Anticholinergics have been claimed to reduce primarily the volume of gastric. Newcaetle upon Tyne NEJ 7RU

Transcription

1 J. Phyeiol. (198), 36, pp With 8 text-figures Printed in Great Britain RELATONSHP BETWEEN HYDROGEN ON CONCENTRATON AND FLOW OF GASTRC JUCE DURNG NHBTON OF GASTRC SECRETON N THE CAT BY B. H. HRST, L. A. LABB, THE LATE J. D. REED AND J. G. STEPHEN* From the Department of Physiology, Medical School, University, Newcaetle upon Tyne NEJ 7RU (Received 23 October 1979) SUMMARY 1. The normal relationship between the [H+] and rate of flow of gastric juice was determined in conscious cats prepared with cannulated gastric fistulae. Gastric secretion was monitored during stimulation with pentagastrin, insulin and histamine. 2. [H+] rose asymptotically with the flow of gastric juice. This relationship was quantified by applying the data to the integrated form of the Fick equation for diffusion, a graphical plot of log [H+] vs. 1/flow. The calculated relationships were similar for gastric secretion stimulated by pentagastrin, insulin and histamine, and were used to define the normal relationship between gastric [H+] and flow. 3. Significant inhibition of pentagastrin-stimulated gastric secretion with the histamine H2-receptor antagonists, metiamide and cimetidine, atropine or somatostatin did not alter the normal relationship between [H+] and flow; the [H+] observed fell within the normal range observed at that flow rate in the presence of pentagastrin alone. Similarly, inhibition of insulin-stimulated secretion with cimetidine, atropine or somatostatin, and histamine-stimulated secretion with metiamide, did not alter the normal relationship between [H+] and flow of gastric juice. 4. These data provide evidence that histamine H2-receptor antagonists, atropine and somatostatin all act to reduce the primary rate of acid secretion and do not influence the [H+] per se, either by interfering with back-diffusion of H+, or by changing the proportions of a non-parietal component of gastric secretion added to the parietal H+ component. NTRODUCTON t has been suggested that drugs which primarily reduce hydrogen ion concentration, [H+], and thus increase intragastric ph, would have a greater potential in the therapy of peptic ulceration than those drugs which had a primary action in reducing the volume of gastric juice (Torchiana, Stone, Cook & Weise, 1977). Anticholinergics have been claimed to reduce primarily the volume of gastric juice, whilst histamine H2-receptor antagonists are claimed to cause a primary * Present address: Department of Surgery, University of Malaya, Kuala Lumpur, Malaysia /8/ $ The Physiological Society

2 52 B. H. HRST AND OTHERS reduction in the [H+] (Wormsley, 1977), and would thus be expected to be of greater therapeutic use. Reed (1977), however, suggested that these presumed differential effects of the gastric inhibitors may in fact only be a consequence of the well known relationship between [H+] and flow, in which [H+] increases asymptotically with flow rate (Hollander, 1932; Gray, Bucher & Harman, 1941; Gray & Bucher, 1941; Teorell, 1947; Hollander, 1952; Nordgren, 1963; Makhlouf, MacManus & Card, 1966). Detailed evidence of the relationship between [H+] and flow of gastric juice during inhibition of secretion is lacking. n this study, therefore, the normal relationship between gastric [H+] and flow was established when secretion was stimulated with pentagastrin, histamine and insulin. The effect of inhibition of secretion on these relationships was then examined with histamine H2-receptor antagonists, an anticholinergic and somatostatin. Preliminary reports of these studies have been communicated to the British Society of Gastroenterology and the Physiological Society (Hirst, Blair, Labib, Reed & Stephen, 1978; Hirst, Labib, Reed & Stephen, 1979). METHODS Experiments were carried out in eighteen conscious cats prepared with cannulated gastric fistulae under full surgical anaesthesia at least 1 year earlier. Animals were fasted for 36 h before each experiment, although allowed free access to water. Gastric juice was collected continuously by gravity drainage into calibrated receivers attached to the fistulae and divided into 15 min samples. The volume of juice was measured to the nearest -1 ml, and [H+] determined by electrometric titration of a sample (1- ml. or less as appropriate) to ph 7 with.1 M-NaOH (Radiometer, Copenhagen, Denmark). Acid output was calculated as the product of the volume of secretion and the [H+]. A percutaneous needle (Butterfly 21G, Abbott Labs. Ltd., England) was inserted into a cephalic vein and 9 % saline infused at 12 ml. h-'. All materials were added to this.v. infusion. Materiat8 Pentagastrin (Peptavlon,.C.. (Pharmaceuticals) Ltd., Macclesfield, England), histamine, as the acid phosphate (B.D.H., England), or insulin (Wellcome Foundation Ltd., England) were used as the stimulants of acid secretion. Acid secretion was inhibited by either somatostatin (prepared in the cyclic form by solid phase methods (Coy, Coy, Arimura & Schally, 1973, a gift from Professor Schally and Drs Coy and Meyers), atropine sulphate (Antigen, Roscrea, reland), or metiamide or cimetidine (Smith Kline & French Labs. Ltd., Welwyn Garden City, England). Pentagastrin, insulin, atropine and cimetidine were supplied as sterile solutions. Somatostatin and histamine were dissolved in -9 % saline; metiamide was dissolved in 1 M-HC1, brought to ph 6- with -1 M-NaOH and diluted with water. These compounds were sterilized by microfiltration (Millipore, -22 jum). Analy8 of results The results are expressed as means + 1 s.e. of mean (n) of gastric flow rates (ml. 15 min-), [H+] (#equiv ml.-'), and acid outputs (#equiv 15 min-'). Correlation lines were calculated by the method of least squares. Significance of differences between means were calculated by Student's t test for paired data, or Student's t-test or Cochran's modification of this test for unpaired data as appropriate. Significance was set at P < 5.

3 GASTRC [H+] AND FLOW * 12 E cr 8' 4 - _ 16 r 12 A o B To a Pe > a P5 O P5 L3 A P.5 * P5 ~~~~~~~~P Pentagastrin n = 358 U P5 * cr r C a) : Histamine n = Gastric flow l (ml. 15 min-) Fig. 1. The relationships between flow of gastric juice and [H+] when stimulated by A, pentagastrin *5 (@), 1 (E), 8 (A), 16 (A), 32 () and 64 (A),ug kg-' h-1 (358 observations in six cats); B, insulin -2 u. kg-' h-' (325 observations in eighteen cats); C, histamine acid phosphate 5 and 25,ug kg-' h-' (428 observations in twelve cats). Each point represents a single 15 min observation in one cat. The lines are obtained by transforming to the arithmetic form the linear regression lines obtained by substituting the experimental results in the integrated form of the Fick equation for diffusion with limits of + 1 S.D. (see Fig. 2).

4 54 B. H. HRST AND OTHERS RESULTS 1. Normal relationship between [H+] and gastric flow (a) Pentagastrin stimulaion 358 observations in six cats during continuous infusions of pentagastrin (.5, 1, 8, 16, 32 and 64 /sg kg-1 h-1) demonstrated a curvilinear relationship between [H+] and flow (Fig. A). The maximum [H+] observed was 168 tequiv ml.-', and the maximum flow rate was 15*6 ml. 15 min'. At rates of flow below about 3 ml. 15 minthere was an obvious fall in [H+] tending towards zero. A. 24 r. 2-1 og = r =- 4688_ r = Pentagastrin nsulin Histamine *4-9 O _ a /Gastric flow (1/ml. 15 min-) B 16r Histamine F :1 4p- L -J Gastric flow (ml. 15 min-') Fig. 2. A, the relationship between log [H+] and 1/flow of gastric juice stimulated by pentagastrin, insulin and histamine. The lines are calculated from the data illustrated in Fig. 1. B, transformation of the lines illustrated in A to the arithmetic axes of [H+i and flow, + 1 s.e. of mean. For detailed description, see Results. (b) nsulin stimulation A similar curvilinear relationship was observed between [H+] and flow rate with 325 observations in eighteen cats stimulated with insulin, 2 u. kg-' h-1 (Fig. 1 B). The maximum [H+] observed was 167,equiv ml.-', and the maximum flow rate 13 ml. 15 min-l.

5 GASTRC [H+] AND FLOW 55 (c) Hi8tamine 8timulation Secretion stimulated by histamine acid phosphate (5 and 25,sg kg-1 h-l) demonstrated a similar relationship between [H+] and flow in 428 observations in twelve cats (Fig. 1 C). The maximum [H+] observed was 172,equiv ml.-, and the maximum flow rate 13-8 ml. 15 min-'. The first 15 min sample of gastric juice during stimulation with pentagastrin and histamine, and the first three 15 min samples of gastric juice during stimulation with insulin were not included in the calculations. This was to exclude samples of juice likely to be contaminated with unstimulated gastric secretion. 2. Quantitation of the relationship between [H+] and gastric flow The relationships between [H+] and gastric flow were converted to a linear form by substituting the experimental results in the integrated form of the Fick equation for diffusion (Defares & Sneddon, 196): log (u-a) = log (u-a)-2.33 (2nrrlh)- where: uo = [H+] in primary parietal cell secretion, u = [H+] in gastric juice sample, a = [H+] in extracellular fluid, VO = gastric flow rate, h = permeability of the mucosa to H+, and 2irrl = area available for diffusion. Equating the [H+] of the extracellular fluid (a) with that of plasma, i.e. 4 x 18 M (ph 7.4), as the [H+] in the gastric juice during stimulation varied from about to 1*6 x 1-1 M, a approximates to zero. Therefore a plot of log u versus V gives a line with slope - 2*33 (27rrlh) and intercept log uo. Substituting the experimental results from pentagastrin-, insulin-, and histaminestimulated secretion in this equation gave significant correlation lines as illustrated in Fig. 2A. The lines were not significantly different for the three stimuli. The [H+] in the primary parietal cell secretions (uo) calculated from the intercept of the correlation lines were 165, 147 and 189,equiv ml.-l for pentagastrin-, insulin, and histaminestimulation, respectively. These values are not significantly different from one another and are similar to the highest values observed in this study. Transformation of these linear plots of log [H+] vs. 1/flow, back to arithmetic values gave the curves illustrated in Fig. 2B with confidence limits of 1 s.e. These lines are also superimposed as the mean + 1 S.D. on the data shown in Fig. 1. These curves are used to delineate the normal relationships between [H+] and flow of gastric juice.

6 56 B. H. HRST AND OTHERS 3. Effect of inhibitors on the relationship between [H+] and gastric flow (a) Pentagastrin stimulation (i) nhibition of acid output Histamine H2-receptor antagonists. Metiamide and cimetidine were added to the infusion of pentagastrin during the formation of dose-response curves by the continuous infusion method; pentagastrin 1,tg kg-' h-1 was infused for -75 h and thereafter the dose of pentagastrin was doubled every half-hour (Hirst, Labib & Reed, 1978). The acid outputs during the last half-hour of infusion of pentagastrin 1l- A j2 8 F cimetidine 2 2 o metiamide O_ * * H2 antagonist mg kg-' h-1 Ps 1 P58 _1 B,o X 6 i C 4 - co 2_ o Atropine 1 Mg kg-' h-1 Q P5 1 P58 1 C _ * Somatostatin pg kg-' h-' Fig. 3. Percentage inhibition of pentagastrin-stimulated (P6) gastric acid secretion produced by histamine H2-receptor antagonists, atropine and somatostatin. A, percentage inhibition of pentagastrin-, 1 and 8 jg kg-' h-1, stimulated secretion by cimetidine (@), 2 and 2 mg kg-' h-', and metiamide (O), 2 mg kg-' h-' (twelve observations in six cats). B, percentage inhibition of pentagastrin-, 1 and 8 jug kg-' h-', stimulated secretion by atropine, 1 jag kg-' h-1 (twelve observations in six cats). C, percentage inhibition of pentagastrin-, 8 jag kg-' h-1, stimulated secretion produced by somatostatin, 1, 2, 4, 1 and 2 jug kg-l h-' (six observations in six cats). Detailed descriptions of these experiments are given in the Results. n each case the points represent the mean + 1 s.e. of mean percentage inhibition. * Significant inhibition compared with control experiments in same animals.

7 GASTRC [H+] AND FLOW 57 1 jug kg-' h-l, and during the infusion of pentagastrin 8,ug kg-' h-', with and without histamine H2-receptor antagonism in the same six cats, were calculated. Both cimetidine and metiamide significantly reduced the acid secretion in response to pentagastrin and the percentage inhibitions of secretion are illustrated in Fig. 3A. Atropine. The effect of atropine on acid secretion evoked by pentagastrin was calculated in a similar manner to that described above for the H2-receptor antagonists. Atropine only significantly reduced the response to pentagastrin 1 1ug kg-' h-1 (Fig. 3B). Pentagastrin 16 r H2-Blockers Atropine 7 Ē: 8 - ' Gastric flow (ml. 15 min') Gastric flow (ml. 15 min') 16 r Somatostatin 12 F. _ * t 12p- 41-8p Gastric flow (ml. 15 min-) Fig. 4. Effect of inhibition of gastric acid secretion by histamine H2-receptor antagonists, atropine and somatostatin on the relationship between [H+] and flow of pentagastrin-, 1 or 8 jug kg-' h-1, stimulated gastric secretion. A, H2-blockers. Pentagastrin alone (O), pentagastrin plus cimetidine (@), pentagastrin plus metiamide (U). Suffixes indicate doses of metiamide and cimetidine in mg kg-' h-1. B, atropine. Pentagastrin alone () and pentagastrin plus atropine (@). Suffixes indicate the dose of atropine in,ug kg-' h-1. C(, somatostatin. Pentagastrin alone is indicated by shaded symbols, and pentagastrin with somatostatin by open and half-shaded symbols. Suffixes indicate doses of somatostatin in jag kg-' h-1. Each point represents the mean + 1 s.e. of mean [H+] and flow of the data shown in Fig. 3. The lines illustrate the normal relationship + 15.D. between [H+] and flow during pentagastrin-stimulation as shown in Fig. 1 A.

8 58 B. H. HRST AND OTHERS A W- *'E 12_ CcDntrol B 14 -qnl. ZU P_ : 8 -._ E _ ; 4. _ :._ Metiamide (mg kg-' h-')._3 g l Gastric flow (ml. 15 min-') Fig. 5. A, effect of metiamide on histamine acid phosphate, 25,tg kg-' h-1, stimulated gastric acid secretion. Each point represents the mean acid output + 1 s.e. of mean of twelve observations in six cats. Two groups of six cats were used and their control responses to histamine alone are illustrated (). Details of experimental design are given in Results. B, the relationship between [H+] and gastric flow for the data plotted in A. Each point is the mean + 1 s.e. of mean [H+] and flow for histamine alone (O. F]) and histamine plus metiamide (, ). Each symbol indicates the responses in one group of cats. Suffixes are the doses of metiamide (mg kg-' h-1). The normal relationship + 1 S.D. between [H+] and flow during histamine-stimulated secretion is indicated by the lines as shown in Fig. 1C. ;-1 E 6.> 4 X 2 Ad Control A C _ E._ m 8-4 _ 1 p Somatostatin Gastric flow (ml. 15 min-') (pg kg' h-1) Fig. 6. A, effect of somatostatin on insulin-, -2 u.kg-l h-l, stimulated gastric acid secretion. B, the relationship between [H+] and gastric flow for the data plotted in A. The normal relationship + 1 S.D. between [H+] and flow during insulin-stimulated secretion is indicated by the lines as shown in Fig. 1 B. Each point is the mean E. of mean (n = 12). Two control responses, in the same group of six cats, to insulin alone are illustrated (). Suffixes indicate the dose of somatostatin in jag kg-' h-1. See Results for details of experimental design, and Fig. 5 for description of presentation of data. 8

9 GASTRC [H+] AND FLOW 59 Somatostatin. Pentagastrin was infused at 8 jug kg-1 h-1 for up to 4 h in six cats. On separate occasions pentagastrin was infused alone for 75 h and then somatostatin (1, 2 and 4, or 4, 1 and 2 jtg kg-' h-1) was infused for subsequent *75 h periods. The acid output during the last 15 min of infusion of each dose of somatostatin was calculated as the percentage inhibition of the response in the same cats at the same time stimulated by pentagastrin alone (Brown, Coy, Gomez-Pan, Hirst, Hunter, Meyers, Reed, Schally & Shaw, 1978). nhibition was related to the dose and significant at each somatostatin dose (Fig. 3C)..' E 24 A Control r. E F B._ ) Cimetidine (mg kg-' h'1) a Gastric flow (ml. 15 min-') Fig. 7. A, effect of cimetidine on insulin, *2 u.kg-1 h-l, stimulated gastric secretion. B, the relationship between [H+] and gastric flow for the data plotted in A. Suffixes indicate doses of cimetidine in mg kg-' h-l. See Results and Figs. 5 and 6 for detailed description. *' m2._3 A Control E..._ t: _ 12 E r 8 F L.tu r ' B a l Atropine (;Lg kg-' h-1) a * Gastric flow (ml. 15 min-') Fig. 8. A, effect of atropine on insulin-, -2 u.kg-1 h-l, stimulated gastric secretion. B, the relationship between [H+] and flow for the data plotted in A. Suffixes are doses of atropine (fig kg-' h-l). See Results and Figs. 5 and 6 for details.

10 6 B. H. HRST AND OTHERS (ii) Effect on [H+] vs. flow relationship The inhibition of acid output (Fig. 3) caused by the H2-antagonists, atropine and somatostatin, produced a reduction in the [H+] of the gastric juice. However, in each case, the [H+] observed fell within the normal range observed at that flow rate in the presence of pentagastrin alone (Fig. 4). (b) Histamine stimulation Histamine, 25,sg kg-' h-', was infused for 2-5 h in control and test experiments in the same six cats. n test experiments one of three doses of metiamide was added to the histamine infusion. Metiamide caused a significant dose-related reduction of acid output calculated during the 8th and 9th 15 min periods of infusion (Fig. 5A). The relationship between [H+] and gastric flow with each dose of metiamide was virtually identical to that observed during stimulation with histamine alone (Fig. 5B). The effects of somatostatin (Albinus, Blair, Hirst, Reed, Schally & Shaw, 1977) and atropine (Konturek, Radecki, Demitrescu & Dembinski, 1974) against histaminestimulated secretion were not investigated since these compounds are poor inhibitors of acid secretion stimulated by this agonist. (c) nsulin stimulation nsulin, -2 u. kg-' h-1 was infused for 2'5 h in control and test experiments in the same six cats. n each test experiment only one dose of antagonist was studied. Somatostatin (6th and 7th 15 min periods of infusion), cimetidine, and atropine (8th and 9th 15 min periods of infusion) each produced significant dose-related reductions of insulin-stimulated secretion (Figs. 6A, 7A and 8A). n each case the relationship between [H+] and gastric flow was within the normal range to that observed during stimulation with insulin alone (Figs. 6B, 7B and 8B). DSCUSSON The normal relationship between [H+] and gastric flow t has long been recognized that the [H+] of gastric juice varies asymptotically with flow (vide supra). The mechanisms responsible for these findings have been subject to many theories. The most common of these are exemplified in one form or another by the analyses of Hollander and Teorell. Hollander's (1932, 1952) hypothesis is, briefly, that H+ is secreted by the parietal cells at a high primary concentration and that this concentration is reduced by admixture with a non-parietal secretion rich in Na+. n contrast, Teorell (1947) suggested that the defined relationship between [H+] and gastric flow can best be explained by the primary secretion of a parietal fluid with high [H+] from which H+ diffuses back across the gastric mucosa down its concentration gradient. n the present study it was assumed, by analogy with studies on the secretions of the exocrine pancreas (Case, Harper & Scratcherd, 1968), that the relationship between [H+] and flow is due to back-diffusion of H+, and therefore Fick's equation for diffusion was used to transform the data into a linear relationship. However, it

11 GASTRC [H+] AND FLOW 61 should not be implied that back-diffusion of H+ is the only possible explanation of these data and indeed a recent review of the question concluded there is no direct evidence that the disappearance of H+ from the lumen of the stomach is due to back-diffusion (Thjodleifsson & Wormsley, 1977). This method of analysis has simply been used in order to quantify the normal relationship between [H+] and gastric flow in response to the three agonists studied in this work. Moreover, mathematical analysis of data relating [H+] and flow do not allow separation of the Hollander and Teorell hypotheses (Makhlouf et al. 1966). The values for [H+] in the primary gastric secretion calculated from the linear correlations of log [H+] Vs. 1/flow compare favourably with the highest values observed in this study and in previous studies in the cat (167 mm, Gudiksen, 195; 17 mm, Linde, 195). Previously Obrink (1948) and Nordgren (1963) derived an equation to explain the variations in [H+] on the basis of the back-diffusion hypothesis. Makhlouf et al. (1966) derived equations to explain the variations in [H+] on the basis of dilution, and dilution plus neutralization. All the equations predicted the relationship between [H+] and 1/flow to be linear (cf. our use of log [H+] and 1/flow). We preferred the use of the Fick equation for diffusion since we found this more accurately described our data. However, there was neither a tendency for any of the calculated lines or the experimental points to curve towards the origin at the lowest secretary rates (Fig. 1), as predicted by the back-diffusion hypothesis. Therefore, we must favour, as have others (Makhlouf et al. 1966), the admixture hypothesis. Moreover, the recently demonstrated active secretion of HCO by the gastric mucosa in vitro (Flemstr6m & Sachs, 1975; Fromm, Schwartz, Robertson & Fuhro, 1976; Flemstr6m, 1977) and in vivo (Garner & Flemstr6m, 1978) is firm evidence for this hypothesis. Furthermore, the spontaneous rate of HCO secretion in vivo is in quantitative agreement with the continuous loss of H+ from the lumen of the normal stomach. Effect of inhibitors on the relationship between [H+] and gastric flow The relationships between [H+] and flow rate in response to stimulation by pentagastrin, histamine or insulin were not affected by histamine H2-receptor antagonists, somatostatin or atropine (Figs. 4-8). Therefore, it appears that all these inhibitors act to reduce the primary rate of acid secretion and do not influence the [H+] per se, either by interfering with back-diffusion of H+, or by changing the proportions of a non-parietal component of secretion added to the parietal H+ component. n the case of histamine H2-receptor antagonists, this conclusion is supported by evidence that these inhibitors do not influence gastric HCO secretion (Garner & Flemstr6m, 1978; Garner & Heylings, 1979) or loss of H+ from the stomach (Harris, Smy, Reed & Venables, 1975). n conclusion, it should be emphasized that, just as the pathophysiology of peptic ulcer disease is unlikely to be the sole result of the digestive activity of acid and pepsin (Bralow, 1969; Wormsley, 1974), there are also more factors involved in the choice of potential drugs for peptic ulcer therapy than inhibition of gastric acid secretion. Moreover, with the three antagonists studied, their comparative usefulness in ulcer healing is independent of their mechanisms of inhibition of acid secretion which are similar; simple inhibition of the stimulus to cause secretion.

12 62 62 B. H. HJST AND OTHERS t is a pleasure to acknowledge the assistance of Dr J. R. Greenwell in the computation of the results. Mr K. Elliott provided excellent technical assistance. We thank Drs D. H. Coy, C. A. Meyers and Professor A. V. Schally of Tulane University Department of Medicine, New Orleans, U.S.A. for the somatostatin, and Smith, Kline & French Labs, Ltd., Welwyn Garden City, for the metiamide and cimetidine. J. G. S. was supported by Smith, Kline & French Labs. Ltd., for which we are grateful. REFERENCES ALBNus, M.,BLGn, E. L., HRST, B. H., REED, J. D., ScHALLY, A. V. & SHAW, B. (1977). The effects of somatostatin and metiamide on tachyphylaxis of pentagastrin stimulated gastric acid and pepsin secretion in the conscious cat. J. Phy8iol. 266, BRALow, S. P. (1969). Current concepts of peptic ulceration. Am. J. dig. Di8. 14, BROWN, M. P., Coy, D. H., Gomzz-PAN, A., HET, B. H., HUNTER, M., MEYERS, C., REED, J. D., ScHALLY, A. V. & SHAW, B. (1978). Structure-activity relationships of eighteen somatostatin analogues on gastric secretion. J.Physiol. 277, CASE, R. M., HARPER, A. A. &SCRATCHERD, T. (1968). Water and electrolyte secretion by the perfused pancreas of the cat. J. Phy8iol.196, Coy, D. H., Coy, E. J., ARMuRA, A. &SCHATuTY, A. V. (1973). Solid phase synthesis of growth hormone-release inhibiting factor. Biochem. biophy8. Re8Ċommon. 54, DEAREs, J. G. & SNEDDON,. N. (196). An ntroduction to Biology. Amsterdam: North Holland Publ. Co. Am. J. Physiol. 233, E1-12. FLEMSTROM,G. & SACHS,G. (1975). on transport by amphibian antrum the MathematiC8 of Medicine and FLEMSTROM, G. (1977). Active alkalinization by amphibian gastric fundic mucosa in vitro. characteristics. Am. J. Physiol. 228, in vitro.. General FROMM, D., ScHwARTZ, J. H., ROBERTSON, R. & FuHRo, R. (1976). on transport across isolated antral mucosa of the rabbit. Am. J. Physiol. 231, GARNER, A. & FLEMsTROM, G. (1978). Gastric HCO; secretion in the guinea pig. Am. J. Phyeiol. 234, E GARNER, A. & HzYLNGS, J. R. (1979). Stimulation of alkaline secretion in amphibian-isolated gastric mucosa by 16,16-dimethyl PGE2 and PGF2a. A proposed explanation for some of the cytoprotective actions ofprostaglandins. Gastroenterology 76, GRAY, J. S. & BUCHER, G. R. (1941). The composition of gastric juice as a function of the rate of secretion. Am. J. Phy8sol. 133, GRAY, J. S., BUCHER, G. R. & HARMAN, H. H. (1941). The relationships between total, acid, and neutral chlorides of gastric juice. Am. J. Physiol. 132, GUDRsEN, E. (195). nvestigations on the composition of gastric juice. C. r. Trav. Lab. Carl8- berg. 27, HARms, D. W.,SMy, J. R., REED, J. D. & VENABLEs, C. W. (1975). The effects of burimamide and metiamide on basal gastric function in the cat. Br. J. Pharmac. 53, HRST, B. H., BLAm, E. L., LABrB, L. A., REED, J. D. & STEPHEN, J. G. (1978). Effect of inhibitors on the relationship between hydrogen ion concentration and flow of gastric juice in the cat. Gut 19, A434. HRST, B. H., LABm, L. A. & REED, J. D. (1978). Characteristics and tachyphylaxis of gastrinstimulated gastric acid secretion in the cat. J. Physiol. 276, HRST, B. H., LABmB, L. A., REED, J. D. & STEPHEN, J. G. (1979). Effect of inhibitors on the relationship between histamine- and insulin-stimulated gastric hydrogen ion concentration and flow in the cat. J. Phyaiol. 296, 33P. HOLANDER, F. (1932). Studies on gastric secretion. V. Variations in the chloride content of gastric juice and their significance. J. biol. Chem. 97, HOLLANDER, F. (1952). Gastric secretion of electrolytes. Fedn Proc. 11, KONTuREK, S. J., RADECK, T., DEMTRESCU, T. & DEMBrNsx, A. (1974). Comparison of effects of metiamide and atropine on gastric and pancreatic secretion and peptic ulcer formation in cat. Digeution 1, LNDE, S. (195). Studies on the stimulation mechanism of gastric secretion. Acta. phy8iol. 8cand. 21, Suppl. 74.

13 GASTRC [H+] AND FLOW 63 MAKHLOuF, G. M., MACMANwus, J. P. A. & CARD, W.. (1966). A quantitative statement of the two-component hypothesis of gastric secretion. Gastroenterology 51, NoRDGREN, B. (1963). The rate of secretion and electrolyte content of normal gastric juice. Acta phyriol. 8cand. 58, Suppl. 22. OBRNK, K. J. (1948). Studies on the kinetics of the parietal secretion of the stomach. Acta phy.iol. 8cand. 15, Suppl. 51. REED, J. D. (1977). Discussion. n (Jimetidine: Proceedings of the Second nternational Sympoaium on Histamine H2-receptor Antagonists, ed. BuRLND, W. L. & SimKiNs, M. A., p Amsterdam: Excerpta Medica. TEoRFT, T. (1947). Electrolyte diffusion in relation to the acidity regulation of the gastric juice. Gaetroenteroloy 9, TLODLESOwN, B. & WORMsiEY, K. (1977). Back-diffusion - fact or fiction? Digestion 15, TORCHANA, M. L., STONE, C. A., COOK, P. G. & WEsE, S. J. (1977). Effect of new synthetic analogs of somatostatin on gastric secretion in the chronic fistula dog. Proc. Soc. exp. Biol. Med. 154, WORMsLEY, K. G. (1974). The pathophysiology of duodenal ulceration. Gut. 15, WORMsLEY, K. G. (1977). Discussion. n (imetidine: Proceedings of the Second nternational Symposium on Hiatamine H2-receptor Antagonists, ed. BuRLAND, W. L. & SMKTis, M. A., p Amsterdam: Excerpta Medica.