HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) All Versions of this Article: 293/2/F541    most recent 00427.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (7) Citing Articles via Google Scholar Google Scholar Articles by Lee, F. N. Articles by Youn, J. H. Search for Related Content PubMed PubMed Citation Articles by Lee, F. N. Articles by Youn, J. H.

Evidence for gut factor in K⁺ homeostasis

Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California

Submitted 27 October 2006 ; accepted in final form 9 May 2007

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION GRANTS REFERENCES

 
We tested the hypothesis that K⁺ intake is sensed by putative K⁺ sensors in the splanchnic areas, and renal K⁺ handling is regulated by this signal. K⁺ was infused for 2 h into overnight-fasted rats via the jugular vein (systemic infusion), hepatic portal vein (intraportal infusion), or stomach (intragastric infusion) (n = 5 each), and plasma K⁺ concentration ([K⁺]) and renal K⁺ excretion were measured during the 2-h preinfusion, 2-h K⁺ infusion, and 3-h washout periods. During systemic K⁺ infusion, plasma [K⁺] increased by 1.3 mM (P < 0.05), and, on cessation of the K⁺ infusion, plasma [K⁺] fell to the preinfusion level within 1–2 h. Renal K⁺ excretion changed in proportion to the changes in plasma [K⁺]. During intraportal or intragastric K⁺ infusion, plasma [K⁺] and renal K⁺ excretion profiles were similar to those with systemic infusion. The effects of K⁺ infusions via the different routes (n = 5 or 6 each) were also studied during simultaneous feeding of overnight-fasted rats with a K⁺-deficient diet. During the meal, intraportal infusion resulted in increases in plasma [K⁺] similar to those with the systemic K⁺ infusion, while intragastric K⁺ infusion did not significantly increase plasma [K⁺]. Thus, when the intragastric K⁺ infusion was combined with a meal, there was marked enhancement of clearance of the K⁺ infused, which was associated with an apparent increase in renal efficiency of K⁺ excretion. These data suggest that there may be a gut factor that enhances renal efficiency of K⁺ excretion during meal (or dietary K⁺) intake.

feedback control; feedforward control; potassium sensor; potassium excretion

According to the traditional view, extracellular [K⁺] is the major factor in the regulation of renal K⁺ excretion (8, 9). Extracellular [K⁺] increases during dietary K⁺ intake, and this increase stimulates renal K⁺ excretion by a direct action on K⁺ secretion in the collecting duct (9). In addition, increased extracellular [K⁺] stimulates aldosterone secretion, which would further stimulate renal K⁺ excretion (16, 17). Increased renal K⁺ excretion will then help to normalize extracellular [K⁺]. Thus the maintenance of K⁺ homeostasis has been traditionally understood based on the concept of negative feedback control (Fig. 1). However, Rabinowitz (16, 17) challenged this traditional view. He pointed out that plasma K⁺ and aldosterone can stimulate renal K⁺ excretion only at levels above their normal ranges (2, 19, 23, 24). In his studies in the sheep (18), meal intake produced a pronounced kaliuresis, which was accompanied by no change in plasma aldosterone concentration. Plasma [K⁺] increased during meal intake, but the increase was only 0.5 meq/l, which was too small (when reproduced by intravenous K⁺ infusion) to account for the meal-induced kaliuresis (19). Thus the meal-induced kaliuresis could not be explained by changes in plasma K⁺ or aldosterone concentration. To explain the increase in renal K⁺ excretion following meal (i.e., K⁺) intake, he proposed a kaliuretic reflex arising from sensors in the splanchnic bed (i.e., gut, portal circulation, and/or liver). According to this proposal, renal K⁺ excretion can be increased, without (or before) increases in extracellular [K⁺], by a mechanism controlled by sensing of K⁺ intake (i.e., sensing of local increases in [K⁺] in splanchnic areas during K⁺ intake). Thus a new concept of feedforward control has been proposed (Fig. 1). This idea was supported by the study of Morita et al. (14), which demonstrated that an intraportal injection of KCl in rats increased hepatic afferent nerve activity (HANA), suggesting a hepatoportal mechanism that senses the portal venous [K⁺]. However, the mode of K⁺ administration (e.g., injection) in the Morita et al. study was not physiological, which undermines the physiological significance of the proposed hepatoportal mechanism (see DISCUSSION).

View larger version (9K): [in this window] [in a new window]   Fig. 1. Schematic diagrams illustrating control of extracellular fluid (ECF) K+ concentration ([K+]) via the classic feedback and hypothetical feedforward mechanisms.

	METHODS

TOP ABSTRACT METHODS RESULTS DISCUSSION GRANTS REFERENCES

 
Animals and surgical procedures. Male Wistar rats weighing 250–300 g were obtained from Simonsen (Gilroy, CA) and housed under controlled temperature (22 ± 2°C) and lighting (12 h light, 0600-1800; 12 h dark, 1800-0600), with free access to water and standard rat chow. One week before the experiment, rats were chronically cannulated either in the jugular vein (JV), the hepatic PV, or the stomach. Surgeries were performed under single-dose anesthesia (3:3:1 ketamine HCl, xylazine, acepromazine maleate; 0.1 ml/100 g body wt ip). Cannulas were placed in the JV [Silastic, 0.012-cm inner diameter (ID)] or the hepatic PV via the superior mesenteric vein (Silastic, 0.03 cm ID), as described by Hevener et al. (10). Gastric cannula (Silastic, 0.076 cm ID) was implanted in the forestomach, as described by Tsukamoto et al. (22). All cannulas were tunneled subcutaneously and exteriorized at the back of the neck. Animals were placed in individual cages, and spring coils and swivels were used for the protection of cannulas and free movement of animals within the cages. Patency for IG cannula was maintained with a constant infusion of distilled water (0.5 ml/h), while jugular and PV cannulas were flushed with heparinized saline (50 U/ml) twice weekly. In addition, at least 4 days before the experiment, the animals were placed in tail restraint as previously described (3, 4) to protect a tail arterial catheter for blood sampling, which was placed in the morning of the experiment (i.e., 0600). Animals were free to move about and allowed unrestricted access to food and water. All procedures were approved by the Institutional Animal Care and Use Committee at the University of Southern California.

Experimental protocols. In study 1, the effects of K⁺ infusion on plasma [K⁺] and renal K⁺ excretion were studied in conscious overnight-fasted rats. Food was removed at 1700 on the day before the experiment, and the experiments were started at 0900. Each experiment consisted of three periods: 2-h preinfusion, 2-h KCl infusion, and 3-h washout periods. K⁺ was infused into the stomach (IG), PV ("intraportal"), or JV ("systemic") to test the presence of the putative K⁺ sensors in the splanchnic bed. The rationale of this design was that, if K⁺ sensors (and subsequent regulation of [K⁺] by this signal) exist in the splanchnic bed, the impact of each K⁺ infusion on plasma [K⁺] and renal K⁺ excretion would be different, depending on the location of sensors and the route of K⁺ infusion (see Fig. 2). K⁺ was infused as 300 mM KCl (19) at a rate of 100 mg·kg^–1·h^–1 (or 2.5 ml/h of 300 mM KCl) (n = 5 each). Blood samples were collected for determination of plasma [K⁺] at variable intervals during the 2-h preinfusion, 2-h K⁺ infusion, and 3-h washout periods. Urinary K⁺ excretion was determined by collecting urine every hour throughout the experiment using specially designed cages. The animal cages had wire floor but were open at the bottom and were placed on an aluminum tray. The tray was replaced every hour to collect urine passed. To avoid the contamination of urine passed by fecal K⁺, a mesh screen was placed underneath the wire floor to separate feces from urine passed. To obtain a constant flow of urine, animals were infused with a constant volume (4 ml/h) of fluid (saline or saline + KCl during the K⁺ infusion period) throughout the experiment. This volume infusion did not appear to affect K⁺ excretion, as the baseline K⁺ excretion rate was indistinguishable from the basal rate of K⁺ excretion estimated without fluid infusion by measuring K⁺ in the urine collected during the light phase (i.e., between 7 AM and 7 PM) without food (data not shown). Each animal was used for only one experiment and killed by an overdose of pentobarbital sodium at the end of the experiment.

View larger version (8K): [in this window] [in a new window]   Fig. 2. Schematic diagrams illustrating the sensing of K+ entry via different K+ infusion sites by hypothetical K+ sensors in the gut, portal vein, and liver. Intragastric (IG) K+ delivery (left) would be sensed by all of the sensors, whereas systemic K+ delivery (right) may not be directly sensed by any of the splanchnic K+ sensors. Middle: intraportal K+ delivery may be sensed by the portal vein (PV) and hepatic K+ sensors.

Determination of plasma and urine [K⁺] and gastric K⁺ contents. Plasma and urine K⁺ levels were determined by flame photometry using a Radiometer FLM 3 flame photometer, as previously reported (4). In some experiments, K⁺ content was determined in the stomach and the small and large intestines by collecting and homogenizing luminal contents of these organs and measuring K⁺.

Calculations. Basal rate of urinary K⁺ excretion was calculated by averaging the values determined hourly during the 2-h preinfusion period. Increases in urinary K⁺ excretion (U_K) were calculated as the sum of urinary K⁺ excretions during the 2-h K⁺ infusion and the 3-h washout periods minus the 5-h equivalent of basal K⁺ excretion (i.e., basal K⁺ excretion x 5 h). Basal plasma [K⁺] was also determined during the preinfusion period. In some experiments, plasma [K⁺] decreased below or increased above the preinfusion basal level at the end of the experiments, although, on average, the final hour plasma [K⁺] was not different from the preinfusion values. Therefore, basal plasma [K⁺] was calculated as the average of the preinfusion and final-hour plasma [K⁺], and this helped to reduce the variations in the estimation of area under the [K⁺] curve above basal (AUC_K) (see below). Total area under the plasma [K⁺] curve was calculated using the trapezoidal method during the 2-h K⁺ infusion and the 3-h washout periods. AUC_K was then calculated by subtracting the area under the baseline (i.e., basal plasma [K⁺] x 5 h) from total area under the plasma [K⁺] curve.

Statistical analysis. Data are expressed as means ± SE. The significance of the differences in mean values among different treatment groups was evaluated using one-way or two-way ANOVA followed by ad hoc analysis using the Newman-Keuls' multiple-range test. Differences were considered significant at P < 0.05.

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION GRANTS REFERENCES

 
Time course changes in plasma [K⁺] during the systemic, intraportal, and IG K⁺ infusions in the fasting state. During systemic K⁺ infusion (via the JV), plasma [K⁺] increased by 1.3 mM, that is, from the preinfusion baseline of 3.8 ± 0.1 to 5.1 ± 0.1 mM during the second hour of the K⁺ infusion (Fig. 3A). On cessation of the K⁺ infusion, plasma [K⁺] fell to the preinfusion level within 1–2 h. The average plasma [K⁺] during the final hour, i.e., between 2 and 3 h after the cessation of the K⁺ infusion, was identical to the preinfusion baseline, indicating that the infused K⁺ was completely disposed during the 2-h K⁺ infusion and the subsequent 3-h washout periods. During intraportal K⁺ infusion, the plasma [K⁺] profile was very similar to that with the systemic infusion, except that the changes were slightly slower (Fig. 3A). This difference might be due to a buffering capacity of the liver to take up K⁺ during the K⁺ infusion and release it into the blood during the subsequent washout period. When K⁺ was infused into the stomach (IG infusion), plasma [K⁺] rose rapidly and showed a profile similar to that with the systemic K⁺ infusion with a slight dynamic delay, as observed with the intraportal K⁺ infusion (Fig. 3B). The plasma [K⁺] profile was virtually identical between the intraportal and the IG K⁺ infusion, indicating that K⁺ absorption from the stomach (or gut) was extremely fast.

View larger version (20K): [in this window] [in a new window]   Fig. 3. Time courses of plasma [K+] (A and B) and renal K+ excretion (C and D) and total K+ excretion (0–300 min; E) with the systemic [jugular vein (JV)], intraportal (PV), and IG K+ infusion (KINF) in overnight-fasted rats. The time course data were compared between the systemic vs. the intraportal (A and C) or the systemic vs. the IG (B and D) K+ infusion. Values are means ± SE for 5 experiments.

Time course changes in plasma [K⁺] and renal K⁺ excretion during the systemic, intraportal, and IG K⁺ infusions with a K⁺-deficient meal. The effects of the K⁺ infusions via different routes were also studied during feeding of overnight-fasted rats with a K⁺-deficient diet to examine potential signals stimulated by ingesting a meal with the K⁺, the normal route of K⁺ intake. Compared with the fasting state, the rise in plasma [K⁺] during the K⁺ infusion, regardless of route of administration, was smaller when the K⁺ infusion was combined with a meal (Fig. 4). The rise in plasma [K⁺] was suppressed the greatest with the IG K⁺ infusion: plasma [K⁺] increased in only two of the five animals studied; thus there was not a significant increase in average plasma [K⁺] in the IG K⁺ infusion + K⁺-deficient meal group (P > 0.05). Renal K⁺ excretion was not much different between the fasting vs. meal groups in the systemic and intraportal infusion groups (P > 0.05). However, in the IG K⁺ infusion group, renal K⁺ excretion during the 2-h K⁺ infusion period was significantly reduced with a meal vs. infusion during the fasting state (P < 0.05), presumably due to the lack of significant increases in plasma [K⁺]. However, it is important to note that renal K⁺ excretion was substantially elevated above basal, especially during the washout period, despite the fact that plasma [K⁺] was not significantly different from preinfusion baselines (Fig. 5). In the three animals in which no increase in plasma [K⁺] occurred, renal K⁺ excretion was increased significantly above basal (570 ± 102 µmol, P < 0.01), suggesting the presence of an IG factor that is regulated independent of plasma K⁺ that stimulates renal K⁺ excretion. This is further supported by the finding that the pattern of changes (i.e., continued increases) in renal K⁺ excretion after the termination of IG K⁺ infusion was clearly different from that with other infusions, where renal K⁺ excretion fell, together with plasma [K⁺], immediately after the termination of K⁺ infusion (Fig. 4).

View larger version (16K): [in this window] [in a new window]   Fig. 4. Time courses of plasma [K+] (A, B, and C) and renal K+ excretion (D, E, and F) with the systemic (left), intraportal (middle), and IG (right) K+ infusions during a K+-deficient meal compared with the data obtained in the overnight-fasting state (Fig. 3). Values are means ± SE for 5 or 6 experiments.

View larger version (12K): [in this window] [in a new window]   Fig. 5. Plasma [K+] () and renal K+ excretion (staircase plot) profiles with IG infusion during a meal. These data are also shown in Figs. 4, C and F. *P < 0.05 and **P < 0.01 vs. basal.

View larger version (10K): [in this window] [in a new window]   Fig. 6. Increases in plasma [K+] {change in area under the [K+] curve (AUCK); 0–300 min; A} and renal K+ excretion [change in urinary K+ excretion (UK) 0–300 min; B] and the relationship between UK and AUCK (C). In C, open and solid symbols represent the groups studied in the fasting state and during a meal, respectively, and circles, diamonds, and squares represent the groups with the systemic, intraportal, and IG K+ infusion, respectively. Lines are drawn for the groups studied in the fasting state (slope = 5.0), the JV and PV groups (slope = 7.5), or the IG group (slope = 20) studied during a meal. Values are means ± SE for 5 or 6 experiments. *P < 0.05 vs. fasting; #P < 0.05 vs. JV or PV.

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION GRANTS REFERENCES

In the fasting state, the IG K⁺ infusion produced a profile of plasma [K⁺] identical to that with the intraportal K⁺ infusion, indicating that K⁺ absorption from the gut was very fast with an empty stomach. However, when the stomach is filled with food during a meal, the K⁺ infused might be retained by the food, and K⁺ absorption might be slowed. Therefore, it may be conceivable that a slow absorption of K⁺ from the gut (or delayed K⁺ entry into the blood) was responsible for the lack of a significant rise in plasma [K⁺] with the IG K⁺ infusion during a meal. Nonetheless, a slow K⁺ absorption alone cannot explain the lower plasma [K⁺] profile throughout the experiment (or three- to fourfold decreases in AUC_K). In theory, AUC_K would be determined as the amount of K⁺ that appeared in the blood (or absorbed from the gut) divided by K⁺ clearance (when K⁺ clearance is reasonably constant). Therefore, AUC_K would be reduced if K⁺ clearance increases, and/or if plasma K⁺ appearance is reduced. We determined the degree of absorption of K⁺ that enters the stomach with a meal within our experimental time frame, and our results indicate that nearly all (85%) of the dietary K⁺ was absorbed during the 2-h refeeding and the subsequent 3-h follow-up periods (Table 1). These data suggest that a slow K⁺ absorption cannot explain the three- to fourfold decreases in AUC_K with IG K⁺ infusion during a meal, and, if so, this must be due to increased plasma K⁺ clearance.

Our data indicate that the rise in plasma [K⁺] during K⁺ infusion was reduced during a K⁺-deficient meal, compared with the fasting state, regardless of route of infusion, indicating increased clearance of the K⁺ infused. This was likely due, at least in part, to increased insulin levels during a meal, which stimulate cellular K⁺ uptake (1, 12). However, insulin's effect alone cannot entirely account for the lack of a significant rise in plasma [K⁺] with the IG K⁺ infusion during a meal, as plasma [K⁺] increased significantly with the systemic or intraportal infusion during a meal. Therefore, there must be an additional factor that accounts for enhanced clearance of plasma K⁺ with the IG K⁺ infusion during a meal. Despite the lack of increase in plasma [K⁺], there was a significant increase in renal K⁺ excretion with IG K⁺ infusion during a meal. Although absolute amounts of renal K⁺ excretion showed a tendency to be lower, renal efficiency, defined as the ratio of increase in renal K⁺ excretion to plasma [K⁺] (i.e., U_K/AUC_K), was markedly enhanced with the IG infusion during a meal compared with other routes of infusion (Fig. 6C). On the other hand, the apparent reduction in absolute amounts of renal K⁺ excretion suggests that extrarenal cellular K⁺ uptake was increased with IG K⁺ infusion during a meal. Since this occurred without a significant increase in plasma [K⁺], it is likely that the efficiency of cellular K⁺ uptake was also enhanced. This effect may be more dramatic than the effect on K⁺ excretion, explaining that absolute amount of K⁺ excretion was less with IG K⁺ infusion during a meal, compared with other infusions, even with enhancement of renal efficiency. Thus our data suggest that the lack of a significant rise in plasma [K⁺] with the IG K⁺ infusion during a meal is due to enhanced efficiency of both renal and extrarenal K⁺ handling.

Efficiency of renal K⁺ excretion was markedly enhanced only when the IG K⁺ infusion was combined with a meal (Fig. 6C). In other words, K⁺ excretion efficiency was enhanced when K⁺ entered the stomach, together with a meal, as in the normal situation of dietary K⁺ intake. Thus there may be a mechanism in the gut for sensing of normal dietary K⁺ intake (i.e., the presence of both a meal and K⁺), which provokes enhanced renal K⁺ excretion efficiency. Such a mechanism may be important for ensuring that renal K⁺ excretion is increased only when a meal includes K⁺ (which increases total body K⁺ content), but not when a meal lacks K⁺, and not when plasma [K⁺] transiently increases as a result of a K⁺ shift between intracellular and extracellular spaces (without increases in total body K⁺ content), such as in exercise.

What is the mechanism by which the presence of both meal and K⁺ are sensed in the stomach (or the gut)? One possibility is that there is a type of cells in the stomach or the gut that senses K⁺, but this sensing requires the presence of nutrients (e.g., glucose) from a meal. Alternatively, K⁺ may be sensed in the intestine rather than the stomach, and this K⁺ sensing is affected by a meal as follows: without a meal (i.e., with empty stomach), the K⁺ infused into the stomach may be rapidly absorbed there before it can reach the intestine. K⁺ was infused in our preliminary study as 300 mM KCl solution at a volume rate of 40 µl/min. As the KCl solution was slowly dripped onto the surface of the stomach, a high K⁺ gradient from the lumen to the stomach cells might allow a rapid K⁺ absorption in the stomach. However, with a meal, the K⁺ infused into the stomach may be mixed and retained by food, carried over to the intestine, and sensed by K⁺-sensing cells there. Regarding this possibility, it would be important to test whether a direct K⁺ infusion into the intestine stimulates renal K⁺ excretion in the absence of a meal.

One may argue that the relationship between plasma [K⁺] and K⁺ excretion may not necessarily be linear, and the apparent increase in renal efficiency of K⁺ excretion with IG infusion during a meal may be due to smaller increases in plasma [K⁺]. Regarding this, our separate study showed that systemic K⁺ infusion at a rate of 40 mg·kg^–1·h^–1 increased plasma [K⁺] by 0.67 ± 0.09 mM (n = 4) or 50% of the increase with 100 mg·kg^–1·h^–1 in the present study, which was accompanied by increases in renal K⁺ excretion (during 2-h K⁺ infusion), equivalent to only 15% of that with 100 mg·kg^–1·h^–1. These data indicate that renal efficiency, i.e., the ratio of increases in K⁺ excretion to plasma [K⁺], was actually lower rather than higher, with smaller increases in plasma [K⁺]. This is directly supported by studies of the relationship between plasma [K⁺] and renal K⁺ excretion in dogs (23, 24). In fact, in the present study, renal efficiency was lower during the first hour, when [K⁺] was lower, than the second hour of K⁺ infusion (data not shown) in all groups, except for the group of IG K⁺ infusion during a meal, in which renal efficiency was very high in the first hour because of a significant increase in renal K⁺ excretion in the absence of an increase in plasma [K⁺] (Fig. 5). Taken together, these data suggest that the apparent increase in renal efficiency with IG infusion during a meal cannot be accounted for by a nonlinear relationship between plasma [K⁺] and renal K⁺ excretion.

Our data clearly indicate that intraportal K⁺ infusion resulted in plasma [K⁺] and renal K⁺ excretion profiles identical to those with systemic K⁺ infusion, regardless of whether the K⁺ infusions occurred with or without a meal. These data suggest either that portal venous or hepatic K⁺ sensing does not exist or that, if it does, its impact on K⁺ homeostasis is quantitatively insignificant. Morita et al. (14) demonstrated that intraportal infusions of KCl in rats increased HANA and urinary K⁺ excretion. However, in their experiments for measurement of HANA, KCl solution was injected into the PV as a bolus. If the bolus injection was given in a very short period of time, the hepatoportal area might be exposed to very high [K⁺]. For example, if the 50 mM KCl solution was given in 3 s at the dose of 1.0 ml/kg (Fig. 2 of Ref. 14), the portal venous [K⁺] might rise to a level of 28 mM above basal [assuming portal plasma flow of 36 ml·kg^–1·min^–1 in rats = 1.04 ml·min^–1·g liver^–1 (10) x 34.5 g liver/kg body wt (11)]. Although this exposure might be of a short duration, such high [K⁺] would depolarize most of cells in the area. Therefore, it is not surprising to see significant responses of HANA to portal K⁺ injection. In their experiments for measurement of urinary K⁺ excretion, 50 mM KCl were infused for 30 min at a rate of 50 µl·kg^–1·min^–1 (via the PV and the vena cava). This small rate of K⁺ infusion did not alter plasma [K⁺], but was reported to increase urinary K⁺ excretion. Therefore, there may be K⁺ sensors in the PV or liver and a kaliuretic reflex from these sensors. However, our data indicate that such a kaliuretic reflex may be quantitatively insignificant or undetectable under the present conditions of dietary K⁺ intake.

Most homeostatic regulation in the body is under feedback control, as it offers a robust control (13). However, this type of control can be slow to respond to an external disturbance and inevitably mandates an error signal, a significant disturbance of the system. In the present study, renal K⁺ excretion increased as plasma [K⁺] increased during the systemic K⁺ infusion, a renal response that certainly helps to prevent excessive rises of plasma [K⁺] above basal, constituting the classic feedback mechanism. However, activation of this mechanism required substantial increases in plasma [K⁺] (i.e., 1.3 mM in the fasting state). In contrast, feedforward control would provide a quick control of output function (e.g., renal K⁺ excretion) in anticipation of rise of the signal (i.e., plasma [K⁺]). This type of control may add speed or accuracy to the control (at the expense of robustness). Providing evidence for a gut factor that senses dietary K⁺ intake and enhances renal efficiency of K⁺ excretion, the present data support the feedforward control of K⁺ homeostasis proposed by Rabinowitz (16, 17). With this mode of control, significant increases in plasma [K⁺] were prevented during the IG K⁺ infusion. The combination of both feedback and feedforward mechanisms may provide both robustness and accuracy (or speed) of the regulation, which appears to be the case in the regulation of K⁺ homeostasis.

In summary, the present data indicate that intraportal K⁺ entry was not sensed by the body, as it resulted in plasma [K⁺] and renal excretion profiles very similar to those during systemic K⁺ infusion. In contrast, IG K⁺ infusion, when combined with a meal (K⁺ deficient), increased plasma K⁺ clearance and prevented significant increases in plasma [K⁺] during the K⁺ infusion. These data suggest that there is sensing of K⁺ intake in the gut, but not in the PV or the liver, which increases plasma K⁺ clearance (via increasing the efficiency of renal and/or extrarenal K⁺ handling), and thereby maintains [K⁺] homeostasis during dietary K⁺ intake.

	GRANTS

TOP ABSTRACT METHODS RESULTS DISCUSSION GRANTS REFERENCES

 
This study was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK 65998 (to J. H. Youn) and DK 057678 and DK 34316 (to A. A. McDonough).

	ACKNOWLEDGMENTS

 
We thank Dr. C. Donovan for helping us to set up the surgical procedures for implantation of chronic cannulas.

	FOOTNOTES

 

Address for reprint requests and other correspondence: J. H. Youn, Dept. of Physiology and Biophysics, USC Keck School of Medicine, 1333 San Pablo St., MMR 626, Los Angeles, CA 90089-9142 (e-mail: youn{at}usc.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

	REFERENCES

TOP ABSTRACT METHODS RESULTS DISCUSSION GRANTS REFERENCES

 

1. Bia MJ, DeFronzo RA. Extrarenal potassium homeostasis. Am J Physiol Renal Fluid Electrolyte Physiol 240: F257–F268, 1981.[Abstract/Free Full Text]
2. Calo L, Borsatti A, Favaro S, Rabinowitz L. Kaliuresis in normal subjects following oral potassium citrate intake without increased plasma potassium concentration. Nephron 69: 253–258, 1995.[Web of Science][Medline]
3. Choi CS, Lee FN, McDonough AA, Youn JH. Independent regulation of in vivo insulin action on glucose versus K(+) uptake by dietary fat and K(+) content. Diabetes 51: 915–920, 2002.[Abstract/Free Full Text]
4. Choi CS, Thompson CB, Leong PK, McDonough AA, Youn JH. Short-term K⁺ deprivation provokes insulin resistance of cellular K⁺ uptake revealed with the K⁺ clamp. Am J Physiol Renal Physiol 280: F95–F102, 2001.[Abstract/Free Full Text]
5. DeFronzo RA, Sherwin RS, Dillingham M, Hendler R, Tamborlane WV, Felig P. Influence of basal insulin and glucagon secretion on potassium and sodium metabolism. Studies with somatostatin in normal dogs and in normal and diabetic human beings. J Clin Invest 61: 472–479, 1978.[Web of Science][Medline]
6. Donovan CM, Cane P, Bergman RN. Search for the hypoglycemia receptor using the local irrigation approach. Adv Exp Med Biol 291: 185–196, 1991.[Medline]
7. Forte LR, Fan X, Hamra FK. Salt and water homeostasis: uroguanylin is a circulating peptide hormone with natriuretic activity. Am J Kidney Dis 28: 296–304, 1996.[Web of Science]
8. Gennari FJ. Hypokalemia. N Engl J Med 339: 451–458, 1998.[Free Full Text]
9. Gennari FJ, Segal AS. Hyperkalemia: an adaptive response in chronic renal insufficiency. Kidney Int 62: 1–9, 2002.[Web of Science][Medline]
10. Hevener AL, Bergman RN, Donovan CM. Novel glucosensor for hypoglycemic detection localized to the portal vein. Diabetes 46: 1521–1525, 1997.[Abstract]
11. Ishise S, Pegram BL, Tamamoto J, Kitamura Y, Frohlich ED. Reference sample microsphere method: cardiac output and blood flows in conscious rat. Am J Physiol Heart Circ Physiol 239: H443–H449, 1980.[Free Full Text]
12. Kurtzman NA, Gonzalez J, DeFronzo R, Giebisch G. A patient with hyperkalemia and metabolic acidosis. Am J Kidney Dis 15: 333–356, 1990.[Web of Science]
13. McDonough AA, Thompson CB, Youn JH. Skeletal muscle regulates extracellular potassium. Am J Physiol Renal Physiol 282: F967–F974, 2002.[Abstract/Free Full Text]
14. Morita H, Fujiki N, Miyahara T, Lee K, Tanaka K. Hepatoportal bumetanide-sensitive K⁺-sensor mechanism controls urinary K⁺ excretion. Am J Physiol Regul Integr Comp Physiol 278: R1134–R1139, 2000.[Abstract/Free Full Text]
15. Nakazato M. Guanylin family: new intestinal peptides regulating electrolyte and water homeostasis. J Gastroenterol 36: 219–225, 2001.[CrossRef][Web of Science][Medline]
16. Rabinowitz L. Homeostatic regulation of potassium excretion. J Hypertens 7: 433–442, 1989.[CrossRef][Web of Science][Medline]
17. Rabinowitz L. Aldosterone and potassium homeostasis. Kidney Int 49: 1738–1742, 1996.[Web of Science][Medline]
18. Rabinowitz L, Green DM, Sarason RL, Yamauchi H. Homeostatic potassium excretion in fed and fasted sheep. Am J Physiol Regul Integr Comp Physiol 254: R357–R380, 1988.[Abstract/Free Full Text]
19. Rabinowitz L, Sarason RL, Yamauchi H. Effects of KCl infusion on potassium excretion in sheep. Am J Physiol Renal Fluid Electrolyte Physiol 249: F263–F271, 1985.[Abstract/Free Full Text]
20. Rossetti L, Klein-Robbenhaar G, Giebisch G, Smith D, DeFronzo R. Effect of insulin on renal potassium metabolism. Am J Physiol Renal Fluid Electrolyte Physiol 252: F60–F64, 1987.[Abstract/Free Full Text]
21. Stokes JB. Potassium intoxication: pathogenesis and treatment. In: The Regulation of Potassium Balance, edited by Seldin DW and Giebisch G. New York: Raven, 1989, p. 157–174.
22. Tsukamoto H, Reidelberger RD, French SW, Largman C. Long-term cannulation model for blood sampling and intragastric infusion in the rat. Am J Physiol Regul Integr Comp Physiol 247: R595–R599, 1984.[Abstract/Free Full Text]
23. Young DB. Quantitative analysis of aldosterone's role in potassium regulation. Am J Physiol Renal Fluid Electrolyte Physiol 255: F811–F822, 1988.[Abstract/Free Full Text]
24. Young DB, Paulsen AW. Interrelated effects of aldosterone and plasma potassium on potassium excretion. Am J Physiol Renal Fluid Electrolyte Physiol 244: F28–F34, 1983.[Abstract/Free Full Text]

This article has been cited by other articles:

				M. Greenlee, C. S. Wingo, A. A. McDonough, J.-H. Youn, and B. C. Kone Narrative Review: Evolving Concepts in Potassium Homeostasis and Hypokalemia Ann Intern Med, May 5, 2009; 150(9): 619 - 625. [Abstract] [Full Text] [PDF]

				Y. Jin, Y. Wang, Z.-J. Wang, D.-H. Lin, and W.-H. Wang Inhibition of angiotensin type 1 receptor impairs renal ability of K conservation in response to K restriction Am J Physiol Renal Physiol, May 1, 2009; 296(5): F1179 - F1184. [Abstract] [Full Text] [PDF]

				L. Thomas and R. Kumar Control of Renal Solute Excretion by Enteric Signals and Mediators J. Am. Soc. Nephrol., February 1, 2008; 19(2): 207 - 212. [Abstract] [Full Text] [PDF]

				Highlights From The Literature Physiology, October 1, 2007; 22(5): 299 - 302. [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 293/2/F541    most recent 00427.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (7) Citing Articles via Google Scholar Google Scholar Articles by Lee, F. N. Articles by Youn, J. H. Search for Related Content PubMed PubMed Citation Articles by Lee, F. N. Articles by Youn, J. H.