Effect of Metiamide, a Histamine H2-Receptor Antagonist, on Mucosal Blood Flow and Serum Gastrin Level

66: 982-986. 197 ~ Copyright © 1974 by The Williams & Wilkins Co.

Vol. 66, No.5

GASTROENTEROLOGY

Printed in U.S.A.

EFFEOT OF METIAMIDE, A HISTAMINE H 2 -RECEPTOR ANTAGONIST, ON MUCOSAL BLOOD FLOW AND SERUM GASTRIN LEVEL STANISj(AW J. KONTUREK, M.D., JANINA TASLER, M.D., WOJCIECH OBTUj(OWICZ, M.D., AND JENS F. REHFELD, M.D.

Institute of Physiology, Medical Academy, Krakow, Poland, and Department of Clinical Chemistry, Bispebjerg Hospital, Copenhagen, Denmark

In dogs with gastric fistulae and vag ally denervated Heidenhain pouches, metiamide, a histamine H 2 -receptor antagonist, infused intravenously in a dose of 12 ,umoles per kg-hr, inhibited near maximal acid responses to histamine, pentagastrin, Urecholine, or a peptone meal. Atropine sulfate (0.12 ,umole per kg-hr) did not significantly affect acid output induced by histamine, but was a more effective inhibitor of acid secretion stimulated by pentagastrin, Urecholine, or a peptone meal. Serum gastrin response to a peptone meal was unchanged by metiamide but partly suppressed by atropine. The inhibitory effect of metiamide was always associated with a marked reduction in mucosal blood flow. The ratio of aminopyrine concentration in the gastric juice and blood plasma was not significantly changed by metiamide, indicating that the persistent reduction in gastric mucosal blood flow was secondary to an inhibition of gastric secretion. It has recently been shown that the H 2 -receptor antagonist, metiamide, causes a strong inhibition of gastric acid response to a variety of gastric secretory stimulants. 1-3 Although gastric secretion and mucosal blood flow are related, no information is available concerning the simultaneous influence of metiamide on gastric mucosal blood flow and gastric acid secretion. This study was designed to determine the effect of metiamide on mucosal blood flow and serum gastrin concentration, and to compare the resulting changes with those obtained with atropine.

Methods Four mongrel dogs (16 to 18 kg) with gastric fistulae (GF) and Heidenhain pouches (HP) were used. The studies reported here were Received July 18, 1973. Accepted December 4, 1973. Address requests for reprints to: Dr. Stanisraw J. Konturek, Institute of Physiology, Krakow, UL. Grzegorzecka 16, Poland.

started about 2 months after surgery. Food was withheld for at least 18 hr before each test. Secretions from GF (except in tests with a peptone meal) and HP were collected continuously and divided into 15-min samples. Acid output was determined in each sample according to the method described previously.3 Basal secretion was collected for two 15-min periods, and then the stimulant was given in a dose that has been shown to produce near maximal acid output. Acid secretion from the main stomach in response to peptone meal was determined by the modified method of intragastric titration described by Fordtran and Walsh. 4 Aqueous solution of 10% peptone in a volume of about 300 ml (Bactopeptone, Difco Lab., Detroit, Mich.) was allowed to flow continuously into the gastric fistula from a reservoir barostat, maintained at lO-cm water pressure. The cannula of the GF was attached to a 20-ml volume plastic chamber and occluded by a rubber stopper through which passed: the glass and calomel electrodes; a tube connected to a barostat containing a peptone solution; a tube for infusing sodium bicarbonate from an auto buret and two mixing tubes, one, with the tip in the chamber, and the other with the tip in the gastric lumen. The electrodes were connected to

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MET/AMIDE EFFECT ON MUCOSAL BLOOD FLOW

May 1974

a pH-meter (Radiometer, PHM26, Copenhagen, Denmark) which in turn was connected to a recording pH-stat assembly (Titrator TTT-l1; Autoburet ABU13; recorder SBR2c; all Radi-

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acid secretion by the stomach was calculated in terms of milliequivalents of bicarbonate infused in each 15-min period. Ninety minutes after starting the secretory stimulant, when the secretory rate was relatively stable, metiamide, in a dose of 12 /.Lmoles per kg-hr, or atropine sulfate, in a dose of 0.12 /.Lmole per kg-hr, was added to intravenous infusion for a 1-hr period. In control studies on the same animals, secretory stimulant alone was given throughout the experiment. The doses of metiamide or atropine were selected as ones which gave near maximal inhibition of pentagastrin-induced acid secretion, Metiamide. N-methyl-N'12[(5-methylimidazol-4yllmethiol]ethyllthiourea, was kindly supplied by Professor J. W. Black of Smith, Kline and French Laboratories, Ltd ., England. Aminopyrine clearance was used to measure mucosal blood flow according to the procedure described by Jacobson et aJ.s By determining t he relationship of aminopyrine clearance (an estimate of mucosal blood flow) to the rate of secretion from the GF or HP, a ratio (R) is obtained which provides information concerning the dynamics of secretion. 6 In tests with peptone meal, gastrin concentration in serum was measured by radioimmunoassay.7 The routine detection limit of the assay, as employed in this study, was 5 pg equivalents of synthetic human gastrin per ml of serum. B Mean values for gastric acid outputs, for

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Vol . 66, No.5

KONTUREK ET AL .

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clearances. and for R values of both control and metiamide- or atropine-treated series were calculated. The differences of the means for each 15-min period were compared according to the paired t-test. 9

Results Metiamide inhibited histamine-induced acid secretion from both GF and HP (fig. 1). Atropine did not significantly inhibit either the GF or HP. During the secretory inhibition by metiamide, there was significant decline in aminopyrine clearance from both GF and HP of about 85% within the period of peak secretory inhibition (fig. 2). R values were not significantly altered during the same period. Both metiamide and atropine strongly inhibited pentagastrin-stimulated acid secretion from both the GF and HP (fig. 3). The mucosal clearance of aminopyrine was significantly depressed by metiamide, but the R value was not significantly changed by this drug (fig. 4). Urecholine produced a high rate of acid secretion from the HP but a negligible response from the GF. Both metiamide and atropine inhibited this response. Inhibition by atropine was greater, and lasted longer,

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METIAMIDE EFFECT ON MUCOSAL BLOOD FLOW

May 1974

than inhibition by metiamide (fig. 5). Metiamide-induced inhibition of gastric acid secretion stimulated by Urecholine was accompanied by a reduction in aminopyrine clearance, but the R values remained unchanged (fig. 6). Gastric secretion in response to a peptone meal was as great as the response to pentagastrin in the main stomach and in the HP. Both metiamide and atropine resulted in a marked inhibition of this acid response (fig. 7). The clearance of aminopyrine in tests with peptone meals was measured only from HP, and it showed a sharp decrease during the metiamide administration. The R value, however, remained unchanged throughout the experiment (fig. 8). Serum gastrin concentration in tests with peptone meal, kept at pH 5.0 and adjusted by barostat to a distention pressure of 10 cm, showed an abrupt rise above the fasting level, and reached a peak occurring about 90 min after the start of the experiment. The elevated serum gastrin concentration was maintained throughout the experiment. Metiamide did not affect serum gastrin response to the test meal.

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When atropine was administered, the serum gastrin response to the meal was lower than in control tests with only a peptone meal (fig. 9). Discussion Our results show that submaximal acid secretion induced by continuous intravenous infusion of histamine, pentagastrin, Urecholine, or peptone meal was strongly inhibited by metiamide. A reduction of

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Vol. 66, No.5

acid output was observed in both the crease of serum gastrin response, but failed vagally innervated and denervated por- to suppress completely the release of gastions of the stomach, ruling out the role of trin by a peptone meal. This confirms the vagal action in the inhibitory effect ob- previous suggestion 10. 11 that the release of gastrin by food in the stomach is nonserved. The decrease of gastric secretory re- cholinergic and that systemic atropine insponse was accompanied by a parallel hibits gastric secretion in response to food decrease in the mucosal clearance of ami- mainly by direct action on the oxyntic nopyrine. The ratios of aminopyrine con- glands. centration in the gastric juice and blood plasma remained virtually unchanged durREFERENCES ing the time of metiamide inhibition, indi1. Black JW, Duncan WAM, Durant CJ, et al: cating that this drug primarily affected Definition and antagonism of histamine H 2 gastric secretion but did not limit the receptors. Nature 236:386-390, 1972 gastric mucosal microcirculation. 6 2. Grossman MI, Konturek SJ: Inhibition of acid Atropine was found to be a somewhat secretion in dog by metiamide. a histamine anmore potent inhibitor than metiamide of tagonist acting on H, receptors. Gastroenterology acid secretion stimulated by pentagastrin, 66:517-521, 1974 Urecholine, or a peptone meal, but did not 3. Konturek SJ, Dimitrescu T, Radecki T: Role of histamine receptors in the stimulation of gastric affect histamine-induced secretion inhibacid secretion. Am J Dig Dis (in press) ited strongly by metiamide. Metiamide 4. Fordtran JS, Walsh J: Gastric acid secretion rate has, therefore, a wider spectrum of inhibiand buffer content of the stomach after eating; tion, but for all stimuli except histamine, it results in normal subjects and in patients with is a less potent inhibitor, on a molar basis duodenal ulcer. J Clin Invest 52:645-657, 1972 than atropine. 5. Jacobson ED, Linford RH, Grossman MI. Gastric There is now considerable evidence that secretion in relation to mucosal blood flow studgastric stimulation after the introduction ied by a clearance technique. J Clin Invest of a protein meal into the stomach is the 45:1-13, 1966 6. Jacobson ED, Swan KG, Grossman MI: Blood result of at least two mechanisms: (1) flow and secretion in the stomach. Gastroenterolgastrin release by distention, neutralizaogy 52:414-420, 1967 tion, or chemical stimulation of the an7. Rehfeld JF, Stadil F: A radioimmunoassay for trum, and (2) direct cholinergic stimulagastrin employing immunosorbent. Scand J Clin tion of the oxyntic glands by local or long Lab Invest 31:459-465, 1973 fundic reflexes elicited by distention. The 8. Rehfeld JF, Stadil F, Rubin B: Production and gastric distention was controlled in our evaluation of antibodies to gastrin for radioimstudy using a barostat technique whereas munoassay. Scand J Clin Lab Invest 30:221-227, the antral pH was maintained constant by 1972 intra gastric titration at pH 5.0 which was 9. Snedecor GW, Cochran WG. Statistical methods. Sixth edition. Ames, Iowa State University Press, shown to be above the threshold for the 1967 inhibition of gastrin release. The failure of an effective gastric acid inhibitory dose of 10. Csendes A, Walsh .JH, Grossman MI: Effect of atropine and of antral acidification on gastrin metiamide to change serum gastrin rerelease and acid secretion in response to insulin sponse to a meal indicates that the secreand feeding in dogs. Gastroenterology 63:257-263, tory inhibition cannot be attributed to the 1972 reduction of gastrin release by this com- 11. Nilsson G, Simon J, Yalow RS, et al: Plasma pound. gastrin and gastric acid responses to sham feeding Atropine, resulting in a similar degree of and feeding in dogs. Gastroenterology 63:51-53, secretory inhibition, caused a certain de1972