ION TRANSPORT CHANGES DURING CALCITONIN-INDUCED INTESTINAL SECRETION IN MAN

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1 GASTIIOENTEROLOGY 71: , 1976 Copyright ~ 1976 by The William. '" Wilkin. Co. Vol. 71, No.3 Printed in U.s.A. ION TRANSPORT CHANGES DURING CALCITONIN-INDUCED INTESTINAL SECRETION IN MAN T. KENNEY GRAY, PATRICIA BRANNAN, DAVID, JUAN, STEPHEN G. MORAWSKI, AND JOHN S. FORDTRAN Department o/intemol Medicine, Uniuersity a/texas Health Science Center at Dallas, Southwestern Medical School, Dallas, Texos, and Department. 0/ Medicine and Pharmacology, Uniuersity 0/ North Carolina School of Medicine, Chopel Hill, North Carolina Previous studies have shown that synthetic salmon calcitonin (SCT) infused intravenously causes secretion of water and electrolytes in the jejunum of normal human subjects. The present experiments were carried out to learn more about the nature ofthis intestinal secretory process. During SCT - or synthetic human calcitonin (HCTHnduced intestinal secretion, the following observations were made: (1) There was no change in potential difference; (2) CI was secreted against an electrochemical gradient; (3) unidirectional Na flux out of the lumen was decreased while the opposite flux was normal; (4) luminal pco, fell; (5) addition of glucose to the jejunal contents stimulated Na absorption, and this in tum counteracted the secretory effect of calcitonin. These findings suggest that calcitonin induces active CI secretion and inhibits active Na absorption, and that HCO, absorption is reduced by virtue of OH secretion; furthermore, jejunal glucose absorption and glucose-stimulated Na absorption are intact during calcitonin-induced secretion. Intravenous infusion of HCT caused intestinal secretion only when blood levels were much higher than occur physiologically; therefore, calcitonin is probably not a mediator of spontaneous variations of intestinal transport in normal people. However, because calcitonin induces secretion in the ileum as well as in the jejunum, hypercalcitonemia (within the range commonly found in patients with medullary carcinoma of the thyroid) could be a cause of severe secretory diarrhea. The intravenous infusion of synthetic salmon calcitonin (SCT), at a rate that does not reduce serum Ca concentration, causes secretion of fluid and electrolytes by the human jejunum. 1 This suggests that the effect of intravenous calcitonin infusion on small bowel function might provide insight into the mechanisms of intestinal secretion and secretory diarrhea, and in this report we describe the results of an additional series of such studies. The three major purposes of the experiments reported in this paper were: (1) to learn more about the possible physiological and pathophysiological role of calcitonin as a regulatory hormone for intestinal water and electrolyte transport; (2) to see whether glucose in the intestine modifies calcitonin-induced secretion; and (3) to gain insight into the mechanism of intestinal secretion stimulated by calcitonin. Methods Absorption in a 30-cm segment of jejunum or ileum was studied by the triple lumen perfusion method that has previously been described in detail. I., This involves the infusion of Received January 26, Accepted March 5, This study was supported by United States Public Health Service Grant 5 ROI AM06506 from the National Institute of Arthritis, Metabolism and Digestive Diseases, and Public Health Services Research Grant RR 46 from the General Clinical Research Centers Branch of the Division of Research Resources. 392 isotonic electrolyte solutions into the jejunum or ileum at a rate of 11 ml per min and continuous sampling of luminal fluid 10 and 40 cm beyond the infusion point, Where indicated, mannitol or glucose was substituted for NaCI in isoosmotic amounts. UNa was added to some test solutions in a concentration of jlc per liter. Polyethylene glycol (PEG) was the nonabsorbable volume marker. Test solutions were bubbled with 5% CO,-95% O. for 30 min before and during the experiment. Luminal samples were aspirated from the proximal and distal apertures at a rate of 1 ml per min into plastic syringes which were capped immediately after the collection of each 30-min pool. Subjects were normal volunteers, ages 21 to 40, who granted an informed consent. None had a positive reaction to skin testing with calcitonin. Experiments were begun when the infusion aperture of the tube was at the ligament of Treitz or in the mid ileum as determined by fluoroscopy. SCT (provided by Dr. James Lesh, Armour Pharmaceutical Co., Kankakee,Ill., as AL0997, 4334 Medical Research Council (MRC) U per mg) was given in a dosage of 1 MRC U per kg per hr. SCT was diluted in 0.9% saline and given intravenously at a rate of 0.5 ml per min. Synthetic human calcitonin (HCT, (Provided by Dr. A. S. Ling, Ciba-Geigy Corporation, Summit, N. J., as Ba (estimated 100 MRC U per mg» was given in one of three dosages, 0.5, 1.0, or 2.5 jlg per kg per hr. Lyophilized HCT was dissolved in 0.9% saline-o.l% human serum albumin and given intravenously at a rate of 0.5 ml per min. All subjects received saline intravenously during the control period at the same rate. Intestinal samples were discarded during the 1st hr (equilibration period) and collected

2 September 1976 CALCITONIN-INDUCED INTESTINAL SECRETION 393 for analysis during the 2nd hr of the intravenous infusion of saline or calcitonin_ When these HCT experiments were performed, we unfortunately did not have available a reliable assay for HCT concentration in plasma, nor did we anticipate that this would become available to us in the near future. The assay was subsequently perfected, and we therefore repeated the HCT infusions in normal subjects (who were not studied by jejunal perfusion) in order to compare blood levels of HCT with the secretory response that we had observed with different infusion rates of HCT. Blood samples were obtained (from the arm not receiving the intravenous infusion) before and every 15 min during the infusion_ Samples were placed in heparinized tubes on ice and centrifuged at the end of the infusion. Plasma samples were frozen immediately after aspiration and stored for future radioimmunoassay. The radioimmunoassay of HCT was performed by John Hennessy, M.D., Department of Medicine, University of North Carolina School of Medicine. The assay system, which has been previously described,' has a lower limit of detection of 0.24 ng per ml. Plasma samples were analyzed by radioimmunoassay in a random fashion and the chronological sequence of the samples was not identified until after all of the immunoassay results were available. Luminal aspirates were analyzed for ph, pca" osmolality, Test solution" TABLE 1. PD in the jejunum of /0 subjects Lumen Na" (meq/l) PO' (mv) Saline 138 ± ± 0.5 Mannitol 65 ± ± 3.8 Glucose 115 ± ± 1.2 "The infused saline solution contained 140 mm NaCI and 5 mm KCI; the infused mannitol solution contained 270 mm mannitol and 5 mm KCI ; the infused glucose solution contained 100 mm glucose, 85 mm NaC!, and 5 mm KCI. The glucose concentration at the aspiration site during infusion of the glucose solution was 40 mm. Fluid for Na concentration was obtained 5 cm proximal to the PD electrode. 'Positive values mean lumen positive to blood. Negative values mean lumen negative to blood. and the concentrations of electrolytes and PEG by standard procedures that have been previously described. I. Absorption or secretion rates were calculated from the perfusion rate, the change in the concentration of PEG, and the change in concentration of the electrolytes. Calculation of unidirectional flux rates was done by the method of Berger and Steele.' The results are expressed as means ± 1 SEM. Statistical analysis of the results is based on the t-test using paired values from each subject in a group. Potential difference (PO) between peripheral venous blood and luminal contents was measured by a silver-silver chloride electrode. The method is similar in principle to the techniques we have used previously, except that peripheral blood rather than skin was used as a reference. That this system can detect changes in PD is shown by the data in table 1. With saline infused into the lumen, the PO was near zero. With a mannitol-saline solution, the PO became positive in accord with the expected sodium diffusion potential. With a glucose-saline solution, the PD was negative in accord with the stimulation of electrogenic sodium transport." 7 Results Effect 0/ synthetic human calcitonin (HeT) on water and electrolyte movement in the jejunum. Table 2 shows the absorption or secretion rates of water and electrolytes in the jejunum of normal subjects during intravenous infusion of saline and HCT. The test solution infused into the jejunum was a balanced electrolyte solution, the exact makeup of which is shown in the footnote to table 2. HCT infusion at 0.5 ~ per g kg per hr reduced mean water and electrolyte absorption rates, but none of the differences (except potassium) were statistically significant. The infusion of 1.0 and 2.5 ~ g per kg per hr induced an approximately equal secretion of water and electrolytes. No significant change in the serum calcium concentration occurred during HCT infusion at any of the three infusion rates. Plasma levels of immunoreactive HCT (ihct) during constant intravenous HCT infusion in another group of TABLE 2. 'Dose-response effects of HCT on the net movement of water and electrolytes in the jejunum" HCT dosage Net H.O NelNa Net K :-';et CI ( ~ ~! k g / h r ) (ml/hr/30em) (meq/hr/30em) (meq/hr/30em) (meq/hr/30 em) 1'el HCO. (meq/hr/30 em) 0.5 n = 5 Control -109 ± ± ± ± 2.3 HCT - 67 ± ± ± ± 2.5 pz NS' NS NS 1.0 n - 5 Control -98 ± ± ± ± 1.4 HCT +24 ± ± ± ± 5.0 P n=5 Control -119 ± ± ± ± 2.4 HCT +12 ± ± ± ± 3.2 p= om ± ± 1.3. NS ± ± 3.4 NS -1.8 ± ± 2.7 NS Q ( - ) = net absorption; (+) net secretion. Test solutions contained: NaC) 105 mm; KCI 4 mm; NaHCO. 30 mm. ens, not significant.

3 394 GRAY ETAL. Vol. 71, No.3 normal subjects are shown in fig. 1. Basal concentrations of ihgt were undetectable «0.24 ng per ml). The 2.5 Ilg per kg per hr dosage produced relatively constant elevations in plasma concentrations ranging from 10 to 12 ng per ml and the 1.0 #Lg per kg per hr dosage produced ihct levels ranging from 1.8 to 2.4 ng per ml. In a single subject given 0.5 Ilg per kg per hr of HCT, the plasma concentration of ihct rose to 0.7 to 1.0 ng per ml. Effect of HeT on potential difference in the jejunum. As shown in table 3, intravenous infusion of Illg per kg per hr HCT had no statistically significant effect on jejunal PD. During the HCT infusion, sodium and chloride were secreted into the jejunal lumen. The chloride secretion was against an electrochemical gradient. Effect of glucose on the response to SeT in the jejunum. This series of experiments was designed to determine the effect of an intravenous infusion of SCT on the movement of water and electrolytes when the lumen contained glucose. As shown in table 4, with glucose in the test solutions, SCT reduced the rate of water and electrolyte absorption, but did not induce secretion. The difference in the rate of absorption with and without SCT was 50 ml of water, 6.7 meq of sodium, and 5.1 meq of chloride. SCT had no effect on glucose absorption. Ē ~ :;; 10 ::i Ul... ct 8!!: en..j w..j Z ~ 6 Z 4 o... u a 2 u z.. ~ 0 o 15 o 25"'9 (41 a 10"'9 (31 05"'9 til TIME (MINUTES) FIG. 1. Effect of different infusion rates of HCT on the serum concentration of calcitonin measured by radioimmunoassay. Nllmbers in parentheses indicate number of subjects studied at each infusion rate of HCT. Shaded area indicates that the assay cannot accurately measure calcitonin concentrations below 0.24 ng per ml. Studies in the ileum. Six subjects were studied with a bicarbonate-free solution and 5 were studied with a bicarbonate-containing solution. As shown in table 5, with both perfusion solutions SCT infusion caused the ileum to secrete water, sodium, potassium, chloride, and bicarbonate. Because intravenous SCT infusion always followed the control period, 5 subjects were given a sham infusion (saline instead of SCT) during the experimental period to make sure that the changes observed during SCT infusion were not due to the extended period of intestinal perfusion. As shown in table 5, absorption rates were similar during the first and second perfusion periods. Therefore, secretion or reduced absorption observed with SCT cannot be attributed to nonspecific changes in intestinal function during the period of intestinal perfusion. Effect of set on sodium unidirectional flux rates in the jejunum and ileum. Data for 5 subjects in the jejunum are given in table 6. SCT infusion reduced net sodium absorption by reducing the flux rate of sodium out of the lumen. The results in six ileal experiments are also shown in table 6. The change from net sodium absorption to net sodium secretion was almost entirely the result of a reduction in the flux out of the lumen, from 27.5 to 15.8 meq per hr per 30 cm. There was no significant change in the sodium unidirectional flux rate into the lumen. Effect of calcitonin on luminal peo, in the jejunum and ileum. Figure 2 shows the effect of SCT on the pco, of luminal contents collected from the distal end of the test segment when the infusion solutions contained TABLE 4. Effect of set with glucose in the luminal solutions in the jejunum of 5 subjects Water. ml/hr/30cm Sodium, meq/hr/30 cm Potassium, meq/hr/30 cm Chloride, meq/hr/30 cm Glucose, mmol/hr/30 cm Intravenous 8aline -188 ± ± ± ± ± 1.7 Intravenous set -138 ± 19" -4.6 ± ± ± ± 1.7 (-) = absorption. Test solutions contained: NaCI 85 mm, KCI 5 mm, and glucose 100 mm. P < 0.05 when compared with comparable value in previous column. TABLE 3. Effect of HeT (1 /lg/kg/hr) on PO, and on water, sodium, and chloride movement in the jejunum of 5 subject, Intravenous PO Net water Proximal Distal Net Proximal Distal!IIet Infu.ion!II. (my) I ml!hr/30 em I!II. No Cl Cl Cl (meqil) (meqil) (meq!hr/30 em) (meqil) {meqil> (meq!hr/30 em) Saline ± ± ± ± ± ± ± ± 0.9 HCT 0.0 ± ± ± ± ± ± ± ± 1.5 P ~ NS' ( -) = net absorption, (+) ~ net secretion of water, sodium, and chloride. Perfused solutions contained NaCll25 mm and KCI5 mm. Proximal and distal refer to fluid collected from eacb end of the 3O-cm test segment. Positive value for PD means lumen positive to blood. NS, not significant.

4 September 1976 CALCITONIN-INDUCED INTESTINAL SECRETION 395 Experiment TABLE 5. Effect 01 SCT on net movement 01 water and electrolytes in the ileum" NetH,O Net Na Net K Netel Net HCO, (mllhr/30 em) (meqlhr/30em) ( m E q l h r / ~ O c(meqlhr/30 ) em) (meqlhr/:1o em) SCT" HCO.-free (n - 6) Control -44 ± ± ± S ± 2.S +4.5 ± 1.0 SCT +62 ± 12 +S.2 ± ± ± ± 1.9 p Q om HCO,'(n - 5) Control -7S ± ± ± S ± I.S -0.5 ± O.S SCT +46 ± ± ± ± ± 1.2 p om Sham' (n = 5) Control - 68 ± ± ±.05 -S.2 ± ± 0.3 Saline - 68 ± 17 -S.9 ± ±.09 -S.3 ± ± 0.4 p = NS' NS NS NS NS " ( - ) = net absorption; (+) = net secretion. Perfusion solutions contained: NaCI 80 mm, KCI 5 mm, mannitol 100 mm. 'Perfusion solutions contained NaCI 105 mm, KCl 5 mm, NaHCO. 30 mm. NS, not significant. TABLE 6. Sodium flux rotes' Lumen Na (meqil) SodIUm nux. meq/hr/30 em Net Flux out Flux In Jejunum (n = 5) Intravenous saline 100 ± ± ± ± 1.9 Intravenous SCT 105 ± ± ± ± 1.5 p= NS NS neum (n - 6) Intravenous saline 83 ± ± ± ± 1.5 Intravenous SCT 87 ± ± ± 2.S 24.0 ± 3.9 p- NS NS In the jejunal studies 100 mm glucose was present in the infused test solutions (same experiment as shown in table 4). In the ileal studies 100 IUId mannitol was present in the infused test solutions (same experiment as shown in table 5, HCO.-free experiment). NS, not significant. ~ 30 - : ' ~ ~, - : ~ ::>..J Cont,ol SCT I Cont,ol I Saline FIG. 2. Effect of SCT infusion on the PCO. in fluid collected from the distal end of the test segment. On the right side is shown pco.!vhen saline rather than SCT was infused during the experimental Period (sham experiment). bicarbonate. In every subject but I, SCT caused a fall in PC0 2 When saline rather than SCT was infused intravenously during the second half of the experiment, the pco. of luminal fluid was not changed. Arterial pco. was measured in 2 subjects during intravenous infusion of SCT, and in neither instance did pco. change from the control level. Thus, the fall in luminal pco. during SCT infusion cannot be attributed to a fall in blood pco. Discussion When the human small intestine is perfused with physiological test solutions, there is a wide variation in the rate of fluid and electrolyte movemcllt between different normal people and from day to day in the same person. Most subjects absorb, but in some normal people fluid secretion rather than absorption is observed. The control mecanism(s) for this spontaneous fluctuation in small intestinal activity has not been determined, but presumably some hormonal, circulatory, or neurogenic influence must be involved. Whether or not the active ionic secretion that occurs occasionally in normal people is the same as that which causes secretory diarrhea is not known, but it is theoretically possible that some of the hormones which have been implicated as the cause of secretory diarrhea in

5 396 GRAYETAL. Vol. 71, No.3 patients with tumors might be the physiological regulators "Of intestinal absorption-secretion. In laboratory animals, a large number of hormones (gastrin, prostaglandins, cholecystokinin, glucagon, vasoactive intestinal peptide, and gastric inhibitory peptide) have been reported to either reduce intestinal absorption or produce intestinal secretion, but results in different studies are so contradictory (perhaps due to species difference') that it is difficult to apply them to the human small intestine. Antidiuretic hormone, I prostaglandin (PGE 1 ),1O synthetic salmon calcitonin! glucagon, 11 secretin,li and cholecystokinin 11 have been reported to reduce absorption or produce secretion by the human small intestine. The mechanism of the intestinal effects produced by these hormones is unknown at present, although the prostaglandins are believed to act by stimulating the synthesis of cyclic AMP." 10 With this background, the results reported in this paper will be discussed in three sections, corresponding to the major purposes of this research as enumerated at the beginning of the paper. Physiology and pathophysiology. The results of our studies indicate that SCT infusion converts the lower as well as the upper part of the small bowel from an absorbing organ to one which secretes water, sodium, chloride, and potassium. Also, SCT either reduces the rate of bicarbonate absorption or augments the spontaneous rate of bicarbonate secretion. The rates of water and electrolyte secretion in the jejunum and ileum are such that the secreted fluid would rapidly overwhelm the absorptive capacity of the colon 14 (even if colonic absorption remained normal during calcitonin infusion), and diarrhea would be expected if the SCT infusion was continued for several hours. However, before interpreting these results in terms of human physiology and pathophysiology, it was important to make certain that human calcitonin has basically the same effect on intestinal absorption and secretion as the salmon variety. To test this, we infused synthetic HCT intravenously and found that doses of 1 and 2.5 #lg per kg per hr induced a marked and equal change in fluid movement, but that 0.5 #lg per kg per hr had no statistically significant effect. In a separate group of normal subjects, we infused these same doses of HCT and measured plasma calcitonin concentration by radioimmunoassay (mct). By correlating plasma ihct concentrations with jejunal absorption and secretion rates, we conclude that plasma concentrations of greater than 1.5 ng per ml are required to reduce absorption to a statistically significant extent, but that plasma concentrations of 2 ng per ml cause as much secretion as when plasma ihct is raised to 10 to 12 ng per ml. The blood concentrations required to influence intestinal absorption-secretion are much higher than ever occur in normal people, even after calcitonin release has been stimulated by calcium infusion or pentagastrin injection.".. Therefore, it seems unlikely that spontaneous fluctuations in the rate of absorption-secretion in normal subjects could be due to changes in plasma calcitonin concentration. On the other hand, patients with medullary carcinoma of the thyroid (MCT) often have plasma calcitonin concentrations greater than 2 ng per ml, so that calcitonin might be responsible (directly or indirectly) for diarrhea in this disease. MCT also may secrete prostaglandins, II and Matuchansky and Bernier have shown that PGE, perfused intraluminally can cause jejunal secretion. IO Therefore, diarrhea in MCT might be due to calcitonin or PGE" or to their combined effects. Of interest is a patient with MCT who had severe diarrhea, normal plasma concentration of prostaglandins and an ihct concentration of 278 ng per ml, reported by Isaacs et a!. 11 At least in this patient, calcitonin seems a more plausible cause of the diarrhea than prostaglandins. However, not all patients with MeT and high mct have diarrhea, so it must be assumed that chronic elevation of plasma HCT does not always reduce absorption or induce secretion, at least not to an extent sufficient to produce diarrhea. Modification of calcitonin-induced jejunal secretion by intraluminal glucose. Glucose enhances net sodium absorption in the normal human jejunum,7 and oral ingestion of glucose-saline solutions can reduce or correct salt and water depletion in patients with cholera. 18 Where it was assumed that calcitonin might be a mediator of secretory diarrhea, it therefore was of interest to determine what effect glucose in the lumen has on jejunal secretion stimulated by calcitonin infusion. Our results show that in the presence of glucose, SCT has about the same over-all effect on sodium movement as we noted previously when the jejunal lumen was perfused with a sodium chloride solution. I However, because the control rate of absorption was so high, SCT did not induce jejunal secretion in the presence of glucose. Bicarbonate in luminal fluid also increases the control rate of sodium absorption in the jejunum, I. II but bicarbonate does not prevent the jejunum from secreting when SCT is infused. I To a degree, this may be explained by the fact that bicarbonate does not enhance the control rate of absorption as much as glucose. However, SCT infusion also causes a larger net change in the rate of fluid and electrolyte movement when the lumen contains bicarbonate than when it contains glucose (fig. 3). Probably this is explained by the fact that SCT markedly inhibits jejunal bicarbonate absorption 1 but has no effect on jejunal glucose absorption (table 4). Thus, although both glucose and bicarbonate stimulate the control rate of jejunal sodium absorption, only glucose remains effective during SCT infusion. These results suggest that oral glucose-saline solutions might help reduce salt and water depletion' in patients with secretory diarrhea associated with high blood concentrations of calcitonin. Mechanism of calcitonin-induced intestinal secretion. As calcitonin blood concentrations are progressively increased, the rate of water and electrolyte absorption is progressively decreased until the intestine begins to secrete. This effect begins within 1 hr of starting a calcitonin infusion, and intestinal function returns to near normal within 1 hr of cessation of the calcitonin. I This rapid recovery and the fact that glucose absorption

6 September 1976 CALCITONIN-INDUCED INTESTINAL SECRETION 397 after exposure to cholera toxin" and during calcitonin infusion, and absorption of glucose reduces or prevents the secretion which otherwise would have been caused by the toxin or the hormone. On the other hand, our results with calcitonin differ from the effect of cholera toxin in vivo in that cholera secretion, at least in dogs,21 is associated with a striking change in transmembrane PD (mucosal side negative), whereas we can find no evidence that the calcitonin secretion in humans is associated with a change in PD. Our results with + I O - - ~ C ~ o ~ ~ ~ r O ~ I ' S ~ C Y T calcitonin are - - different in at least one respect from the -10 A -Nael o -NaCI + No HC03 - NoCI + Glucose FIG. 3. Effect of SCT on jejunal sodium movement when the luminal perfusion solutions contained NaCI. NaCI plus NaHCO and NaCI plus glucose. The data with NaCI and NaCI plus NaHCO. have been previously reported I and are reshown here in order to better illustrate the effect of glucose in the jejunal lumen. is unaffected (table 4) suggests that calcitonin has a specific influence on the ion transport mechanisms of the intestinal cells. The results shown in table 3 indicate that chloride is transported against an electrochemical gradient during calcitonin infusion, and it is reasonable to conclude that active chloride secretion is at least one of the transport processes which mediates calcitonin-induced fluid secretion. The observation that PD does not change significantly (table 3) as secretion is in progress suggests either that the over-all secretory process is electrically neutral, or that the mucosa is so permeable to cations (sodium and potassium) that the charge generated by electrogenic chloride secretion is rapidly balanced by passive cation secretion. Radioactive sodium was added to jejunal and ileal test solutions in some of these experiments, so that the unidirectional flux of sodium in both directions across the mucosal cells could be calculated. We found that calcitonin reduced the flux of sodium out of the lumen, but that it had no effect on sodium flux into the lumen. Because the transmembrane PD is near zero and is not significantly influenced by calcitonin, these findings Suggest that calcitonin infusion inhibits active sodium absorption. This analysis assumes that calcitonin has no effect on the passive permeability of the mucosa to sodium (see final paragraph of Discussion). Calcitonin infusion inhibits bicarbonate absorption in the jejunum and increases the normal rate of bicarbonate secretion in the ileum. In addition, the pc02 of luminal fluid falls during calcitonin infusion. One possible explanation for this fall in pc0 2 is that reduced absorption or secretion of bicarbonate is mediated by OH-secretion. 20 Other possible explanations for a fall in pc0 2 during bicarbonate secretion have been discussed elsewhere. I. 20 It is interesting to compare the present findings with calcitonin to the effects of cholera toxin. Both cholera toxin and calcitonin stimulate active chloride secretion." 21 Both cause a reduction in luminal pc SUggesting that the mechanism of bicarbonate secretion may be similar. Furthermore, glucose transport is intact effects of PGE I in humans as reported by Matuchansky and Bernier. 10 These workers found that PGE 1 induced sodium secretion mainly by increasing the plasma-tolumen flux, whereas with calcitonin this flux is unchanged. Whether these differences in PD with cholera and unidirectional flux rates with PGE 1 indicate a basic difference in the transport effects of these agents is not clear, because PD and unidirectional flux rates may be altered by changes in mucosal permeability as well as by changes in active ion transport REFERENCES 1. Gray TK, Bieberdorf FA. Fordtran JS: Thyrocalcitonin and the jejunal absorption of calcium. water and electrolytes in normal subjects. J Clin Invest 52: Fordtran JS, Rector FS, Carter NW: The mechanisms of sodium absorption in the human small intestine. J Clin Invest 47: Hennessy JF. Wells SA. Ontjes DA. et al: A comparison of pentagastrin injection and calcium infusion 8S provocative agents for the detection of medullary carcinoma of the thyroid. J Clin Endocrinol Metab 39:487-4; Berger EY. Steele JM: The calculation of transfer rates in two compartment systems not in dynamic equilibrium. J Gen Physiol 41 : Bieberdorf FA. 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