INTRODUCTION

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SKELETAL MUSCLE, comprising ~45% of the body's total mass, is capable of rapid gas, ion, and fluid exchange with the extracellular fluids (ECFs). The blood acid-base disturbances and exercise performance in response to NaHCO₃ ingestion have been studied since the 1920s and have been summarized recently (20, 26). Previous studies have also shown that the changes in plasma H⁺ concentration ([H⁺]) and HCO₃ concentration ([HCO₃]) in response to small amounts (1 mmol/kg body mass or less) of ingested KHCO₃ (37, 38) are similar to those seen with NaHCO₃ (20). However, the processes involved in the acute, nonrenal regulation of arterial plasma ion and acid-base balance in response to ingestion of these solutions are not well understood (20). Increases in plasma [H⁺] and [HCO₃] resulting from NaHCO₃ ingestion appear to be due to an increase in plasma Na⁺ concentration ([Na⁺]) and a decrease in plasma Cl concentration ([Cl]; see Ref. 20). Although acute effects of KHCO₃ ingestion have not been extensively studied in humans (28, 37, 38), a generalized response may be obtained from the data of van Buren and co-workers (37, 38). KHCO₃ ingestion (1.0 mmol/kg body mass over a 2-h period) resulted in no change in plasma [H⁺]; however, plasma [HCO₃] increased from 25 ± 1.2 to 28 ± 1.5 meq/l during the 1st h after ingestion and was restored by the 2nd h after ingestion. Ingestion of 0.75 mmol/kg to 1 mmol/kg body mass KCl or 1.0 mmol/kg body mass KHCO₃, over a 2-h period, increased plasma K⁺ concentration ([K⁺]) by >0.5 meq/l and aldosterone concentration from 0.6 to 1 µmol/l in the 2nd h after ingestion. Neither the KCl nor the KHCO₃ treatments affected plasma [Cl]. Increases in plasma [K⁺] in these studies were remarkably low compared with estimated rates of intestinal K⁺ absorption, suggesting, to us, that substantial K⁺ was extracted from the circulation by the tissues.

The physicochemical origins of plasma fluid and ion disturbances to ingested Na⁺ and K⁺ are expected to be different due to differences in their distribution and handling (28). The cations Na⁺ and K⁺ are absorbed by different mechanisms within the small intestine and have a different distribution in the body (3, 17). The bulk of Na⁺ absorbed from the intestinal tract remains in the ECFs and, if not fully excreted, will result in an increased ECF volume (ECFV); on the other hand, K⁺ rapidly enters intracellular fluid compartments (30). Accordingly, the origins of the acid-base changes are also expected to differ between NaHCO₃ and KHCO₃ ingestion. The present paper uses the physicochemical approach detailed by Stewart (34, 35) to quantify the origins of acid-base disturbances with respect to the independent variables: strong ion difference ([SID]), the total concentration of weak acids and bases (A_Tot), and CO₂ (23, 25).

Previous research has demonstrated that the arm, representing inactive tissues, is capable of modifying the composition of perfusing blood during and after high-intensity exercise (24). The rapidity of gas and ion exchange processes indicated a primary involvement of skeletal muscle in the acute regulation of plasma ion and acid-base status. In the present study, the involvement of skeletal muscle in the correction of acute disturbances in fluid and ion balance resulting from NaHCO₃ and KHCO₃ ingestion was assessed. The amount of KHCO₃ administered was about threefold greater than that used in previous studies (37, 38) and identical to that shown to be of ergogenic benefit with NaHCO₃ (20). We tested the hypothesis that skeletal muscle in particular, and tissues in general, modify the fluid, ion, and acid-base composition of the perfusing blood back toward "normal" after NaHCO₃ and KHCO₃ loading. It was also hypothesized that skeletal muscle would play a greater role in regulating the disturbance resulting from KHCO₃ loading than NaHCO₃ loading, due to the 100-fold greater permeability of cell membranes to K⁺ compared with Na⁺.

	METHODS

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Six healthy male subjects, age 27 ± 2 yr old and mass 78 ± 6 kg, participated. The order of presenting the experimental treatments was randomized and separated by at least 2 wk to allow for normalization of hematocrit (Hct). Written informed consent was obtained after the procedures and potential risks were fully described to the subjects. The study was approved by the University's human ethics committee.

Experimental Protocol

Before insertion of catheters, the skin was infiltrated with 0.5 ml of 2% Xylocaine (lidocaine) without epinephrine (Astra Pharma, Mississauga, ON). A brachial artery and an antecubital vein (opposite arm) extending into the deep tissues were catheterized percutaneously with 20-gauge 1.25-in.-long Teflon catheters (Becton-Dickenson Angiocath; Baxter, Mississauga, ON). The patency of the catheter was maintained using a slow drip (200 µl/min) of isotonic saline.

After insertion of catheters the subjects sat quietly for 30 min. Baseline (control) blood samples were obtained at 10 and 30 min (experiment time 20 and 0 min, respectively). After this 30-min period (experiment time 0 min), the subjects began ingestion of 3.57 mmol/kg body mass KHCO₃ or NaHCO₃ as a 600 mosmol/l flavored solution (Kool Aid with Nutrasweet). The ~920 ml were ingested in six aliquots over six sequential 10-min periods. The subjects were observed for a further 210 min in the postingestion period.

Safety Precautions

An appropriate ingestion protocol for KHCO₃ was established using a pilot study using two subjects. The criteria were to induce a large and rapid increase in plasma [K⁺] within safe limits (peak plasma [K⁺] at or below 7 meq/l with no ECG abnormalities). The dose of KHCO₃ (3.57 meq K⁺/kg body mass) was the same as that shown to be of ergogenic effect with NaHCO₃ (20). A 30-min ingestion period resulted in a pronounced and long-lasting hyperkalemia; however, plasma [K⁺] reached 6-8 meq/l for 1-2 h and was associated with a tenting of T waves. Consequently, the ingestion period was increased to 60 min, and this resulted in a slower rate of increase of plasma [K⁺] without tenting of T waves in either subject. In the subsequent experiments, one of the six subjects had pronounced tenting of T waves after 40 min of ingestion of the KHCO₃ solution and was promptly treated with intravenous glucose and Ca²⁺ (36). This resulted in immediate reversal of T wave forms and rapid normalization of plasma [K⁺]. This individual's data are excluded from the experiment. As a consequence, the results include data from the five subjects that fully completed both protocols.

Measurements and Analysis

Calculations

The percent change in PV (%PV) was calculated using [PP]

(1)

where [PP]_i and [PP]_t are the initial and experimental time (t) [PP], respectively. This calculation assumes a constant plasma protein (PP) content within the vascular compartment (14); this is probable given that the subjects remained seated at rest for the entire trial. The PV at each time point was calculated by factoring the %PV_PP with the estimated initial PV. The plasma compartment was assumed to be in or near electrochemical and physicochemical equilibrium with other ECF compartments and was taken as representative of the entire ECF compartment.

A discrepancy in the value for %PV calculated using Hct (%PV_Hct) with that of %PV calculated using PP (%PV_PP) was used to determine if red blood cells gained or lost volume (12, 19) as a result of NaHCO₃ or KHCO₃ ingestion. The %PV_Hct was calculated as (14)

(2)

where Hct_i and Hct_t are initial and experimental time Hct (%), respectively. This equation estimates the %PV only when there has been no change in hemoglobin concentration or in red blood cell mean corpuscular volume (MCV; see Refs. 14 and 19). Therefore a discrepancy between %PV_Hct and %PV_PP may be taken as evidence of a change in MCV.

Estimates of the total content of electrolyte in the plasma and ECF compartments were obtained from the product of the arterial plasma ion concentration and the PV or ECFV, respectively. This was necessary to properly assess ion balance due to simultaneous changes in PV and ion concentrations that occurred in response to the ingestion of solutions.

The cumulative net flux of Na⁺ (in the NaHCO₃ trial) and K⁺ (in the KHCO₃ trial) across the tissues of the forearm was used to estimate whole body skeletal muscle Na⁺ or K⁺ flux

(3)

where a-v[ion] is the arteriovenous (a-v) ion concentration difference in meq/l, is a mean tissue perfusion rate of 0.02 l · min¹ · kg¹ (11), skeletal muscle mass was taken as 45% of total body mass (BM, in kg; see Ref. 10), and t is total time in minutes. This recognizes that the skeletal muscle component of the forearm is dominant with respect to gas (29) and ion (9) exchange.

The plasma [SID] was calculated as the sum of the plasma strong cation concentrations minus the sum of the strong anion concentrations (34, 35)

(4)

where [lactate] is lactate ion concentration. Plasma pH was converted to [H⁺] by logarithmic transformation. In addition, plasma [H⁺] was calculated according to the following equation consistent with mass action equilibria and electroneutrality of solutions (34, 35)

(5)

where K_A = 3.0 × 10⁷ eq/l (34, 35), K_C = 2.46 × 10¹¹ eq/l (34, 35), K₃ = 6.0 × 10¹¹ eq/l (15), and K'_W = 4.4 × 10¹⁴ eq/l (18).

Plasma A_Tot concentration ([A_Tot]) was calculated as [PP] × 2.85; the empirical factor of 2.43 (34, 35) used previously (23, 25) yielded consistently low [A_Tot] compared with those calculated from [SID], PCO₂, and [H⁺] (Eq. 5). The reason for the discrepancy arose primarily from the inclusion of plasma [Ca²⁺] in the calculation of [SID], thus resulting in a higher [SID] (by ~3 meq/l) than if [Ca²⁺] was omitted. Plasma [Ca²⁺] was included in the calculation of [SID] because it can change and because of its interaction with PPs, the [A_Tot] portion of plasma. In addition, in the present study, the nonfasted state of the individuals may have resulted in lower plasma free fatty acid concentrations that allowed for greater binding of H⁺ to PPs (33). Unmeasured weak anions did not have a significant effect on the physicochemical assessment of acid-base balance. The ionized form of [A_Tot], [A], was 18.0 ± 0.7 meq/l when calculated using [SID]  [HCO₃]  [A] = 0 (34), very similar to that calculated using measured [H⁺], with [SID], and PCO₂ (Eq. 5).

Statistics

	RESULTS

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PP and Change in PV

View this table: [in this window] [in a new window]   Table 1.   [PP]a and [PP]v, Hct, and %PVHct in NaHCO3 and KHCO3 trials

View larger version (34K): [in this window] [in a new window]   Fig. 1.   Percent change in arterial plasma volume (PV) determined from plasma protein concentration {[PP]; %change in PV calculated using PP (PVPP)} before, during, and after NaHCO3 () and KHCO3 () ingestion. The KHCO3 trial data are significantly different from the NaHCO3 trial data. Values are means ± SE for n = 5 subjects. Hatched bar indicates 60-min ingestion period. * Mean significantly different (P < 0.05) from time 0. ** Mean significantly different from peak or nadir.

The magnitude of changes in arterial and venous (not shown) Hct were quantitatively different from that of [PP] (Table 1), allowing changes in MCV to be estimated from the difference between %PV_PP and %PV_Hct. Between 90 and 270 min in the NaHCO₃ trial, the change () in PV_Hct increased by 356 ml (12%); this was about twofold greater than that calculated using [PP], indicating a decrease in red blood cell MCV equivalent to ~180 ml for the entire red blood cell compartment. In contrast, in the KHCO₃ trial, between 50 and 270 min, PV_Hct decreased by 235-415 ml; this was 60-100 ml less than that calculated using [PP], indicating an increase in red blood cell MCV.

In the NaHCO₃ trial, PV, estimated ISFV, and ECFV were all elevated at 135 min (Table 2). However, in the KHCO₃ trial, the 445 ± 89 ml decrease in PV at 135 min represented a 2.5-liter decrease in ECFV and a 2.1-liter decrease in ISFV (Table 2); by 270 min, ECFV had recovered 70% of the deficit that existed at 135 min.

K⁺

View larger version (36K): [in this window] [in a new window]   Fig. 2.   A: arterial plasma K+ concentration ([K+]) in NaHCO3 () and KHCO3 () trials. B: plasma arteriovenous (a-v) [K+] in NaHCO3 and KHCO3 trials. C: arterial plasma K+ content (PV × plasma [K+]). Two treatments were significantly different from each other. Hatched bar indicates 60-min ingestion period. * Mean significantly different (P < 0.05) from time 0.

View this table: [in this window] [in a new window]   Table 3.   Venous plasma ion concentrations, [SID], [Atot], [H+], and [HCO3]

With KHCO₃ ingestion, arterial and venous [K⁺] increased to 7.17 ± 0.13 meq/l at 110 min and to 6.36 ± 0.19 meq/l at 135 min, respectively (Fig. 2A and Table 3). The decrease in PV (Fig. 1) accounted for 35-40% of the increase in plasma [K⁺] from 50 min onward (Fig. 2A). The remainder of the increase in plasma [K⁺] and content (Fig. 2C) must therefore have resulted from the net movement of K⁺ into the ECF compartments from the intestinal tract. The net amount of K⁺ transported into the plasma compartment at 100 min was estimated to be 5.5 meq or ~27 meq for the entire ECF. Arm K⁺ extraction between 30 and 240 min (Fig. 2B) resulted in a peak a-v[K⁺] of 1.22 ± 0.25 meq/l at 70 min. Assuming a forearm blood flow of ~20 ml · min¹ · kg¹ (11), this represents a net K⁺ influx of 24.4 µeq · min¹ · kg¹ or 66 meq/h for 45 kg of mass (10) capable of exchanging K⁺. At the end of the experiment only 3% of the ingested K⁺ was estimated to be in the ECF compartment, whereas K⁺ extraction by the tissues accounted for 35% of ingested K⁺ (Table 4).

Na⁺

View larger version (48K): [in this window] [in a new window]   Fig. 3.   A: arterial plasma Na+ concentration ([Na+]) in NaHCO3 () and KHCO3 () trials. B: arterial plasma Na+ content in NaHCO3 and KHCO3 trials. Hatched bar indicates 60-min ingestion period. * Mean significantly different (P < 0.05) from time 0.

In the KHCO₃ trial, arterial (Fig. 3A) and venous (Table 3) plasma [Na⁺] decreased by ~3 meq/l between 100 and 270 min. The decrease in plasma Na⁺ content between 60 and 240 min (Fig. 3B) was largely accounted for by the decrease in PV (Fig. 1).

Cl

View larger version (41K): [in this window] [in a new window]   Fig. 4.   A: arterial plasma Cl concentration ([Cl]) in NaHCO3 () and KHCO3 () trials. B: arterial plasma Cl content in NaHCO3 and KHCO3 trials. Hatched bar indicates 60-min ingestion period. * Mean significantly different (P < 0.05) from time 0.

In the KHCO₃ trial, there was no net release or uptake of [Cl]. The decrease in arterial plasma [Cl] (Fig. 4A and Table 3), together with the decrease in PV, resulted in a significant decrease in plasma Cl content between 60 and 210 min; plasma Cl content recovered by 240 min (Fig. 4B).

Ca²⁺, Lactate, and Glucose

In the NaHCO₃ trial, arterial plasma [lactate] decreased significantly from 0.7 ± 0.2 meq/l preingestion to 0.5 ± 0.2 meq/l at 90 min postingestion and thereafter remained unchanged. In the KHCO₃ trial, [lactate] did not change with time. In both trials, a net negative a-v[lactate] of ~0.2 meq/l remained unchanged over time. There was no effect of treatment on plasma glucose concentration ([glucose]; remained at 5.8 ± 0.3 mmol/l), and, in both trials, arterial plasma [glucose] was greater than venous (not shown) by ~0.3 mmol/l.

Acid-Base Status

Origins of change in [H⁺]. Plasma [H⁺] calculated from the independent variables [SID], PCO₂, and [A_Tot] was not different from that calculated from measured pH; the difference between the means averaged 0.7 ± 0.02 neq/l for both trials combined. This allowed us to evaluate the physicochemical origins of the changes in plasma [H⁺] from changes in the independent variables [SID], [A_Tot], and PCO₂.

View larger version (50K): [in this window] [in a new window]   Fig. 5.   Arterial plasma H+ concentration ([H+]) and origins of change in arterial plasma [H+] in NaHCO3 (A) and KHCO3 (B) trials. , Measured arterial plasma [H+]; , calculated arterial plasma [H+] when only PCO2 changes and strong ion difference ([SID]) and total concentration of weak acids and bases ([ATot]) are kept constant; , calculated arterial plasma [H+] when only [ATot] changes and [SID] and PCO2 are kept constant; , calculated arterial plasma [H+] when only [SID] changes and PCO2 and [ATot] are kept constant. Hatched bar indicates 60-min ingestion period. * Mean significantly different (P < 0.05) from time 0.

View larger version (35K): [in this window] [in a new window]   Fig. 6.   The a-v for arterial plasma [H+] () and arterial PCO2 () in NaHCO3 trial. Decrease in a-v[H+] can be explained by the decrease in a-vPCO2. Hatched bar indicates 60-min HCO3 ingestion period. * Mean significantly different (P < 0.05) from time 0.

View larger version (43K): [in this window] [in a new window]   Fig. 7.   A: arterial [SID] in NaHCO3 () and KHCO3 () trials. B: arterial plasma [ATot] in NaHCO3 and KHCO3 trials. C: arterial PCO2 in NaHCO3 and KHCO3 trials. Hatched bar indicates 60-min ingestion period. * Mean significantly different (P < 0.05) from time 0.

Origins of change in [HCO₃]. In the NaHCO₃ trial, arterial plasma [HCO₃] reached a peak of 32.7 ± 0.8 meq/l at 90 min compared with an initial value of 26.0 ± 0.4 meq/l (Fig. 8A). Venous plasma [HCO₃] was consistently greater (by 2-3 meq/l) than arterial, and there was no change in a-v[HCO₃] with time (not shown). The increase in [SID] was the primary (and nearly sole) determinant for the rise in [HCO₃]; changes in PCO₂ and [A_Tot] alone or in combination did not significantly influence changes in [HCO₃].

View larger version (46K): [in this window] [in a new window]   Fig. 8.   Arterial plasma HCO3 concentration ([HCO3]) and origins of change in arterial plasma [HCO3] in NaHCO3 (A) and KHCO3 (B) trials. , Measured arterial plasma [HCO3]; , calculated arterial plasma [HCO3] when only PCO2 changes and [SID] and [ATot] are kept constant; , calculated arterial plasma [HCO3] when only [ATot] changes and [SID] and PCO2 are kept constant; , calculated arterial plasma [HCO3] when only [SID] changes and PCO2 and [ATot] are kept constant. Hatched bar indicates 60-min ingestion period. * Mean significantly different (P < 0.05) from time 0.

	DISCUSSION

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The present study found that the forearm, of which skeletal muscle is dominant with respect to fluid and ion exchange, modified the ionic and acid-base composition of perfusing blood during and after NaHCO₃ and KHCO₃ ingestion. Both NaHCO₃ and KHCO₃ produced a metabolic alkalosis; however, differences in the magnitude and time course reflected different origins of the fluid and ion disturbance, depending on whether the cation was Na⁺ or K⁺. These differences are associated with different processes for the intestinal transport of water, Na⁺ and K⁺, and their differential distribution in extra- and intracellular fluid compartments. Particularly noteworthy in the KHCO₃ trial was the >1 meq/l reduction in plasma [K⁺] that occurred as blood perfused the tissues from the arterial to the venous side of the circulation. It has been shown that tissue ion exchange processes effectively regulated plasma ion composition and acid-base state and are of physiological importance to the acute correction of plasma fluid and ion disturbances.

Methodology and Limitations

It is relevant that if only antecubital venous blood, and not arterial blood, had been sampled, the interpretation of the effects of NaHCO₃ and KHCO₃ loading on systemic function would be markedly different from that presented here. This is because the magnitude and time course of changes in venous plasma often varied from that of arterial plasma due to the rapidity of gas and ion exchange processes in skeletal muscle.

Plasma Acid-Base Balance

Increased PCO₂, in the NaHCO₃ trial, had an acidifying effect that partially offset the decrease in [H⁺] and increase in [HCO₃] that would have been induced by increases in [SID] alone. In the KHCO₃ trial the more modest increases in arterial plasma [HCO₃] were not associated with increases in PCO₂. It is speculated that this may have been associated with a measurably greater rate of ventilation and CO₂ in the KHCO₃ trial compared with the NaHCO₃ trial (unpublished observation).

In the KHCO₃ trial, large and rapid increases in [A_Tot] had an acidifying effect that contributed to partially offsetting the [SID]-induced decrease in [H⁺] and increase in [HCO₃]. This, however, was not evident in the NaHCO₃ trial. Thus a similar picture of acid-base disturbance in the two trials, with respect to plasma [H⁺] and [HCO₃], are seen to have markedly different origins with respect to the independent physicochemical determinants of acid-base control.

Water Balance

In both trials the subjects ingested solutions that had an osmolality ~570 mosmol/kgH₂O and were thus hypertonic to body fluids. Although net intestinal water flux is passive, it is coupled to net Na⁺, but not K⁺, transport (21), such that the intestinal epithelium is able to transport fluid against an osmotic gradient (13). In the NaHCO₃ trial, there was no evidence for net water movement into the gastrointestinal tract since PV was initially unchanged and subsequently (after 120 min) was observed to increase. The rate of water absorption after the ingestion of isotonic saline-HCO₃ (150 meq/l Na⁺, 120 meq/l Cl, 30 meq/l HCO₃) has been reported to be 4.20 ml · h¹ · cm¹ of small intestine (32). This rate of water absorption (assuming 100 cm of jejunum) would have moved 1,890 ml of fluid, or twice the ingested volume, during the 270-min experiment. Therefore, it is probable that the entire volume of ingested NaHCO₃ was absorbed in the present study. At the end of the experiment, the body was in positive water balance by 715 ml, with the ECF compartment in positive balance by 954 ml (Table 2), suggesting a net loss of intracellular fluid volume (ICFV) of ~240 ml. This is consistent with the estimated decrease in red blood cell MCV in this trial. Correction of the fluid disturbance occurred primarily by increased renal excretion of water, Na⁺, and base equivalents by the kidneys (unpublished observation).

In the KHCO₃ trial, the 15% decrease in PV within 70 min after completion of ingestion (at 120 min) represented a net loss of ~2 liters of water from the ECF into the gastrointestinal tract and possibly other tissues. Although net water flux into tissues was not detectable, the change in PV estimated from Hct underestimated that calculated from [PP], suggesting that there was a net increase in red blood cell MCV.

The proximal portion of the duodenum is highly permeable to water, and this allows for dilution of concentrated solutions in the proximal small intestine, thus facilitating absorption in the distal regions (17). In the KHCO₃ trial it is suggested that the initial rapid decrease in PV was due to the net movement of water and Na⁺ (see below) into the proximal duodenum. This appeared to be followed by elevated rates of net water, Na⁺, and K⁺ absorption in the distal small intestine, consistent with the gradual recovery of PV and subsequent diuresis, natriuresis, and kaliuresis (unpublished observations). Complete intestinal absorption of the ingested volume may have occurred by 270 min. In support, ingestion of 5 mmol/l KCl with 95 mmol/l NaCl and 45 mmol/l NaHCO₃ in humans resulted in a net rate of water absorption of 4-5 ml · h¹ · cm¹ of small intestine (21). In the present study, the minimum mean jejunal water absorption rate required to achieve full absorption of the ingested KHCO₃ solution (915 ± 59 ml) was estimated to be 2.6 ml · h¹ · cm¹, ~60% of the value obtained by Hicks and Turnberg (21).

Na⁺ Balance

1

1

In contrast to the NaHCO₃ trial, KHCO₃ ingestion resulted in a hyponatremia that appeared to be due to net water, Na⁺, and Cl secretion in the gastrointestinal tract (17) and to increased renal Na⁺ excretion (unpublished observations); there was no evidence of net Na⁺ movement into cells.

K⁺ Balance

It is suggested that all, or at least a majority, of ingested K⁺ was absorbed from the intestine by the end of the experiment. Duodenojejunal K⁺ transport is dependent on the electrochemical potential difference for K⁺ between plasma and intestinal lumen and is associated with the absorption of Na⁺, water, and other nutrients (3, 17, 31). Passive K⁺ absorption rates of ~0.02 meq · h¹ · cm¹ have been reported from proximal jejunum after ingestion of a solution consisting of 5 mM KCl with 45 mM NaHCO₃ and 95 mM NaCl (21). However, in the present study, the electrochemical potential difference for K⁺ across the small intestine would initially have been large, as ingested solution [K⁺] was 278 meq/l, strongly favoring net K⁺ absorption. If we assume a K⁺ absorption rate in our KHCO₃ trials of 0.02 meq · h¹ · cm¹ (from Ref. 21), then only ~9 meq of K⁺ would have been absorbed by the end of the experiment. In contrast, estimated initial net K⁺ transport rates in the jejunum and ileum, from an assumed mean luminal [K⁺] of 150 meq/l (assumes achievement of osmotic equilibrium between intestinal lumen and plasma), are ~15 (jejunal) and 12 (illeal) meq · h¹ · cm¹ (3) or, on average, ~1,300 meq/h. At this rate, the ingested K⁺ would have been absorbed in just over 11 min (280 meq, 100-cm segment). Because luminal [K⁺] certainly decreased rapidly with time, such high rates would not be maintained. For complete absorption of the ingested K⁺ to have occurred by 270 min, the average net rate of K⁺ absorption would have been 0.8 meq · h¹ · cm¹, markedly less than the estimated peak rates of 12-15 meq · h¹ · cm¹.

Skeletal muscle is recognized for its involvement in the extrarenal regulation of plasma [K⁺] via modulation of Na⁺-K⁺-ATPase activity (6, 9). In the present study, the widened a-v[K⁺] of 1.22 meq/l at 70 min represents an estimated peak K⁺ absorption rate of 66 meq/h (see RESULTS). The short-term regulators of Na⁺-K⁺-ATPase activity include intracellular [Na⁺], extracellular [K⁺], plasma insulin, and plasma catecholamines (9); however, catecholamines do not change in response to NaHCO₃ ingestion (7). Intracellular [Na⁺] would be low under the conditions of this study, and this would prevent marked increases in Na⁺-K⁺-ATPase activity (9). The 3 meq/l increase in arterial plasma (and muscle ECF) [K⁺] should, nonetheless, have resulted in increased flux of K⁺ into muscle. Aldosterone is known to be involved in the long-term control of skeletal muscle Na⁺-K⁺-ATPase activity (6). In the KHCO₃ trial, an increased plasma aldosterone (from 0.2 ± 0.04 to 1.2 ± 0.21 nmol/l at 90 min, unpublished observations) paralleled the increase in plasma [K⁺]. However, aldosterone may have contributed little, if any, to the widening plasma a-v[K⁺] as peak plasma aldosterone occurred between 90 and 150 min, whereas peak plasma a-v[K⁺] occurred at 70 min, and at 130 min plasma a-v[K⁺] was not significantly elevated. Another possibility is that increases in plasma insulin may have increased Na⁺-K⁺-ATPase activity (9) as a result of a plasma [K⁺]-induced release of pancreatic insulin (6). However, it is unlikely that plasma insulin increased in this study as there was no decrease in plasma [glucose], nor an increase in a-v[glucose], in either trial. It is concluded that the primary stimulus for the widened a-v[K⁺] (increased Na⁺-K⁺-ATPase activity) was the increase in arterial plasma and muscle ECF [K⁺].

Given the presence of the K⁺ control systems, it is interesting that plasma [K⁺] increased to >7 meq/l and remained elevated for an extended period. The body possesses an abundance of Na⁺-K⁺ pumps that, in inactive skeletal muscle, operate at only 10-15% of their capacity (9). The total skeletal muscle pool has a maximal capacity for K⁺ reabsorption of ~125 meq/min or 7,500 meq/h (9). At this rate the K⁺ ingested in the KHCO₃ trials could be taken up in 135 s. The limited use of the Na⁺-K⁺-ATPase reserve capacity for K⁺ regulation probably reflects a high intracellular [K⁺] and a low intracellular [Na⁺] in the tissues, preventing larger increases in Na⁺-K⁺-ATPase activity.

In the NaHCO₃ trial, a negative a-v[K⁺] between 30 and 70 min was due to an increase [not significant (NS)] in venous plasma [K⁺] and a decrease (NS) in arterial plasma [K⁺] and plasma K⁺ content. It has been suggested (1, 2) that the alkalosis resulting from NaHCO₃ increases intracellular [Na⁺] through exchange of intracellular H⁺ for extracellular Na⁺ via the Na⁺-H⁺ antiporter (4). Increased intracellular [Na⁺] in turn stimulates Na⁺-K⁺-ATPase activity to reduce extracellular [K⁺] (hypokalemia) and increase intracellular [K⁺] (8). Although the clinical efficacy of intravenous NaHCO₃ therapy to attenuate a developing hyperkalemia is well established (36), only a very modest hypokalemia developed after 160 min in the present study. Measurement of a-v[K⁺] across the arm showed no evidence of increased net movement of K⁺ into the tissues of humans having ingested NaHCO₃.

Perspectives

The markedly different whole body responses to ingested NaHCO₃ and KHCO₃ in humans at rest are attributed to the primarily extracellular distribution of ingested Na⁺ and to the primarily intracellular distribution for K⁺. The differential distribution and renal handling of the water and cation loads influenced the magnitude and time course of the acid-base disturbances. NaHCO₃ ingestion was characterized by increases in plasma and extracellular water associated with the increase in [Na⁺] and Na⁺ content. The increase in plasma [Na⁺] and decrease in plasma [Cl] combined to increase plasma [SID], which was the major contributor to the plasma alkalosis. The ingestion of KHCO₃ resulted in a significant hemoconcentration, probably associated with a net water flux into the intestinal lumen early during the ingestion period. Intestinal K⁺ absorption contributed to the marked increase in plasma [K⁺], with K⁺ extraction by skeletal muscle accounting for 37% of ingested K⁺ by 270 min. The metabolic alkalosis that occurred with NaHCO₃ ingestion was primarily the result of increased [SID], but due primarily to increases in plasma [K⁺] and secondarily to decreases in plasma [Cl].