We sought to determine whether naproxen adversely affected hydration and electrolyte balance during moderate-intensity endurance cycling in either hot or ambient conditions. Based on previous research (
Cheng and Harris 2005), we hypothesized that NSAIDs would promote fluid retention through decreased Uvol and renal vasoconstriction, subsequently diluting plasma electrolytes, increasing hydration status, and increasing BP. Our results did not support our hypotheses, finding that an acute (24-h) naproxen dose did not significantly affect plasma electrolytes, plasma and urine hydration indices, or cardiovascular strain compared with placebos. We also report that responses did not differ between either hot or ambient environmental conditions.
Fluid and electrolyte balance
Naproxen is highly effective at inhibiting renal PGs, resulting in decreased renal blood flow (
Garella and Matarese 1984). Specific renal consequences include decreased glomerular filtration rate, increased vasopressin, increased sodium retention, and decreased Uvol. Naproxen also suppresses the renin–angiotensin–aldosterone system, which is responsible for maintaining BP, plasma volume, and electrolyte balance (
Cheng and Harris 2005). Independently or concurrently, naproxen’s effects cause water retention and vasoconstriction (
Cheng and Harris 2005). In extreme cases, cell necrosis, interstitial nephritis, and renal failure may develop (
Garella and Matarese 1984). Milder consequences, although they can also become severe, include electrolyte imbalance, edema, and hypertension (
Cheng and Harris 2005;
Rosner and Kirven 2007).
Decreasing Uvol and increasing water retention is what makes NSAIDs a suspected contributor to hyponatremia. Despite this information, few studies have examined this relationship, with most being observational studies with conflicting results (
Davis et al. 2001;
Hsieh et al. 2002;
Almond et al. 2005;
Wharam et al. 2006). Ultra-distance triathletes using NSAIDs had significantly lower post-race P[Na
+] compared with non-NSAID users (
Wharam et al. 2006). The six participants who experienced hyponatremia all reported using NSAIDs (
Wharam et al. 2006). Of 15 marathon runners hospitalized with severe hyponatremia, 28.6% used NSAIDs (
Davis et al. 2001). In contrast, other observational studies have found no relationship between NSAIDs and hyponatremia (
Hsieh et al. 2002;
Almond et al. 2005;
Scotney and Reid 2015). One inherent issue with existing literature is not knowing the NSAID type or dosage. All NSAIDs inhibit PGs, but their COX selectivity and chemical make-up, along with an individual person’s unique response, means that each NSAID exerts its effects differently.
Another contributing factor for developing hyponatremia is an individual consuming hypotonic fluid in excess of fluid lost through sweat and respiration (
Rosner and Kirven 2007). If combined with other factors that dilute P[Na
+], the individual can be at greater risk for hyponatremia. Current recommendations advise matching individual sweat losses rather than drinking in excess or following generalized protocols (
Casa et al. 2000;
Sawka et al. 2007). Calculating sweat rate is relatively simple. However, lack of knowledge, ability, or resources may prohibit a person from calculating their sweat rate. Instead, the person may guestimate their fluid intake during endurance activity or determine it by trial and error. We chose to provide a standardized water protocol, rather than match sweat rates, and participants were allowed to consume more if desired. In part, using a standardized intake mimicked what an individual who does not know their personal water needs may do. Consuming water volumes exceeding sweat loss during 90 min of cycling did not significantly deplete P[Na
+], and there was no effect from naproxen. The lack of P[Na
+] depletion is likely due to the short exercise duration. Exertional hyponatremia is typically associated with endurance exercise lasting longer than 3 h (
Noakes et al. 2005;
Rosner and Kirven 2007), but has also occurred in football (
Creamer and Hagedorn 2008;
Blevins and Apel 2014;
Stevens 2014). Our cycling session likely did not allow enough time to significantly deplete P[Na
+]. During the 3-h rest, when participants were allowed to drink water ad libitum they maintained euhydration and plasma electrolyte balance.
One interesting note is our mean P[Na
+] was <135 mmol/L in all conditions and time points except pre- and 3 h post-exercise in the NpxHeat trials. Plasma sodium < 135 mmol/L without signs or symptoms is considered biochemical or asymptomatic hyponatremia (
Noakes et al. 2005). Many individuals do not experience symptoms until P[Na
+] decreases below 130 mmol/L, and severe hyponatremia typically occurs below 120 mmol/L (
Sawka et al. 2007). Our participants maintained normal diets, consuming an average 2401.1 ± 759.2 mg of sodium daily. The low P[Na
+] can be explained by participants being instructed to arrive at the laboratory hydrated and by maintaining hydration during the exercise protocol. Pre-exercise Usg, Uosm, and Posm indicated that our participants were slightly hyperhydrated and became extremely hyperhydrated (
Armstrong et al. 2010) by 3 h post-exercise.
It was also interesting that participants in the NpxHeat trials averaged more fluid consumed and had the lowest Uvol. The trend for naproxen trial participants to produce less urine while consuming more fluid suggests that participants were retaining water. We did not see significant decreases in P[Na
+], Posm, or Usg pre- to post-exercise. The low sample size for P[Na
+] and Posm makes it difficult to definitively assess whether fluid was retained during naproxen trials. However, we presume a portion of water remained in the stomach. Intense exercise, such as with our cycling protocol, slows gastric emptying, which prevents fluid from being absorbed and (or) used to maintain physiological processes (
Robinson et al. 1995).
In principle, increased Fvol and decreased Uvol should lead to BM gains. No significant differences in BM were found among our experimental conditions. Both the Npx and NpxHeat trial participants averaged pre- to post-exercise BM losses, whereas both Control and Heat trial participants showed a slight increase in BM or no change (
Table 1). From immediately post- to 3 h post-exercise, this trend flipped with Control and Heat trial participants showing more weight loss than Npx and NpxHeat trial participants. Once exercise ceased, it is possible that gastrointestinal and renal function returned to normal, promoting gastric emptying and water excretion as necessary to maintain fluid–electrolyte balance. Support for this explanation is found with the slightly higher Uvol in Control and Heat treatments. In contrast, the continuation of naproxen’s effects throughout the rest period would explain the slight weight gain and lower average Posm 3 h post-exercise. This is important to note considering reported cases of hyponatremia developing hours after activity (
Creamer and Hagedorn 2008;
Stevens 2014). Sustained water retention combined with continued hypotonic fluid consumption would place the person at even greater risk for diluted P[Na
+].
Our participants remained within normal P[K
+] levels (<5 mmol/L) (
Clausen 2010). Potassium is tightly regulated by the kidneys because elevated plasma levels may cause cardiac arrhythmias and death (
Clausen 2010). Even during exercise, when plasma levels can quickly spike due to working muscles releasing or failing to re-uptake potassium (
Clausen 2010), the kidneys work efficiently to clear potassium. However, potassium will stay elevated if renal blood flow is decreased (
Franscesconi et al. 1997). NSAIDs, known to decrease renal blood flow (
Garella and Matarese 1984), can induce hyperkalemia (
Lafrance and Miller 2012), but little scientific information is available regarding this association during exercise. The increase in our overall P[K
+] mean values are similar to those reported in existing literature (
Wharam et al. 2006;
Dumke et al. 2007;
McKenney et al. 2015). Although not significantly different among conditions, the higher means for naproxen compared with placebos suggest that there could be some effect from the NSAID. Among triathletes, NSAIDs resulted in significantly higher post-race P[K
+] compared with those not using NSAIDs (
Wharam et al. 2006). In contrast, over-the-counter ibuprofen did not significantly affect P[K
+] in ultra-distance runners (
Dumke et al. 2007). The type of NSAID was not reported by
Wharam et al. (2006); therefore, it is not possible to make comparisons among specific NSAIDs. However, research has established that, compared with no NSAID exposure, the odds for developing hyperkalemia are higher with the use of naproxen than with ibuprofen (
Lafrance and Miller 2012). Using a higher naproxen dose for a longer duration may induce significant P[K
+] changes during exercise.
Gender
The current literature indicates that females are at higher risk for hyponatremia because of smaller BM, excessive water intake, and longer race times compared with males (
Rosner and Kirven 2007). Though these factors play a role, hormonal differences between genders are also an important consideration. Resting plasma vasopressin varies in females depending on menstrual phase. Vasopressin is significantly lower than males during the early follicular phase, but not during the luteal phase (
Wenner and Stachenfeld 2012). These variances may help explain why we found differences in Fvol between genders. Males consumed significantly more fluid than females both during exercise and overall. Interestingly, males consumed significantly more fluid during exercise in the NpxHeat trials, and approached significance in the Npx trials, compared with females. Gender differences did not occur during the Control and Heat trials, and we found no difference in females’ Fvol among conditions. Considering the change in vasopressin during menstrual phases, which we did not account for, the lack of significant findings among females could be partially explained by hormones.
Thirst is listed as a potential side effect for several NSAIDs, but data are limited for the effect of NSAIDs on thirst or Fvol during exercise. Among NSAID and non-NSAID users completing an 82 km mountain run, NSAID users consumed significantly more fluid than non-users (
Scotney and Reid 2015). Our results support that naproxen use increases fluid intake in males. We used naproxen sodium, which is bioequivalent to naproxen except for the rate of absorption. The salt of a given NSAID is commonly used because it allows the drug to dissolve faster and exert effects earlier. A 220 mg naproxen sodium dose contains approximately 20 mg of sodium. Not all salts exert the same effects and 20 mg is relatively low, but 46 mg/L of sodium chloride added to a flavored beverage significantly increased fluid intake (
Wemple et al. 1997). A possible explanation for increased Fvol in our male participants is that naproxen sodium stimulated thirst. Another mechanism for thirst stimulation is an increase in vasopressin from NSAIDs (
Cheng and Harris 2005). Vasopressin is typically upregulated during dehydration to restore plasma volume, and vasopressin increase is positively and linearly associated with thirst (
Wenner and Stachenfeld 2012). Despite our participants being euhydrated, if naproxen stimulated vasopressin it could have increased their fluid intake.
We identified no differences between or within genders for HR. BP is generally higher for males than females (
Christou et al. 2005), which is attributed to physical differences, hormones, and vascular responsiveness (
Wenner and Stachenfeld 2012). Male baseline BP was slightly higher than females, but not significantly. Naproxen significantly elevated post-exercise male systolic BP compared with females. This did not occur during Control and Heat trials. The increased Fvol with naproxen in males could partially explain the higher systolic BP. Ostensibly, males would have a higher plasma volume, which would increase BP.
Limitations and future research
Measuring aldosterone and vasopressin would provide better insight into how naproxen influences fluid and electrolyte balance. Measuring plasma naproxen concentration would have been useful to determine the drug’s concentration 3 h post-exercise. Naproxen has a long half-life compared with other NSAIDs. Therefore, naproxen is expected to continue exerting effects during the 3-h rest, whereas other NSAIDs would not. This is important when considering post-activity effects. Our 90-min cycling was likely too short to elicit significant P[Na+] changes, considering most hyponatremia research is in marathon and ultra-distance events. Our sample size for plasma electrolytes and Posm was low, preventing us from achieving statistical significance among conditions for Posm, P[Na+], and P[K+]. This also limited our ability to extensively examine cardiovascular effects. Finally, we did not control for menstrual phase.
Future research is warranted to determine the relationship between NSAID use and hydration–electrolyte balance during exercise. Because each NSAID is unique, studies should evaluate different types, dosages (e.g., over-the-counter, prescription), and length of use (e.g., 3 d, 2 weeks). Evaluating longer endurance exercise periods to deplete plasma electrolytes is an important consideration. Longer exercise bouts, particularly marathon and ultra-distance events, is also important due to the high NSAID use among these athletes. At the same time, examining shorter exercise periods is relevant considering the potential for electrolyte depletion due to other risk factors such as inadequate nutrition, excessive hypotonic fluid intake, and (or) excessive sweat sodium loss. Using different hydration regimens (e.g., metered versus ad libitum), fluid types (e.g., carbohydrate-electrolyte beverages), and hydration statuses (e.g., severe hypohydration) is also merited. Considering the trend of increased Fvol with naproxen use, evaluating vasopressin and thirst would be interesting. Along these lines, examining the salts of different NSAID types would provide meaningful information. Finally, controlled studies evaluating markers of renal function and gender differences, including differences during menstrual phases, are merited.