ABslRAcrThe histamine H,-receptor antagonist SK&F 93479 induced gastric neuroendocrine (carcinoid) ECL-cell tumor formation in 6/34 male and 8/37 female rats treated for 22-24 months at 1,000 mg/kg/day PO. Focal ECL-cell hyperplasia was present in 21/34 males and 15/37 females, with local infiltration through the muscularis mucosae in half these cases. No focal hyperplasias or carcinoids were present after 200 m@g/ day PO treatment. Investigative studies showed evidence for marked and sustained hypergastrinemia increasing on chronic dosing which was capable of restoring gastric acid secretion and pH to near control values. Using morphometric analysis of immunoperoxidase anti-chromogranin A stained sections, a doserelated and time-dependent neuroendocrine ECLcell hyperplasia was correlated with the sustained elevated hypergastrinemia. A 2 l-month mouse oncogenicity study showed no focal neuroendocrine cell hyperplasia or carcinoid tumor induction, but a diffuse neuroendocrine cell hyperplasia and an increase in multifocal glandular hyperplasia of the oxyntic mucosa was observed in mice treated with 1,000 m a g SK&F 93479 PO. The morphological changes observed in both rat and mouse were considered to be secondary to the hypergastrinemia resulting from the pharmacological suppression of gastric acid secretion by SK&F 93479. These changes were also observed to a more marked degree following omeprazole treatment and were only slight following oxmetidine treatment in the rat. INTRODUC~IONThe development of the histamine H,-receptor antagonist cimetidine represented a major therapeutic advance in the therapy of peptic ulcer disease.A second generation of more potent, longer-acting H,-antagonists to produce a more sustained blockade of parietal cell stimulation and the development of the irreversible H+/K+ ATPase inhibitor omeprazole demonstrated the ability of such compounds to induce previously unreported gastric enterochromaffin-like (ECL)-cell carcinoid tumors in the rat (1, 5, 13). Despite the long latent period for tumor development (>80 weeks), it has subsequently been possible to demonstrate early neuroendocrine cell hyperplasia (7, 18) with associated hypergastrinemia (9,18) and activation of histidine decarboxylase activity (1 8). Although shorter-acting H,-antagonists such as cimetidine, ranitidine, and oxmetidine have not induced ECL-cell focal hyperplasias or carcinoid tumors in 2-year rat oncogenicity studies, a lower degree of hypergastrinemia and diffuse ECLcell hyperplasia have been demonstrated in shorterterm studies (18). The present report details the short-and long-term gastrin changes associated with SK&F 93479 treatment in rodents, and relates these changes to the ,pharmacological effects of this and other carcinoid-inducing (omeprazole) and non-tumorigenic (oxmetidine) compounds. 93479 was synthesized by SK&F Research Ltd. and was prepared as the acidic aqueous solution of the -A, trihydrochloride salt. The pH of the dosing solution was adjusted to pH 4.0 on measurement days for gastric acid sec...
In 1844 Gris (27) applied solutions of iron salts to chlorotic grape leaves and they became green again. In the intervening 123 years, plant physiologists have pursued this phenomenon and have asked, in various ways, how and why plants require iron. Thus, while the iron nutrition of plants has been avidly studied, and wisdom has accumulated on symptoms of iron deficiency, on the interactions between iron and other elements, and on the best means of supplying iron to plants (d. reviews 10, 29), our un derstanding of the roles of iron and especially the behavior of iron com pounds in deficient plants remains confused and obscure.Since plants contain a multiplicity of iron compounds, we obviously cannot expect to reduce iron nutrition to the elegant simplicity of say, co balt (24), but we can ask what one might expect to happen to iron com pounds in an iron-deficient plant and see if the available data conform to our expectations. We can also inquire if such information provides the basis for predictions concerning the physiology of deficient plants.
SUMMARY1. The action of isoprenaline on gastric acid secretion in rats with Heidenhain pouches has been compared with its action in a rat isolated stomach preparation.2. Isoprenaline (40 ,sg kg-' h-') inhibited the acid secretion in response to pentagastrin (20 ,tg kg-' h-') in conscious rats with Heidenhain pouches.3. This inhibition could be abolished by propranolol (2 mg kg-1) and butoxamine (8 mg kg-1) and partially reversed by practolol (8 mg kg-1).4. Propranolol (2 mg kg-') significantly increased the response to pentagastrin (20 #ug kg-' h-') but butoxamine and practolol (both at 8 mg kg-') and the inactive isomer (+)-propranolol (2 mg kg-1) were without any effect on the pentagastrin response in the rats with pouches. 5. In the rat isolated stomach preparation isoprenaline stimulated acid secretion over the range 10-7 M-10-3 M whereas phenylephrine and methoxamine were without effect.6. Propranolol (2 x 10-5 M) inhibited this stimulatory effect of isoprenaline in vitro but (+ )-propranolol (2 x 10-5 M), practolol and butoxamine (both at 10-4 M) had no effect on the response. 7. Propranolol (2 x 10-5 M) did not have any effect on the response of the isolated stomach to pentagastrin (5 x 10-7 M) or bethanechol (1-7 x 10-5 M).8. Phenylephrine (2 x 10-M) did not affect the in vitro responses to pentagastrin (2-17 x 10-7 M), bethanechol (1t7 x 1O--M) or histamine (5 4 x 10-5 M).9. It is concluded that isoprenaline has a direct stimulatory effect and an indirect inhibitory effect on gastric acid secretion in the rat. Both effects involve stimulation of fl-adrenoceptors. The relative predominance of one or other of these two opposing effects may help to explain the contradictory results in the literature regarding the actions of fl-adrenoceptor agonists on gastric acid secretion.
Further work on compounds 1 has identified the 4-position as a site where substantial modifications are tolerated, leading to analogues which are more potent and less toxic than those described previously. The best compound in the series is 13a (SK&F 96356), which is a potent inhibitor of gastric acid secretion in both the pentagastrin-stimulated rat and the histamine-stimulated dog. This compound shows reversible, K(+)-competitive binding to the enzyme. Because of its fluorescent properties, it is also proving useful in vitro as a probe of the structure and function of the (H+/K+)-ATPase.
The 4-(arylamino)quinoline 4, previously described as an antiulcer compound, is shown to be an inhibitor of the gastric (H+/K+)-ATPase. It is postulated that 1-arylpyrrolo[3,2-c]quinolines 6 act as conformationally restrained analogues of 4. A series of derivatives of 6 has been prepared and shown to be potent inhibitors of the target enzyme in vitro. Substitution in the ortho position of the aryl ring is important for activity. Unsaturation in the 5-membered ring makes little difference, but introduction of heteroatoms into the same ring markedly reduces activity. In more detailed kinetic experiments, 15c and 4 both show reversible, K(+)-competitive binding to the enzyme, with submicromolar Ki values. The compounds appear to act at the lumenal face of the enzyme and to require protonation for activity. Several compounds in the series are shown to be potent inhibitors of pentagastrin-stimulated acid secretion in the rat.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.