Gut: first published as 10.1136/gut.29.7.890 on 1 July 1988. Downloaded from Gut, 1988, 29, 890-893
Alteration of H2 receptor sensitivity in duodenal ulcer patients after maintenance treatment with an H2 receptor antagonist
D B JONES, C W HOWDEN, D W BURGET, CINDY SILLETTI, AND R H HUNT From the Division of Gastroenterology, McMaster University Medical Centre, Hamilton, Ontario, Canada
SUMMARY The effects of a specific H2 receptor agonist impromidine, on gastric acid secretion were measured in six patients with duodenal ulcer in clinical remission before and after three months treatment with ranitidine 150 mg nocte. After treatment basal acid output increased from 1 2 to 2-8 mmol/h and after maximal impromidine stimulation from 36-9 (4 7) to 44-2 (6 2) mmol/h (p<002). Intravenous ranitidine 50 mg was given at the end ofthe impromidine infusion on each study day; the antisecretory effect of intravenous ranitidine was accentuated after the treatment with ranitidine from a trough acid output of8 5 (1-2) mmol/h before, to 3-8 (1-5) mmol/h (p<0 05) after, treatment. The increased response to the H2 agonist impromidine and the H2 antagonist ranitidine after treatment with ranitidine suggests an enhanced sensitivity of the H2 receptor. This might be ex- plained on the basis of an increase in the number of H2 receptors ('up-regulation'). http://gut.bmj.com/
The discovery of the histamine H2 receptor on the a highly potent, and specific agonist for the H2 parietal cell' initiated the development of H2 receptor' exhibiting up to 27 times the affinity of receptor antagonists with potent gastric antisecretory histamine.9 In this study we have examined the effect activity and these agents have now become firmly of three months of treatment with ranitidine 150 mg established in the treatment of peptic ulceration.- nocte on impromidine stimulated gastric acid secre-
After heaing of duodenal ulcer by the H2 receptor tion in six patients with duodenal ulcer in remission. on October 2, 2021 by guest. Protected copyright. antagonists, cimetidine and ranitidine, maintenance treatment with either of these drugs has successfully Methods reduced ulcer relapse rates at 12 months from approximately 80% without therapy to about 30% on PATIENTS continuous maintenance treatment.3 There has been Six male patients, aged 33 to 62 years, participated in some suggestion that the antisecretory effects of H2 the study. All had endoscopically confirmed duo- receptor antagonists may alter with continuous H2 denal ulcer previously healed on conventional doses receptor blockade during prolonged treatment. of H2 receptor antagonists before entry in the study. Previous studies have utilised either pentagastrin or All the patients were non-smokers and none took peptone meals as secretagogues in tests of gastric acid alcohol to excess. None of the patients had con- secretion.' Because the inter-relationship between current disease or was taking any other medication. histamine, muscarinic and gastrin receptors is The study was approved ethically by the Research complex7 neither pentagastrin nor a peptone meal Advisory Committee of the Chedoke-McMaster specifically identifies a potential alteration in H2 Hospitals and written, informed consent was receptor sensitivity after maintenance treatment with obtained from all participants. a competitive antagonist. Impromidine, however, is STUDY DESIGN Address for correspondence: Prof Richard H Hunt, FRCP, FRCPC, McMastcr University Medical Centre, 1200 Main St West, Hamilton, Ontario L8N 3Z5, Patients were pretreated with ranitidine 150 mg nocte Canada. for three days before the first study day. The first Received for publication 12 February 1988. impromidine stimulated gastric secretion study 890 Gut: first published as 10.1136/gut.29.7.890 on 1 July 1988. Downloaded from Alteration ofH, receptor sensitivity in dluodenal ulcerpatients 891 was carried out 10 hours after the last dose of ranitidine. On each study day at 09 00 hours, after an overnight fast, a 14 French Salem Sump tube (Sherwood Medical Industries, St Louis, MO, USA) was placed in the most dependent part of the stomach, and its position checked by the water recovery test. Gastric juice was collected by continu- ous aspiration divided into 10 minute intervals throughout the study. After a one hour basal period, an impromidine (Smith, Kline and French Research Ltd, Welwyn, Herts, UK) step dose intravenous infusion was started at a dose of 2-5 Rg/kg/h for 90 minutes. After 90 minutes, the infusion rate was doubled to 5 0 sg/kg/h for a further 90 minutes, and then doubled again to 10 [xg/kg/h for 210 minutes. At Basal 25 5 10 Post IV the end of 90 minutes of impromidine 10 pig/kg/h, Impromidine (,ug/kg/h) ranitidine ranitidine 50 mg was administered intravenously over 50mg five minutes and gastric secretion continuously Figure Gastric acidsecretion, before and after three aspirated for the next 120 minutes during continued months maintenance ranitidine 150 mg treatment, expressed high dose impromidine infusion. as acid output (mmollh), in basal state (BA 0), after three infusion rates ofimpromidine, and after bolus intravenous The volume of each sample was measured, and ranitidine 50 mg. acid concentration determined by automatic titration (Radiometer, Copenhagen) to pH 7-00 with 0-1 M NaOH. Acid output was calculated as the product of STATISTICAL ANAL YSIS volume and concentration. Data are presented as the mean (SE). Statistical After the impromidine study, all six patients were comparisons were made by paired, two tailed, continued on three months treatment with ranitidine Student's t test," accepting a p value of 0-05 as the 150 mg nocte. Within one week of completion of the minimal level of significance. http://gut.bmj.com/ three months course, the impromidine study was repeated in an identical fashion and started 10 hours Results after the last dose of ranitidine. This approach generated data for each patient before and at the end Before and after maintenance ranitidine 150 mg of a three month course of ranitidine 150 mg/h. nocte, impromidine resulted in a dose dependent stimulation of gastric acid secretion (Table, Figure) DATA PRESENTATION to a maximal acid output of approximately 40 mmol/h on October 2, 2021 by guest. Protected copyright. Basal acid output (BAO) was calculated by summa- during the highest dose. Apart from transient facial tion of the acid outputs over the one hour before flushing, the impromidine infusion was well tolerated impromidine infusion and expressed as mmol/h. with no serious adverse effects. The intravenous Plateau acid outputs during impromidine infusion bolus of ranitidine 50 mg resulted in a prompt and (PIAO) was calculated by summation of the last six dramatic decrease in gastric acid output during the 10 minute aliquots of each 90 minute infusion period, continued high dose impromidine infusion (Table, and the results expressed as mmol/h. In order Figure). to estimate the maximal effect of ranitidine on Three months of treatment with ranitidine 150 mg impromidine stimulated acid output, acid output nocte resulted in a non-significant increase in basal measured between 60 and 90 minutes after bolus acid output from 1-2 (0.4) to 2-8 (0.9) mmol/h ranitidine (representing trough acid output) were (p=025). At each of the three stepwise doses of summated, and expressed as mmol/h. impromidine, three months ranitidine treatment resulted in a significant (p<0.05) increase in Tablc Pre andpost ratitidite treatment impromidine dose impromidine stimulated gastric acid secretion com- response infusion results for acid output expressed in mmollh pared with pretreatment values (Table). At the highest dose of impromidine infusion, gastric acid Basal lInp 25 Inp5 0 Imp 10 RanSng50 output increased from 36-9 (4.8) mmol/h before 44-2 after Prc 191 (0.38) 7-15(2-X80) 21132(5-39) 36 90(4-7) 8-54(1 22) ranitidine 150 mg treatment to (6-2) Post 2-79 (08-9) 22 49(6-16) 3531 (6-38) 44 17(6-2) 3-75 (1*55) (p<002). Similarly, ranitidine treatment resulted in an p 0(25 0(04 0(05 0-02 0-05 accentuated response to the intravenous bolus of Gut: first published as 10.1136/gut.29.7.890 on 1 July 1988. Downloaded from 892 Jones, Howden, Burget, Silletti, and Hunt ranitidine 50 mg (Figure). The pretreatment trough ment, as there is an increase in basal acid output, acid output before maintenance treatment was 8-5 an exaggerated response to the secretagogue (1-2) mmol/h, and was reduced to 3-8 (1.6) mmol/h impromidine and most importantly, an accentuated (p
H2 receptor on the parietal cell results in activation of One possible clinical implication exists, however, http://gut.bmj.com/ adenyl cyclase. The resultant increase in intracellular because of the relationship between the H2 receptor cyclic AMP results in activation of type I and II and the prostaglandin receptor.'7 If an increase in H2 phosphokinases, with possible subsequent mobilisa- receptor number persists for any length of time this tion of calcium ions from intracellular stores. 14 could result in a reduced efficacy of prostaglandins Activation of the phosphokinase system results in given subsequent to treatment with an H2 receptor alteration of the intracellular cytoskeleton with antagonist. Clearly further work is needed to clarify mechanisms and in activation of the secretory canaliculus initiating these their importance clinical on October 2, 2021 by guest. Protected copyright. hydrogen ion secretion by the proton pump. The end practice. result is hydrogen ion secretion from the secretory canaliculus into the gastric lumen. In vitro studies have shown'" that incubation of human gastric cancer We are grateful to Smith, Kline & French Research, cell lines (HGT-1) with histamine results in desensiti- Welwyn, Herts, UK for the gift of impromidine. sation of the H2 receptor after only three hours. This phenomenon is known as 'down-regulation' of the receptor and for any given ligand receptor interac- References tion, the resultant biological event will be reduced. Conversely, it might be expected that continued 1 Black JW, Duncan WAM, Durant GJ, Ganellin CR, exposure of the H2 receptor to an antagonist might Parsons EM. Definition and antagonism of histamine result in 'up-regulation' of the receptor. In previous H2-receptors. Nature 1972; 236: 385-90. studies," the apparent increase in stimulated gastric 2 Meyrick-Thomas J, Misiewicz JJ. Histamine H2- acid secretion after continued H2 receptor antagonist receptor antagonists in the short and long-term treat- to a ment of duodenal ulcer. Clin Gastroenterol 1984; 13: treatment could have been attributed simple 501-41. increase in parietal cell mass, to an increase in H2 3 Misiewicz JJ, Bradbury JE. Review of maintenance receptor density, or to true biological 'up-regulation' treatment for the prevention of duodenal ulcer recur- of the H2 receptor. The present study suggests that rence. In: Misiewicz JJ, Wood JR, eds. Ranitidine the phenomenon of true 'up-regulation' has occurred therapeutic advances. Amsterdam: Exerpta Medica, after three months maintenance ranitidine treat- 1982: 42-71. Gut: first published as 10.1136/gut.29.7.890 on 1 July 1988. Downloaded from A Iteration ofH2 receptor sensitivity in duodenal ulcerpatients 893
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