immersions 1 week apart following a 14-16 h fast. Both immersions were preceded by ingestion of nicotinic acid or placebo (3.2 mg/kg 2 h prior to immersion and 1.6 mg/kg at 30 min intervals before immersion). Plasma FFA levels were significantly lower before and during immersion in the trials with previous ingestion of nicotinic acid. The plasma FFA values with nicotinic acid ingestion were still significantly less than without nicotinic acid ingestion after immersion, despite a 73% increase in FFA levels.
These findings demonstrate that nicotinic acid has a significant effect on fat utilization at rest. Butcher, Baird and Sutherland38 revealed the manner by which nicotinic acid effectively suppresses fat metabolism. Adenosine 3', 5'-monophosphate (cyclic AMP) has been implicated as an intrac-ellular second messenger. A decrease in cyclic AMP, caused by nicotinic acid, blocks the breakdown of white adipose tissue triglycerides to FFA and glycerol. Madsen and Malchow-M0ller39 stated that nicotinic acid inhibited the stimulation of adenylcyclase in adipocytes, causing decreased intracellular concentrations of cyclic AMP, which interfered with the activation of hormone-sensitive lipase. Nicotinic acid also has a direct inhibiting effect on the hormone-sensitive lipase.
B. Nicotinic Acid Effects on Fuel Utilization During Bouts of Exercise
A number of investigations have focused on the effects of nicotinic acid administration on exercise metabolism; more specifically on the contribution of fat and carbohydrate sources to fuel acute or prolonged exercise. Nicotinic acid has been used in these studies because of its marked effect on FFA availability during exercise by the same mechanism as in resting conditions explained earlier. The importance of mobilizing FFA from adipose tissue to fuel exercise is readily apparent because there is only a small amount of stored fat within the skeletal muscles, thus, circulating FFA is essential for continued fat metabolism in the muscle.40 The common findings of these studies was that nicotinic acid decreased fat utilization in a variety of exercise conditions.11-21
Carlson and co-workers12 investigated the effect of nicotinic acid on plasma glycerol and glucose as well as the appearance, oxidation and turnover of FFA at rest and during exercise in two college-aged males. They were infused with 200 mg of nicotinic acid in the middle of the first rest period, followed by 100 mg of nicotinic acid every 15 min throughout the 2 h of exercise and the following 1 h of rest. Expired air and blood samples were collected intermittently. Nicotinic acid decreased the concentration and turnover rate of FFA and profoundly inhibited the usual increase in concentration and turnover rate found in fasted subjects during exercise. The normal increase in concentration of glycerol in fasted exercise was not present in one of the nicotinic acid-infused subjects. In the other nicotinic acid-infused subject, there was an increase in glycerol concentration and turnover rate of FFA during exercise, although the absolute values were lower than the controls. The plasma glucose concentration did not change significantly in the controls. The subject that demonstrated the greatest decrease in turnover rate of FFA had a large drop in the plasma glucose concentration (105 to 68 mg/100 ml) at the end of exercise while the other nicotinic acid-infused subject had little change. Both nicotinic acid-infused subjects had higher plasma glucose concentrations than the controls. Until the last hour of rest, the nicotinic acid-infused subject, who had the lowest glucose level during exercise, had a higher RER than the control subjects. After administration of nicotinic acid, the other subject demonstrated a progressive rise in RER to a higher level than the control subjects at the end of exercise. The levels of lactate and pyruvate in the nicotinic acid-infused subjects changed little during exercise and were comparable to the values of the control subjects. Nicotinic acid did not affect the rate of removal of FFA from the blood, oxidation of FFA, heart rate or mechanical efficiency. The most noteworthy results of the study were that nicotinic acid markedly decreased the rate of FFA mobilization at rest and inhibited the normal increase in FFA mobilization that occurs when fasted subjects exercise.
Jenkins16 followed the work of Carlson et al.12 to determine the metabolic response after nicotinic acid ingestion on a treadmill at 3.5 mph and 10% grade for either 1.5 h (n = 2) or 2.5 h (n = 1). Compared with the control exercise session, the session with prior ingestion of 200 mg of nicotinic acid showed significantly lower plasma FFA levels and a significantly higher RER. Unlike the Carlson12 study, Jenkins16 reported an increase with blood glucose after the nicotinic acid ingestion, which he speculated was caused indirectly by the drop in FFA.
Bergström et al.11 examined the effect of nicotinic acid on physical work capacity and muscle glycogen stores, with particular focus on the possibility of increased glycogen utilization when nicotinic acid blocked mobilization of FFA. In the first series, two males performed a two-leg cycle ergometer protocol that increased work load every 6 min up to a near maximal level. After a 2 h rest, during which 1.6 g of nicotinic acid (1 g intravenous and 0.6 g orally) was given, the same procedure was performed. In the second series, 13 males used one-leg cycle ergometry at a constant load for 60-90 min with a 1 h rest period in between conditions (with and without nicotinic acid). When the work was gradually increased to a near maximal level in the first series, the participants performed the same amount of exercise whether nicotinic acid was administered or not. After nicotinic acid administration, the RER was higher at rest and at lower work loads, although there was no difference in RER at higher work intensities. Arterial lactate and glucose concentrations were lower in the nicotinic acid exercise. In the second series, where the opposite leg was used for the nicotinic acid exercise, they performed the same amount of work, although the second bout of exercise was more fatiguing. The resting heart rate was similar before the two exercise sessions, however, the increase in heart rate during exercise before nicotinic acid administration was significantly higher with a mean difference of 20 beats/min at the end of the exercise. The VO2 was slightly higher in the cycling with prior administration of nicotinic acid (p < 0.10). The RER was slightly higher at rest in the nicotinic acid condition, but was significantly (p < 0.005) higher at the end of exercise in the nicotinic acid trial (0.93 ± 0.03 to 0.77 ± 0.03). There was an increased rate of glycogen utilization after administration of nicotinic acid both at 45-60 min of exercise (p < 0.025) and after 90 min of exercise (p < 0.005). Arterial glucose had large individual variations and was less at rest after nicotinic acid administration and showed no differences during exercise.
The lactate concentration was significantly higher during exercise after nicotinic acid administration. The resting levels of FFA were lower after nicotinic acid in four of five subjects and the normal increase during exercise was almost completely blocked. One nicotinic acid-administered subject showed an increase in FFA concentration with exercise, although the values were lower than the control exercise. The glycerol concentration was lower after nicotinic acid administration both at rest and during exercise.
Pernow and Saltin21 investigated work capacity and substrate utilization with and without 1.2 g of nicotinic acid using one-leg cycling to exhaustion under conditions of glycogen depletion. The glycogen depletion was caused by exhaustive one-leg cycling and a no-carbohydrate diet the previous 24 h, and verified by biopsy. The result of the trial with nicotinic acid showed a significant decrease in work load and time to exhaustion compared with both legs the previous day and with the other leg the same day. With the nicotinic acid blocking the release of FFA, exercise capacity was significantly reduced.
Unlike what many of the previous researchers might predict, Norris et al.20 demonstrate no significant difference in the performance of a 10-mile run without (76 ± 3 min) and with nicotinic acid ingestion (78 ± 3 min). Ten habitual runners were randomized into ingesting 2 g of nicotinic acid or a placebo 2 h before a timed 10-mile run on a measured course. The runners who ingested nicotinic acid showed similarly depressed FFA levels as in previous studies, but did not demonstrate a decrease in performance as a result of the decreased fat oxidation. The authors suggested that the 10-mile run did not deplete glycogen levels enough to affect performance and that when carbohydrate stores are still plentiful, the decreased fat oxidation caused by nicotinic acid did not impair 10-mile run time.
Two other investigations demonstrated a decrease in performance when the exercise was presumably severe enough to deplete glycogen levels to the point where the lack of fat oxidation in the nicotinic acid trial impacted performance. In an abstract, Galbo et al.13 reported a decrease in running time to exhaustion with prior ingestion of nicotinic acid. Seven participants ran at 60% of VO2 max to exhaustion under normal conditions and with prior ingestion of nicotinic acid. The total time to exhaustion was significantly shorter in the nicotinic acid condition (122 ± 8 vs. 166 ± 10 min). In a similar study with cyclists, Heath and collaborators15 published abstract showed significantly decreased time to exhaustion cycling at 68% of VO2 peak but not at 86% of VO2 peak with prior ingestion of nicotinic acid. Five highly trained male cyclists who fasted for 12 h participated in four time-to-exhaustion rides at 68% and 86% of their VO2 peak. The work rates were equivalent at each of the two intensities with 1 g of nicotinic acid ingested before one of the trials at each intensity. The order of the four trials was randomized and conducted at least 1 week apart. The ingestion of nicotinic acid significantly decreased pre- and post-exercise FFA levels, and time to exhaustion was significantly reduced in the niacin trials at 68% VO2 peak (101.6 ± 40.2 vs. 142.3 ± 51.0 min), while there was no effect for the 86% VO2 peak trials (13.9 ± 6.5 vs. 20.3 ± 7.8 min). Most of the difference in the high-intensity time-to-exhaustion rides was from one participant who recorded 25 min 1 s without nicotinic acid and 5 min 55 s with nicotinic acid, showing considerable variation in his response to the metabolic effects of nicotinic acid. Because of the drastic decrease in the nicotinic acid trial at 86% of VO2 peak with this participant, the trial with nicotinic acid was repeated and the results were similar. This confirmed the possibility of marked individual metabolic differences affecting the rides to exhaustion. The authors concluded that, as expected, the inhibition on FFA mobilization caused by nicotinic acid impaired performance at the moderate-intensity exercise. However, at the higher-intensity exercise, where fat utilization has a more minor role, the inhibiting effects of nicotinic acid on FFA availability did not result in differences in performance time.
Supplementation of carbohydrates during prolonged exercise, similar to nicotinic acid, causes a blunted release of FFA, but also has the effect of increasing performance because of its glycogen-sparing effect.41 Murray and co-workers19 predicted that carbohydrate supplementation in combination with nicotinic acid ingestion would enhance performance because of the proven effect of nicotinic acid's increasing carbohydrate reliance. Under four conditions, 10 participants cycled at 68% VO2 peak for 120 min and then completed a 3.5-mile time trial. Every 15 min during the exercise, the participants ingested one of four beverages: (1) water placebo (WP), (2) WP + 280 mg nicotinic acid (NA) per liter (WP + NA), (3) 6% carbohydrate electrolyte drink (CE) and (4) CE + NA. In the two NA conditions (WP + NA & CE + NA) the NA attenuated FFA rise during exercise but the NA + CE condition, although it showed an increase in carbohydrate oxidation, did not demonstrate improved performance on the 3.5-mile cycling time trial. The performance times were 641.8 ± 17 s for CE, 685 ± 34 s for CE + NA, 730.6 ± 36 s for WP and 765.9 ± 59 s for WP + NA. The CE group was significantly better than both the WP and the WP + NA groups. Trends in the data are suggestive that NA ingestion may decrease performance (CE < CE + NA & WP < WP + NA). Comparison of performance times for CE + NA and WP + NA approached significance (p = 0.0517). Thus, Murray et al.'s hypothesis that combining nicotinic acid and carbohydrate electrolyte drink would improve performance compared with all other conditions except the CE trial did not come to fruition. The possibility exists that there was insufficient power to detect differences or that another performance test could have demonstrated the benefits of nicotinic acid and carbohydrate electrolyte ingestion combined.
There is little question that the administration of large doses of nicotinic acid has an adverse effect on fat utilization. This decrease in availability of lipid fuel sources could have a negative impact on lower-intensity exercise, where the contribution from fat sources is considerable. One of the intriguing aspects of this line of research is the relationship between beneficial effects of pharmacologic doses of niacin on cholesterol profiles and the physical activity recommendations to decrease the risk of coronary artery disease. Physical inactivity and the associated low exercise capacity is one of the most powerful changeable risk factors.42 To investigate the possibility of an adaptation to the decreased fat utilization during single bouts of exercise, Heath et al.14 assessed fuel utilization during 3 weeks of nicotinic acid administration. Eight trained male runners performed four 30-min submaximal treadmill runs at 60% of VO2 max. The first treadmill run served as a control and the next three were at the onset, midpoint and end of 3 weeks of nicotinic acid administration. The nicotinic acid dose was built up to a typical regimen to impact cholesterol profile — 3 g/d ingested with meals three times per day. A 1-g nicotinic dose was ingested 1 h prior to the last three treadmill runs, which were conducted in the morning after a 12-h fast. Serum FFA and glycerol levels were significantly lower in the three treadmill runs with nicotinic acid compared with the control run, showing no adaptation over the 3 weeks of nicotinic acid administration. The RER showed a beginning of a possible adaptation starting at 0.871 ± 0.008 in the control condition and peaking with a significant increase at 0.919 ± 0.009 in the initial run with nicotinic acid. After, the RER showed a significant drop compared with the first nicotinic acid run — 0.898 ± 0.007 for the second nicotinic acid run and 0.896 ± 0.009 for the third nicotinic acid run. Although the values for the last two submaximal runs were significantly lower than the first run with nicotinic acid, they were significantly higher than the control run without the nicotinic acid. The possibility exists that a complete adaptation may take longer than 3 weeks. Interestingly, total cholesterol was significantly decreased (195 ± 9.2 to 174 ± 9.2 mg/dl) and HDLC levels were significantly increased (56.2 ± 2.9 to 63.0 ± 3.9 mg/dl) in these habitual healthy runners with the 3 weeks of nicotinic acid administration.
In addition to the fuel utilization changes for skeletal muscle with nicotinic acid administration, Lassers et al.18 demonstrated similar changes in the myocardial metabolism. They showed an estimated 42% decrease in lipid utilization during rest and a 56% decrease during exercise with nicotinic acid administration. There is scant evidence that niacin status impacts performance. Jette et al.17 investigated changes in VO2 max following glycogen supercompensation accomplished by exhaustive exercise and followed by low- and high-carbohydrate diets. VO2 max was slightly decreased following the high-carbohydrate diets where niacin intake and N1-methylnicotinamide excretion was lower compared with the high-protein, low-carbohydrate condition. The authors concluded that the decreased VO2 max with the high-carbohydrate condition might have been associated with compromised oxidative metabolism from lower, although still adequate, niacin intake.
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