Skip to main content

Comparative histological and histochemical studies between ranitidine and nizatidine in treatment of peptic ulcer with evaluation of their adverse effects on male sex hormones

Abstract

Background

Peptic ulcer is an excoriated area of stomach or intestinal mucosa. Two experimental designs were proceeded: the first aimed. on twenty adult male albino rats, used to study the protective effect of both ranitidine and nizatidine; on the second, including sixty adult male albino rats, was used to study the therapeutic effect of ranitidine and nizatidine after induction of ulcer and also to evaluate the adverse effects of therapeutic doses of H2-receptor antagonists on male hormonal profile. The study aims to assess the gastroprotective effects of nizatidine and ranitidine and on treating of non-steroidal anti-inflammatory drugs (NSAIDs) induced peptic ulcer and to evaluate its adverse effect on male sex hormones.

Result

The result revealed that ranitidine and nizatidine reduced incidence of ulceration. Histopathological findings showed a significant recovery of the alteration, and disturbance in male sex hormones.

Conclusion

Nizatidine is better than ranitidine in the management of NSAIDs induced peptic ulcer in rats.

Introduction

Peptic ulcer is a suffering of the gastrointestinal tract (GIT), which includes both GIT and duodenal ulcers.

Ulcers are lesions penetrating through the entire thickness of GIT mucosa and muscularis mucosa (Amandeep et al., 2012) (Fig. 1). One of its major complications was the causes of morbidity and mortality (Sung et al., 2010).

Fig. 1
figure1

Peptic ulcer, human stomach (Prajapati et al., 2014)

Peptic ulcer develops when there is a disturbance between the “aggressive” and “protective” factors at the luminal surface epithelium. Aggressive factors include Helicobacter pylori, as half of the world’s population reported to be colonized by H. pylori, that remains one of the most common causes of the peptic ulcer disease, hydrochloric acid (HCl), pepsins, NSAIDs, bile acids, alcohol, smoking and hypoxia (Siddique et al., 2018). On the other hand, protective factors, which affect a significant variety of individuals worldwide (Harold et al., 2007).

In general, NSAIDs are used for the analgesic, anti-inflammatory, and antipyretic properties and are usually prescribed for the treatment of assorted diseases like rheumatoid and osteoarthritis. As a side effect, gastric ulcer may develop in 35-60% of patients (Hawkey, 2000), and its action is mediated by inhibition of the synthesis of prostaglandins, cyclo-oxygenases (cox), and leukotriene (Yamada et al., 1993 and Gambero et al., 2005).

Ulcers associated with the NSAIDs remain a major problem, which has not been resolved through introduction of selective inhibitors of cyclo-oxygenase (COX) blocker (Wallace, 2005). Stomachic pain, mucosal erosion, and ulceration are created by most NSAIDs to varying extents, but relative stomachic toxicity is the major consideration (Werawatganon et al., 2014 & Fong et al., 2015).

The usual medical treatment for peptic ulceration is either by the inhibition of HCL acid secretion or by the neutralization of the acid. Many categories of pharmacological agents have well-tried to be effective within the management of the acid peptic disorders (Katzung, 2004 & Waller et al., 2005).

H2-receptor antagonists are most generally prescribed drugs for NSAIDs induced stomachic lesions (Patrignani et al., 2011). H2-receptor antagonists (nizatidine and ranitidine) are types of antihistaminic drugs (Panula et al., 2015), known as H2 blockers, because they form a category of medications that block the action of histamine at the histamine H2 receptors of the parietal or oxyntic cells in the stomach. This decreases the production of stomach acid. They are used in the treatment of peptic ulcer disease and gastroesophageal reflux disease (Eriksson et al., 1995).

In male rats, the administration of histamine dose and time dependently increased plasma hormones (GnRH, FSH, LH) and testosterone levels (Niaz et al., 2018).

LH and FSH are secreted under the hypothalamic control of gonadotropin-releasing hormone (GnRH). Leydig-cells are located between seminiferous tubules of the testis secrete testosterone under the control of LH, so they are called interstitial cell-stimulating hormones. Testosterone stimulates the development and maturation of germ cells in seminiferous tubules. FSH acts directly on the seminiferous tubules. Sertoli cells possess receptors for androgen and FSH. So, testosterone and FSH have trophic effects on gametogenesis that are mediated via somatic Sertoli cells. The testis and the hypothalamo-pituitary axis are regulated through hormones. Androgen inhibits the secretion of GnRH and gonadotropins. Inhibin has a negative feedback effect on the release of FSH from the pituitary gland (Nieschlag et al., 2008).

The present work aims to evaluate the gastroprotective effect of two antiulcer drugs (nizatidine and ranitidine as H2-receptor antagonists) and their ability to treat of NSAIDs-induced peptic ulcer in adult male albino rats. It also assesses the possible adverse effects of therapeutic doses on hormonal profiles of male albino rats (follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), total testosterone (T-TESTO), and free testosterone (F-TESTO)).

Experimental animals

Adult male albino rats weighing around 180-200 g, obtained from the Faculty of Veterinary Medicine-Zagazig University, were used. Animals were adapted to laboratory conditions before experimental procedures at normal room temperature (27 °C) and humidity. All the animals were fed under standard roles. All the animals were weighed and numbered. Animals were kept in polypropylene cages.

Induction of gastric ulcer by NSAIDs was produced according to Konturek et al. (1982) by a single oral administration of piroxicam (5 mg/kg b. wt.) followed 60 min later by paracetamol (80 mg/kg b. wt.) as single dosage was given via an oro-gastric tube.

First experiment (gastroprotective effect of H2 blockers)

Twenty adult male albino rats were divided randomly into four equal groups each includes five animals as follow:

  • Group 1: Rats were left as a control group.

  • Group 2: Ulcer induced group, according to Konturek et al. (1982).

  • Group 3: After fasting overnight, animals received a daily dose of ranitidine (27 mg/kg b. wt.) for 1 week before the induction of ulcer on the last day.

  • Group 4: After fasting overnight, animals received a daily dose of nizatidine (27 mg/kg b. wt.) for 1 week before the induction of ulcer.

Second experiment

Sixty adult male albino rats were allocated into four equal groups as follows:

  • Group 1: (Negative control group) this group was maintained on a normal-pelleted diet throughout the duration of the experiment.

  • Group 2: (NSAIDs-induced peptic ulcer group, according to Konturek et al., 1982), this group was considered a positive control group.

  • Group 3: After fasting overnight, animals received a daily dosage of ranitidine (27 mg/kg b. wt.) for 4 weeks after the induction of ulcer.

  • Group 4: After fasting overnight, animal received a daily dosage of nizatidine (27 mg/kg b. wt.) for 4 weeks after the induction of ulcer.

Five rats from these groups were sacrificed throughout the second, the third, and the fourth week.

Animals of all groups were sacrificed under chloroform anesthesia and abdomens were opened by midline incisions in order to take blood samples from hearts.

Stomachs were removed, cut along the greater curvature, and washed with normal saline to remove gastric contents. The glandular parts were observed for the ulceration and ulcer index, kept in 10% neutral formalin, and processed for the histopathological examination.

The score of lesions was calculated according to the 1 to 5 scoring system devised by Wilhelmi and Gdynia (1972) as follows:

  1. 1

    2 min, sporadic, punctuate lesion.

  2. 2

    Several small lesions.

  3. 3

    One extensive lesion or multiple moderate-sized lesions.

  4. 4

    Several large lesions.

  5. 5

    Several large lesions with perforation of the gastric or duodenal wall.

Ulcer index “U.I” (stomach ulceration) was determined according to Radwan and West (1971).

U.I means (X) of the ulcer score of animals similarly treated (X% of the ulcerated animals of the group).

Preventive index “P.I.” (the preventive effect of any anti-ulcer agent used against the severity of ulceration) was calculated according to the method of Hano et al. (1976).

$$ P.I=\frac{\mathrm{U}.\mathrm{I}\ \mathrm{control}-\mathrm{U}.\mathrm{I}\ \mathrm{treated}}{\mathrm{U}.\mathrm{I}\ \mathrm{control}}\times 100\kern0.5em $$

Blood sampling

Blood samples were collected in centrifuge tubes from the heart. Samples were left to clot, then centrifuged at 3000 r.p.m.

After centrifugation, clear sera were carefully separated, then transferred into a clean dry Eppendorf and kept frozen until used for the hormonal analysis of follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), total testosterone, and free testosterone.

Statistical analysis

In order to assess the influence of nizatidine and ranitidine on some pituitary-gonadal hormone data and along with the post-treatment (2, 3, and 4 weeks), one-way analysis of variance (ANOVA), followed by Tukey’s honestly significant difference (Tukey’s HSD) test as post hoc test, was used.

Analysis was done using Statistical Package for Social Sciences version 22.0 (IBM Corp., Armonk, NY, USA).

Results were recorded in means ± SEM (standard error of mean). The value of P < 0.05 was used to indicate statistical significance.

Results

Induction of ulcer

A single oral administration of piroxicam (5 mg/kg) followed, 60 min later, by paracetamol (80 mg/kg) as a single dosage via a gastric tube lead to extensive number of gastric mucosal lesions in the glandular segments of the stomach as shown in Fig. 2, and resulted in a high incidence of ulceration 100% mean ulcer score (4 ± 0.42) and a high ulcer index (400 ± 22.0) in the glandular segments of the stomach.

Fig. 2
figure2

Peptic ulcer induced in our study

A gastroprotective effect of ranitidine, nizatidine (27 mg/kg b. wt.) against NSAIDs-induced ulcer group was observed (Figs. 3c and 4c). They reduced the incidence of ulceration, significantly decreased the mean ulcer score, highly lowered the ulcer index, and importantly improved the preventive index to 50% and 60% in comparison with the positive control group (NSAIDs-treated group) (Table 1 and Fig. 7).

Fig. 3
figure3

a Negative control showed normal parietal cells (PC) distribution with normal gastric pits (GP) and normal surface mucus epithelium (SME) (H&E, X40). b NSAIDs induced peptic ulcer group showed a marked increase of parietal cells (PC) with degenerated gastric glands (DGG) marked degeneration of surface mucus epithelium. With loss of histoarchitecture of gastric mucosa, the submucosal layer showed marked infiltration with inflammatory cells (IFC) (H&E, X10). c Nizatidine prophylactic group showed changes of parietal cells (PC) with mild degeneration of surface mucus epithelium (SE), erosion of mucus membrane (EM) (H&E, X40)

Fig. 4
figure4

a Nizatidine treated group for 2 weeks showed changes in parietal cells with low eosinophilic cytoplasm and low basophilic nucleus, with moderate infiltration of inflammatory cells and mild erosive luminal surface, gastric gland showed mild degenerative changes (H&E,X40). b Nizatidine group treated for 3 weeks showed changes of parietal cells with pale eosinophilic cytoplasm and pale basophilic and karyolyed nuclei, marked infiltration of inflammatory cells, the luminal surface showed marked ulcerative changes with surface epithelium degeneration (H&E, X40). c Ranitidine prophylactic group showed normal distribution of parietal cells (PC) with eosinophilic cytoplasm and basophilic nuclei, degenerative changes of surface epithelium (SE) and mild infiltration of inflammatory cells (IFC), with ulcerative luminal surface (PU) (H&E, X40). d Ranitidine group treated for 2 weeks showed changes of parietal cells with low eosinophilic cytoplasm and low basophilic nuclei, degenerative changes of surface epithelium. With karyolysis, the luminal surface showed mild ulcerative and marked erosive changes (H&E, X40). e Ranitidine-treated group for 3 weeks showed changes of parietal cells with marked eosinophilic cytoplasm and marked basophilic nucleus, mild infiltration of inflammatory cells (IFC) with mild erosive changes at the luminal surface, normal structure of gastric glands (H&E, X40)

Table 1 Effects of oral administration of nizatidine and ranitidine (27 mg/kg b. wt.) on ulceration in rats administrated NSAIDs (piroxicam (5 mg/kg) followed 60 min later by paracetamol (80 mg/kg) as single dosage)

Oral administration of ranitidine, nizatidine (27 mg /kg b. wt.) showed a great effect on the NSAIDs-induced ulcer group. They reduced the incidence of peptic ulceration, significantly decreased the mean ulcer score, reduced ulcer index, and greatly improved the preventive index in the NSAIDs treated (to 40%, 85%, and 90% for ranitidine and to 60%, 90%, and 95% for nizatidine during the second, the third, and the fourth week respectively) versus zero for the positive control group (Table 1 and Fig. 7).

Treatment with H2 blockers caused a significant progressive increase in the level of follicle-stimulating hormone, luteinizing hormone, and prolactin. It also showed a significant progressive decrease in the level of total serum testosterone and free serum testosterone in the group treated with ranitidine and nizatidine in comparison with the control group along the whole duration of the experiment (Table 2 and Fig. 8).

Table 2 Effects of oral administration of nizatidine, ranitidine (27 mg/kg b. wt.) on serum hormones of male albino rats

Histopathological findings

Morphological evaluation of isolated rats’ gastric mucosa

Tissues of isolated rat gastric mucosa were examined by H&E and T.B. stains (Bancroft et al. 2008).

As for control rats, sections of the stomach showed a normal distribution of parietal cells with normal gastric pits and normal surface mucus epithelium (Fig. 3a) beside the normal structure of parietal cells (Fig. 5a).

Fig. 5
figure5

a Negative control group gastric mucosa showing normal distribution and structure of parietal cells (PC), X40 T.B. b NSAIDs-induced peptic ulcer group showing an increased number of parietal cells (PC), X40 T.B. c Nizatidine prophylactic group showing a marked increase in PC, X40 T.B. d Nizatidine-treated group for 2 weeks showing marked infiltration of inflammatory cells (IFC) with increased (PC), X40 T.B. e Nizatidine-treated group 3 weeks showed marked increase of PC with mild infiltration of inflammatory cells, X40 T.B

Histological observation demonstrated a comprehensive damage to the gastric mucosa in the ulcerated control group. Furthermore, the ulcerated stomach in the control group had degenerated gastric glands, marked degeneration of surface mucus epithelium, with the loss of histoarchitecture of gastric mucosa. This showed extensive leucocyte infiltration and edema of the submucosal layer, as illustrated in Figs. 3b and 5b.

The key observation here is that the oral administration of nizatidine and ranitidine as prophylactic altered the secretory function concomitant to its structural degeneration of parietal cells at the first time of administration (Figs. 3c, 4c, 5c, and 6a) and up to 2 weeks as shown in (Figs. 4a, d and 5d).

Fig. 6
figure6

a Ranitidine prophylactic group showed an increased number of (PC), X40 T.B. b Ranitidine-treated group 2 weeks showed increased number of parietal cells (PC) with degenerated surface epithelium (SE) and mild infiltration of inflamatory cells, X40 T. B. c Ranitidine-treated group 3 weeks showed marked increase of parietal cells (PC) and normal surface epithelium (SE) and gastric pit (GP), X 40 T.B

As for ranitidine, the parietal cells were recovered with normal basophilic nucleus and eosinophilic cytoplasm as indicated in Figs. 4e and 6b, c, but the cytoplasm and nucleus still pale for nizatidine after 3 weeks as shown in Figs. 4b and 5e.

Discussion

Gastric ulcers are common diseases constituting one of the main causes of morbidity and mortality for more than a century (Hoogerwerf & Pasricha, 2006). Peptic ulcer is a common disease worldwide defined as “a defect in the mucosa of stomach or duodenum that exceeds the layer of muscularis mucosa injuries as a result of imbalance between the defensive and the aggressive factors affecting the mucosal epithelium” (Asali et al., 2018).

The danger of vital gastrointestinal injury depends on the dose and it increase dramatically once over one anti-inflammatory is used (Feria, 2005).

NSAIDs act on by inhibiting the activity of one of the cyclo-oxygenase enzyme. Cox contains two associated enzymes with two different functions: cyclo-oxygenase activity, changing arachidonic acid liberated from the phospholipid membrane by phospholipase to prostaglandin G2 (PGG2), then converting PGG2 into prostaglandin H2 (PGH2) by a peroxidase activity. PGH2 is then converted to a variety of prostaglandins according to the cell type-specific manner (Werawatganon et al., 2014).

In experimental studies on gastric glands and in vivo, the presence of H2-receptor antagonists downregulates the gastrin stimulatory effect on the parietal cell, suggesting that the gastrin stimulation of acid secretion is regulated mainly by histamine released from the enterochromaffin-like ECL cell (Lindström, 2001). The histamine receptor is thought to be coupled only with adenylate cyclase and that elevation of cAMP is sufficient to stimulate the acid secretion in in vitro models (Chew et al., 1980). In addition, histamine is shown to elevate intracellular calcium in parietal cells, suggesting that this receptor has at least a dual system in the parietal cells (Chew & Brown, 1986). So, H2-receptor antagonists (ranitidine and nizatidine) have an obvious role in inhibiting the secretion of hydrochloric acid.

In the light of the results of the present study, it is noticed that nizatidine and ranitidine decreased the incidence of gastric ulceration, and significantly decreased the mean ulcer score and ulcer index in male albino rats (Figs. 7 and 8). The drug significantly increased the preventive index against NSAIDs induced ulcer. These results are in full agreement with those of Louise et al. (1993), they reported that pretreatment with nizatidine significantly reduces the incidence of ulceration formation in high-risk patients taking future NSAID medical care. It also relieves NSAIDs—associated dyspeptic symptoms in some patients.

Fig. 7
figure7

a Effects of oral administration of nizatidine, ranitidine (27 mg/kg b. wt.) given once a day for 4 weeks on incidence of gastric ulceration in rats administrated NSAIDs (piroxicam (5 mg/kg) followed 60 min later by paracetamol (80 mg/kg) as single dosage). b Effects of oral administration of nizatidine and ranitidine (27 mg/kg b. wt.) given once a day for 4 weeks on mean ulcer score in rats administrated NSAIDs ( piroxicam (5 mg/kg) followed 60 min later by paracetamol (80 mg/kg) as single dosage). c Effects of oral administration of nizatidine, ranitidine (27 mg/kg b. wt.) given once a day for 4 weeks on ulcer index in rats administrated NSAIDs (piroxicam (5 mg/kg) followed 60 min later by paracetamol (80 mg/kg) as single dosage). d Effects of oral administration of nizatidine, ranitidine (27 mg/kg b. wt.) given once a day for 4 weeks on preventive index (%) in rats administrated NSAIDs (piroxicam (5 mg/kg) followed 60 min later by paracetamol (80 mg/kg) as single dosage)

Fig. 8
figure8

a Effects of oral administration of nizatidine, ranitidine (27 mg/kg b. wt.) given once a day for 4 weeks on serum follicle-stimulating hormone of male albino rats. b Effects of oral administration of nizatidine, ranitidine (27 mg/kg b. wt.) given once a day for 4 weeks on serum luteinizing hormone of male albino rats. c Effects of oral administration of nizatidine, ranitidine (27 mg/kg b. wt.) given once a day for 4 weeks on serum prolactin hormone of male albino rats. d Effects of oral administration of nizatidine, ranitidine (27 mg/kg b. wt.) given once a day for 4 weeks on serum total serum testosterone hormone of male albino rats. e Effects of oral administration of nizatidine, ranitidine (27 mg/kg b. wt.) given once a day for 4 weeks on serum free testosterone hormone of male albino rats

Yeomans et al. (2006) stated that there is a marked variation in the healing rates associated with ranitidine treatment among different studies. For instance, Goldstein et al. (2005) and Tildesley et al. (1993) reporting gastric ulcer healing rates in patients continuing NSAID therapy for 4 weeks, but Campbell et al. (2002) and Agrawal et al. (2000) report a double duration. Additionally, the gastric ulcer healing rate of 8 weeks reported by Goldstein et al. (2005) was 20% greater than the rate associated with ranitidine in these two studies. The explanations for this are unclear because all of these studies used a similar ulceration definition (= 5 mm in diameter), but were most likely related to variations within the patient populations.

In the current study, a rapid recovery of the gastric epithelium was observed after using H2-receptors blockers. This recovery can be attributed to different main factors, including the ability of the gastric epithelial cells to restitute by extending lamillopodia to cover the denuded basement membrane (Lacy & Ito, 1984), to prevent hypergastrinemia which occurs due to inhibition of acid secretion (Ryberg et al., 1990) and to increase in the pre-parietal cell production which transformed into new parietal cells due to the cessation of treatment rapidly. The time required for the production of pre-parietal cells ranged from 1 to 2 days and within an additional day, anew parietal cell could be formed (Karam, 1993).

The present study showed a clear degeneration of parietal cells represented in low eosinophilic cytoplasm and low basophilic nuclei, which means that there is an alteration of the secretory function of parietal cells. These results are in agreement with those of Karam and Alexander (2001). They reported that the physiological degeneration of parietal cells is enhanced by inhibiting their secretion using a H2-receptor antagonist.

Based on the present histological results, the distinct observation is that nizatidine and ranitidine altered the secretory function of parietal cells due to the alteration of their histological criteria at the first time of administration and up to 2 weeks. For ranitidine, the parietal cells were recovered with a normal basophilic nucleus and eosinophilic cytoplasm, but in the case of nizatidine, the cytoplasm and nucleus remained pale after 3 weeks, which could lead to the increased tolerability rate of ranitidine more than nizatidine.

The results of the present study disclosed a significant increase in the level of serum FSH and LH and a significant decrease in the level of serum testosterone in H2 blockers-treated groups. These results are in agreement with those of Knigge et al. (1983). They reported that this increase may be attributed to H2-receptor antagonists which have anti-androgen effects. They block androgen receptors in the pituitary or hypothalamus, according to Sinha et al. (2006) who reported that H2-receptor blocker treatment over a period of 2 weeks can cause a significant reduction in epididymal tissue mast cell population and tissue histamine content in caput, corpus, and cauda regions in albino rats. There is also an extremely significant fall in the serum testosterone level.

Serum LH and FSH levels are enhanced most likely due to suppression of feed-back inhibition of anterior pituitary glands (Fattahi et al., 2009).

In the testis, LH binds to receptors on the surface of Leydig cells and stimulates the production of androgenic hormone (Walker & Cheng, 2005). FSH enhances the production of androgen-binding protein by the Sertoli cells of the testes within binding to FSH receptors and this is critical for the initiation of gametogenesis (Boulpaep & Boron, 2005).

The present study recorded an observed increase in the FSH and LH levels along the time of the experiment, which was attributed by Bhale and Mahat (2013) to the stimulation of both the Sertoli and Leydig cells for a proportionate synthesis and secretion of testosterone thereby enhancing of spermatogenesis occurs. The high gonadotropin level (FSH and LH) exercise a negative feedback effect on the hypothalamo—pituitary—testicular axis and thus the plasma testosterone level becomes low.

On the other hand, the result of the present study is in disagreement with those of Aprioku et al. (2014). They reported that cimetidine may cause an alteration of the testicular function, while ranitidine may have no effect on the testis in rats, which use ranitidine, 8, and 16 mg/kg/day in 2 divided doses for 14 days. This difference may be due to the difference in doses or the exposure period of the experiment.

The present study showed a progressive increase in the level of prolactin. On the other hand, Molitch (2005) reviewed that several briefcase reports were published about patients experiencing symptoms related to hyperprolactinemia after the approval of histamine 2-receptor blockers such as cimetidine and ranitidine. However, in larger series, hyperprolactinemia has not been reported, and there has been reported a case of a woman treated with a twice-maximum dose of famotidine.

Conclusion

To sum up the observations of the present study, it could be concluded that nizatidine is much more effective than ranitidine in the management of NSAIDs induced peptic ulcer in rats.

As for histopathological findings, the present study showed that the protective effect of nizatidine surpasses than ranitidine. The effect of both H2-receptors antagonists is to alter the secretory function of parietal cells, but ranitidine was more successful than nizatidine in recovering (or removing) this effect. So, there is a tolerable effect for ranitidine. The present study indicated that oral administration of both drugs elicited a significant increase in FSH, LH, prolactin, and prompted a significant decrease in total and free testosterone in male albino rats.

Availability of data and materials

Data available on request

Abbreviations

NSAIDs:

Nonsteroidal anti-inflammatory drugs

H2:

Blocker histamine blocker

FSH:

Follicle-stimulating hormone

LH:

Luteinizing hormone

PRL:

Prolactin

T-TESTO:

Total testosterone

F-TESTO:

Free testosterone

GnRH:

Gonadotropin-releasing hormone

GIT:

Gastrointestinal tract

H&E:

Hematoxyline and eosin

T.B.:

Toluidine blue

ECL:

Enterochromaffin-like

P.I.:

Preventive index

U.I:

Ulcer index

COX:

Cyclo-oxygenase

H. pylori :

Helicobacter pylori

HCl:

Hydrochloric acid

References

  1. Agrawal, N. M., Campbell, D. R., & Safdi, M. A. (2000). Superiority of lansoprazole Vs ranitidine in healing nonsteroidal anti-inflammatory drug-associated gastric ulcers: Results of a double-blind, randomized, multicenter study. NSAID-Associated Gastric Ulcer Study Group. Arch Intern Med., 160, 1455–1461.

    CAS  Article  Google Scholar 

  2. Amandeep K., Robin S., Ramica S. and Sunil K. (2012): Peptic ulcer: A review on etiology and pathogenesis. Int Res J Pharmacy. 3(6): ISSN 2230:8407.

  3. Aprioku, J. S., Ibeachu, C., & Amah-Tariah, F. S. (2014). Differential effects of H2 receptor antagonists on male reproductive function and hepatic enzymes in Westar rats. Asian J Biomed Pharm Sci, 4(28), 1–6.

    Google Scholar 

  4. Asali, M., Alghamdi, A., Fallatah, M., Alholaily, S., Aldandan, W., Alnosair, R., … Alharbi, R. (2018). Risk factors leading to peptic ulcer disease: Systematic review in literature. Int J Community Med Public Health, 5(10), 4617–4624. https://doi.org/10.18203/2394-6040.ijcmph20183869.

  5. Bancrofit, John D., and Marilyn Gamble. (2008). Theory and practice of histological techniques. 6th ed Oxford: Churchill Livingstone Elsevier. 123-126.

  6. Bhale D.V. and Mahat R.K. (2013): Evaluation of LH, FSH and testosterone in infertile males. International Journal of Recent Trends in Science And Technology, ISSN 2277-2812 E-ISSN 2249-8109, Vol. 9, Issue 2, pp 238-240.

  7. Boulpaep, E. L., & Boron, W. F. (2005). Medical physiology: A cellular and molecular approach. St. Louis, Mo: Elsevier Saunders p. 1125.ISBN 1-4160-2328-3.

    Google Scholar 

  8. Campbell, D. R., Haber, M. M., & Sheldon, E. (2002). Effect of H. pylori status on gastric ulcer healing in patients continuing nonsteroidal anti-inflammatory therapy and receiving treatment with lansoprazole or ranitidine. Am J Gastroenterol., 97, 2208–2214.

    CAS  Article  Google Scholar 

  9. Chew, C. S., & Brown, M. R. (1986). Release of intracellular Ca21 and elevation of inositol trisphosphate by secretagogues in parietal and chief cells isolated from rabbit gastric mucosa. BiochimBiophys, Acta888, 116–125.

    Google Scholar 

  10. Chew, C. S., Hersey, S. J., Sachs, G., & Berglindh, T. (1980). Histamine responsiveness of isolated gastric glands. Am J Physiol Gastrointest Liver Physiol, 238, G312–G320.

    CAS  Article  Google Scholar 

  11. Eriksson, S., Långström, G., Rikner, L., Carlsson, R., & Naesdal, J. (1995). Omeprazole and H2-receptor antagonists in the acute treatment of duodenal ulcer, gastric ulcer and reflux oesophagitis: A meta-analysis. Eur J Gastroenterol Hepatol, 7, 467–475.

    CAS  PubMed  Google Scholar 

  12. Fattahi, E., Parivar, K., Jorsaraei, S. G. A., & Moghadamnia, A. A. (2009). The effects of diazinon on testosterone, FSH and LH levels and testicular tissue in mice. Iran J Reprod Med, 7(2), 59–64.

    CAS  Google Scholar 

  13. Feria M. (2005): Fármacosanalgésicos, antitérmicos y antiinflamatorios no esteroideos. Antiartríticos. En: Flórez J, Armijo JA, Mediavilla A. Farmacología Humana 4ª ed. Barcelona. Masson . p. 375-408.

  14. Fong, S. Y., Wong, Y. C., Xie, C., & Zuo, Z. (2015). Herb-drug interactions between Scutellariae Radix and mefenamic acid: Simultaneous investigation of pharmacokinetics, antiinflammatory effect and gastric damage in rats. J Ethnopharmacol, 170, 106–116.

    CAS  Article  Google Scholar 

  15. Gambero, A., Becker, T. L., Zago, A. S., De Oliveira, A. F., & Pedrazzoli, J. J. R. (2005). Comparative study of anti-inflammatory and ulcerogenic activities of different cyclo-oxygenase inhibitors. Inflammopharmacology, 13, 441–454.

    CAS  Article  Google Scholar 

  16. Goldstein, J. L., Johanson, J. F., & Suchower, L. J. (2005). Healing of gastric ulcers with esomeprazole versus ranitidine in patients who continued to receive NSAID therapy: A randomized trial. Am. Gastroenterol, 100, 2650–2657.

    CAS  Article  Google Scholar 

  17. Hano, J., Bugajski, J., Danek, L., & Wantuch, C. (1976). The effect of neuroleptics on the development of gastric ulcers in rats exposed to restraint-cold stress. Pol J Pharmacol Pharm., 28(1), 37–47.

    CAS  PubMed  Google Scholar 

  18. Harold, Kalant, Grant, Denis M, Mitchel, Jane. (2007): Principles of medical pharmacology, seventh ed. Elsevier Canada Ltd. 557: 558, 559.

  19. Hawkey, C. J. (2000). Nonsteroidal anti-inflammatory drug gastropathy. Gastroenterology., 119, 521–535.

    CAS  Article  Google Scholar 

  20. Hoogerwerf, W. A., & Pasricha, P. J. (2006). Pharmacotherapy of gastric acidity, peptic ulcers, and gastro esophageal reflux disease. In The pharmacological basis of therapeutics, (pp. 967–981). New York: McGraw-Hill Company.

    Google Scholar 

  21. Karam, S. M. (1993). Dynamics of epithelial cells in the corpus of the mouse stomach. IV. Bidirectional migration of parietal cells ending in their gradual degeneration and loss. Anat. Rec., 236, 314–332.

    CAS  Article  Google Scholar 

  22. Karam, S. M., & Alexander, G. (2001). Blocking of histamine H2 receptors enhances parietal cell degeneration in the mouse stomach. HistolHistopathol, 16, 469–480.

    CAS  Google Scholar 

  23. Katzung B.G. (2004): Basic and clinical pharmacology. 9th ed. McGraw-Hill Companies.:1009.

  24. Knigge, U., Dejgaard, A., Wollesen, F., Ingerslev, O., Bennett, P., & Christiansen, P. M. (1983). The acute and long term effect of the H2-receptor antagonist cimetidine and ranitidine on the pituitary gonadal axis in men. ClinEndocrinol (Oxf)., 18(3), 307–313.

    CAS  Article  Google Scholar 

  25. Konturek, S. J., Brzozowski, T., Piastucki, I., & Radecki, T. (1982). Prevention of ethanol and asprin-induced gastric mucosal lesions by paracetamol and salicylate in rats: Role of endogenous prostaglandins. Gut, 23, 536–540.

    CAS  Article  Google Scholar 

  26. Lacy, E. R., & Ito, S. (1984). Rapid epithelial restitution of the rat gastric mucosa after ethanol injury. Lab. Invest., 51, 573–583.

    CAS  PubMed  Google Scholar 

  27. Lindström E, Chen D, Norlén P., Andersson K., Håkanson R (2001): Control of gastric acid secretion: The gastrin-ECL cell-parietal cell axis, Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology,128, Issue 3,503-511,ISSN 1095-6433, https://doi.org/10.1016/S1095-6433(00)00331-7.

  28. Louise, R., Levine, M. D., Michelle, L., Cloud, M. D., Nathan, H., & Enas, M. S. (1993). Nizatidine prevents peptic ulceration in high-risk patients taking nonsteroidal anti-inflammatory drugs. Arch Intern Med., 153(21), 2449–2454.

    Article  Google Scholar 

  29. Molitch, M. E.(2005): Medication-induced hyperprolactinemia. Mayo Clin Proc, Volume 80, Issue 8, 1050 – 1057. https://doi.org/10.4065/80.8.1050

  30. Niaz N., Guvenc G., Altinbas B., Toker M., Aydin B., Udum-Kucuksen D., Alcay S., Gokce E., Ustuner B., Yalcin M. ( 2018): Intracerebroventricular injection of histamine induces the hypothalamic-pituitary-gonadal axis activation in male rats, Brain Res, 1699, 150-157,ISSN 0006-8993, https://doi.org/10.1016/j.brainres.2018.08.020.

  31. Nieschlag E., Weinbauer G.F., Cooper T.G., Wittkowski W. and Cantz T. (2008): Reproduction . In: Speckmann E-J, Hescheler J, Kohling R (eds.) Physiologie 5. Aufl age, Urban & Fischer, Munchenpp 652-677.

  32. Panula, P., Chazot, P. L., & Cowart, M. (2015). International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors. Pharmacol Rev., 67(3), 601–655.

    CAS  Article  Google Scholar 

  33. Patrignani, P., Tacconelli, S., Bruno, A., Sostres, C., & Lanas, A. (2011). Managing the adverse effects of nonsteroidal anti-inflammatory drugs. Expert Rev ClinPharmacol., 4, 605–621.

    CAS  Article  Google Scholar 

  34. Prajapati P.K., Singh S.B. and Jaiswal S. (2014): Overview on anti-ulcer activity of Basella alba: A therapeutic herb. 49-61.

  35. Radwan A.G. and West G.B. (1971): Br.J.Pharmac. Chemother. 41: 167-169. Quoted from Sadik,S.A.E. (1984): Studies on the effect of some antidepressant drugs on gastric secretion and ulceration in rats .M.Sc. Thesis in pharmacology, Al Azhar University.

  36. Ryberg, B., Tielemans, Y., Axelson, J., Carlsson, E., Hakanson, R., Mattson, H., … Willems, G. (1990). Gastrin stimulates the self-replication of rat enterochromaffin like cells in the rat stomach. Effects of omeprazole, ranitidine, and gastrin-17 in intact and antrectomized rats. Gastroenterology, 99, 935–942.

  37. Siddique, O., Ovalle, A., Siddique, A. S., & Moss, S. F. (2018). Helicobacter pylori infection: An update for the internist in the age of increasing global antibiotic resistance. Am. J. Med., 2018(131), 473–479.

    Article  Google Scholar 

  38. Sinha, R. B., Banerjee, P., & Ganguly, A. K. (2006 Mar). (2006): Serum concentration of testosterone, epididymal mast cell population and histamine content in relation to sperm count and their motility in albino rats following H2 receptor blocker treatment. Nepal Med Coll J., 8(1), 36–39.

    PubMed  Google Scholar 

  39. Sung, J. J., Tsoi, K. K., Ma, T. K., Yung, M. Y., Lau, J. Y., & Chiu, P. W. (2010). Causes of mortality in patients with peptic ulcer bleeding: A prospective cohort study of 10,428 cases. Am J Gastroenterol, 105(1), 84–89. https://doi.org/10.1038/ajg.2009.507.

    Article  PubMed  Google Scholar 

  40. Tildesley, G., Ehsanullah, R. S., & Wood, J. R. (1993). Ranitidine in the treatment of gastric and duodenal ulcers associated with non-steroidal anti-inflammatory drugs. Br J Rheumatol., 32, 474–478.

    CAS  Article  Google Scholar 

  41. Walker W.H. and Cheng J. (2005): FSH and testosterone signaling in Sertoli cells. Review. Reproduction journal.130: 15-28.

  42. Wallace, J. L. (2005). Recent advances in gastric ulcer therapeutics. Curropin. Pharmacol, 5, 573–577.

    CAS  Google Scholar 

  43. Waller D.G., Renwick A.G. and Hillier K. (2005): Medical pharmacology and therapeutics, 2nd ed. El Sevier Limited. 347–401.

  44. Werawatganon, D., Rakananurak, N., Sallapant, S., Prueksapanich, P., Somanawat, K., Klaikeaw, N., & Rerknimitr, R. (2014). Aloe vera attenuated gastric injury on indomethacin induced gastropathy in rats. World J Gastroenterol, 20, 18330–18337.

    Article  Google Scholar 

  45. Wilhelmi and Gdynia M. (1972). Quoted from Sadik, S.A.E. (1984): Studies on the effect of some anti depressant drugs on gastric secretion and ulceration in rats. M.Sc. Thesis in pharmacology, AlAzhar University. Pharmacology, 8, 321–328.

    Article  Google Scholar 

  46. Yamada, T., Deitch, E., Specian, R. D., Perry, M. A., Sartor, R. B., & Grisham, M. B. (1993). Mechanisms of acute and chronic intestinal inflammation induced by indomethacin. Inflammation., 17, 641–662.

    CAS  Article  Google Scholar 

  47. Yeomans, N. D., Svedberg, L. E., & Naesdal, J. (2006). Is ranitidine therapy sufficient for healing peptic ulcers associated with non-steroidal anti-inflammatory drug use? Int J ClinPract., 60(11), 1401–1407.

    CAS  Google Scholar 

Download references

Acknowledgements

“Not applicable”

Guidelines followed for handling rats

HU-IACUC Institutional Animal Care and Use Committees in Helwan University

Funding

“Not applicable”

Author information

Affiliations

Authors

Contributions

Experimental design: AA, SE .Data interpretation: EA, AA, SE, AS. Histological examination: AA. Writing and revision: AA, AS. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Ahmed S. Alazzouni.

Ethics declarations

Ethics approval and consent to participate

AS0520-10 HU-IACUC

Consent for publication

“Not applicable”

Competing interests

“Not applicable”

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Alazzouni, A.S., Abdel Aziz, E.A., Elnabtity, S. et al. Comparative histological and histochemical studies between ranitidine and nizatidine in treatment of peptic ulcer with evaluation of their adverse effects on male sex hormones. JoBAZ 81, 61 (2020). https://doi.org/10.1186/s41936-020-00196-6

Download citation

Keywords

  • H2-receptor
  • Antagonists
  • Peptic ulcer
  • Male sex hormones
  • Nizatidine
  • Ranitidine
  • NSAIDs
  • Gastroprotective
  • H2 blocker