EXPERIMENTAL ANIMAL MODELS FOR GASTROINTESTINAL …

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Prabhavalkar et al. World Journal of Pharmacy and Pharmaceutical Sciences

EXPERIMENTAL ANIMAL MODELS FOR GASTROINTESTINAL

ULCER DISEASE

Mrunal Patila and Kedar S. Prabhavalkar

a,*

aDepartment of Pharmacology, SVKM’s Dr. Bhanuben Nanavati College of Pharmacy, Vile

Parle (W), Mumbai, India.

ABSTRACT

Gastric ulcer is one of the most serious gastrointestinal disease. Ulcers

are mainly caused by imbalance between the gastroduodenal mucosal

defensive factors versus aggressive factors. In gastric ulcer disease,

animal models have helped to understand the basic mechanisms

responsible for the formation of gastric ulcers and its treatment. The

limited number of animal models for the study of gastric ulcer has

hindered the process of research in gastrointestinal disorders.

Therefore it is important to review the available literature for animal

models of gastric ulcer. Available models include primates, rats, mice,

rabbits, cats, guinea pigs, ferrets and pigs. The main aim is to provide

scientific information about different animal models to induce gastric

ulcers as well as for the screening of antiulcer activity. In this review,

we summarize different experimental animal models used in clinical research during past few

decades to carry out antiulcerative activity of new agents as well as its underlying

mechanisms.

KEYWORDS: Gastric ulcer; animal models; NSAIDs; antiulcerative activity;

diethyldithiocarbamate; COX.

1.0 INTRODUCTION

Gastric ulcer is a common gastrointestinal disorder, which includes both gastric and duodenal

ulcers affecting many people throughout the world.[1]

It affects around 3%–10% of the global

population.[2]

About 10% of the world population is on high risk of developing gastric ulcer

at some point in their lifetime.[3]

Globally, an estimated 15 mortality was recorded per year

out of every 15,000 complications of gastric ulcer.[4]

It can be defined as a damage to the

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 7.421

Volume 8, Issue 8, 1615-1634 Review Article ISSN 2278 – 4357

*Corresponding Author

Dr. Kedar S.

Prabhavalkar

Department of

Pharmacology, SVKM’s Dr.

Bhanuben Nanavati College

of Pharmacy, Vile Parle

(W), Mumbai, India.

Article Received on

17 June 2019,

Revised on 07 July 2019,

Accepted on 28 July 2019

DOI: 10.20959/wjpps20198-14539


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mucosa that ruptures the muscle layer and forms an injury followed by inflammation.[2], [5]

Generally normal gastric mucosa is exposed to the offensive factors. This may result from an

imbalance between the defensive factors and the offensive factors present in the gastric

mucosal layer.[6]

The defensive factors like mucin, adequate blood flow, nitric oxide,

prostaglandin secretion, bicarbonate and growth factors and the offensive factors include

increased secretion of hydrochloric acid and pepsin, reactive oxygen species, improper

dietary habits, administration of non-steroidal anti-inflammatory drugs, consumption of

alcohol, stressful conditions and infection with Helicobacter pylori infection.[7], [8]

So the

imbalance between these offensive factors and the defensive factors is the main cause for the

pathogenesis of gastric ulcers.[9]

The gastric acid, reactive oxygen species (ROS), and

inflammatory cytokines are continuously in contact with gastric mucosa and can lead to

gastric tissue damage.[10]

Nowadays, the drug therapy for gastric ulcer is mainly based on the

reduction in acid secretion and the protection of gastric mucosa.[11]

The drugs which are

commonly used for the treatment of gastric ulcers consist of antacids, anticholinergics, proton

pump inhibitors and H2- receptor antagonists.[12], [13]

However, the current therapy is not

completely effective and continuous use of these drugs can produce side effects[14]

such as

hypersensitivity, hematopoietic changes, gynecomastia and arrhythmia.[15]

The search for a

new, effective and affordable ulcer treatment, reducing its side effects, current studies are

moving towards natural products.[16]

Hence for the screening of novel antiulcer agents,

suitable animal models are necessary, which can mimic the conditions and show resemblance

to that of the human disease state. Therefore it is important to review the available literature

for animal models of gastric ulcer to screen antiulcer agents. Researchers have used some

technologies to generate transgenic rats[17]

, cats[18]

, dogs[19]

, rabbits, pigs, sheep[20]

, goats,

cattle, chickens[21]

, zebrafish[22]

and non-human primates[23]

as animal models to study

different disease mechanisms.

The main aim is to provide scientific information about different animal models to induce

gastric ulcers as well as for the screening of antiulcer activity. Therefore in this review,

authors putforth different experimental animal models used in clinical research during past

few decades to carry out antiulcer activity of new agents as well as its underlying

mechanisms.


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2.0 Animal models

To study the actual pathogenesis and mechanisms of gastric ulcer in humans, rodent models

are helpful.[24]

Many scientists are using different animal models to induce gastric ulcer such

as pylorus ligation model, alcohol induced ulcers, NSAIDs induced ulcers, stress ulcers,

histamine induced gastric ulcers, cysteamine induced duodenal ulcers. These models could

also serve as effective tool for the better understanding of pathophysiological mechanisms,

like antisecretory, gastroprotective, antioxidant and healing of ulcers. But the limited number

of animal models for the study of gastric ulcer has hindered the process of research in

gastrointestinal disorders.

Certain conditions should be fulfilled while selecting the proper experimental animal model

for the screening of antiulcer agents.

It should be simple and reproducible.

It should be easy for the quantification of the results.

It should induce a proper ulceration at targeted site.

It should involve different mechanisms by which ulcers are produced.

Gastric ulcer can be induced by various methods and can be classified as (A) Physical

methods, (B) Chemical methods and (C) Surgical methods. These models are listed in

Table 1.

Table 1. List of Animal models.

Methods Animal models

Physical methods

Stress induced ulcers

Water immersion stress induced ulcers

Cold restraint stress induced ulcers

Chemical methods

NSAIDs induced gastric ulcers

Ethanol induced gastric ulcers

HCl/ethanol induced gastric ulcers

Acetic acid induced gastric ulcer

Serotonin induced gastric ulcer

Reserpine induced gastric ulcers

Diethyldithiocarbamate induced gastric ulcers

Histamine induced duodenal ulcers

Cysteamine HCl induced duodenal ulcers

Surgical methods

Pylorus ligation induced gastric ulcers

Ischemis reperfusion induced gastric ulcers

Mucosectomy induced gastric ulcers


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The principle along with their underlying mechanism of action is described below and a brief

procedure for the same is given in table 2.

2.1 Physical methods

Certain physical methods are used to induce gastric ulcers in experimental animals. Generally

physical methods are responsible for the production of oxidative stress and increases reactive

oxygen species in the stomch.

2.1.1 Water-immersion stress or cold-resistant stress induced gastric ulcers

Physical stress and psychological stress can cause gastric ulcers in humans. Hence various

stressors are responsible for the production of gastric ulcers in animal models.[25] This

model involves the restraint technique developed by Brodie and Hanson[26]

employed with

coupling of new method developed by Levine i.e. cold water immersion method which

induces gastric ulcers in a synergistic manner. Gastric ulcers induced by water-immersion

stress or cold water-restraint stress or cold-restraint stress in animals are completely resemble

to human ulcer condition by histopathogically.[27]

This model is widely used to study the

gastroprotective and healing effect of test agents, especially those with mucus enhancing and

cytoprotective properties, for gastric ulcers in rats. The pathophysiology behind stress-

induced gastric ulcers is complex and difficult to understand. Generally these ulcers are

produced due to the release of histamine, which resulting into increased acid secretion and

reduced mucus production[22]

and poor gastric blood flow.[28]

Excessive production of

reactive oxygen species and inhibition of prostaglandin synthesis also promote stress induced

ulcer formation.[29], [30]

Increased gastrointestinal motility produced by stress results into

formation of folds in the stomach[31]

which are more susceptible to damage gastric mucosa

when they come in contact with gastric acid. Increased vagal activity is also one of the factor

responsible for the production of stress-induced ulcers.[26]

As mucus plays a crucial role in

the protection of stomach wall and enhances healing of gastric ulcers, this model is suggested

for evaluating mucus enhancing and cytoprotective agents.


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Table 2. Animal models of gastric and duodenal mucosal lesions and ulcers.

Assay Types of

animals Method of induction

Types of

lesions References

Stress induced gastric

ulcers

Water immersion stress

Rat

Animals are placed in

a stress cage and

immerse it vertically

in water bath (15–

20∘C) upto the level

of the xiphoid for 17

hours to induce stress

ulcer.

Gastric,

Acute,

Chronic

[32], [33]

Cold restraint stress Rat

Animals are

restrained in plastic

cages in a ventilated

refrigerator at 2-3∘C

for 2-4 hours and

then sacrificed.

Gastric,

Acute,

Chronic

[34]

NSAIDs induced ulcers

Aspirin

Rat or Mouse

24-36 hrs fasted

animals receive a

single dose of aspirin

(125-150 mg/kg)

administered by oral

route and after 4 hrs

animals are sacrificed

for ulcer

examination.

Gastric,

Acute

[28], [35]–[38]

Indomethacin Rat or Hamster

Animals receive a

single dose of

indomethacin in the

range of 40-100

mg/kg

subcutaneously and

sacrificed after 5 hrs.

Gastric,

Acute,

Chronic

[28], [37], [39]–[42]

Ethanol induced ulcers

(Absolute ethanol) Rat

After 24-36 hrs of

fasting, animals

receive ethanol

(1ml/rat) orally and

sacrificed after 1 hr

to check gastric

lesions.

Gastric,

Acute [41], [43]–[46]

HCl/ethanol induced

Ulcers Rat

Animals receive a

mixture of 1.0 mL

EtOH/HCl (60 mL

ethanol, 1.7 mL

hydrochloric acid,

38.3 mL distilled

Gastric,

Acute [47]


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water) to induce

gastric ulcer.

Acetic acid induced

gastric ulcers Rat, Cat

After an acute

laparotomy, stomach

is exposed and 20%

acetic acid (0.03 mL)

is injected into the

sub-serosal layer of

the antrum at

multiple sites. After

24 hrs animals are

sacrificed.

Gastric,

Chronic [48]–[50]

Serotonin induced

ulcers Rat

After 30 min of drug

treatment, Serotonin

Creatinine Sulphate

(20-50 mg/kg) is

administered

subcutaneously and

after 6 hours animals

are sacrificed.

Gastric,

Acute [51], [52]

Reserpine induced

ulcers Rat

After 36 hrs of

fasting, reserpine (5–

8mg/kg) is

administered

intraperitoneally and

after 24 hrs animals

are sacrificed.

Gastric,

Acute [53]

Diethyldithiocarbamate

inducd ulcers Rat

In this model, acute

glandular lesions are

induced by

subcutaneous

injection of 1 mL of

diethyldithiocarbama

te (800mg/kg) in

saline followed by

oral dose of 1 mL of

0.1N HCl.

Gastric,

Acute [54], [55]

Histamine induced

ulcers Rat

Histamine phosphate

(40–100mg/kg) is

administered

subcutaneously and

after 2 hours animals

are sacrificed.

Gastric,

Duodenal,

Acute

[56], [57]

Cysteamine HCl

induced ulcers

Guinea pig,

Rat,

Mouse

A single dose of

cysteamine

hydrochloride

(400mg/kg p.o.) is

sufficient to induce

acute duodenal ulcers

in experimental rats.

Duodenal,

Acute [35], [36], [40]


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Pylorus ligation induced

ulcers

Rat

After an acute

laparotomy, pyloric

end of animals

stomach is ligated for

4 hrs. Then animals

are sacrificed for

ulcerative lesions

examination.

Gastric,

Acute [38]

Ischemia reperfusion

induced ulcers Rats

A laparotomy is

carried out under

anesthesia, and the

superior mesenteric

artery (SMA) is

clamped with a

bulldog clip for 30

min (The ischemic

stage). After that,

bulldog clip is

removed to permit

reoxygenation of the

gastric tissue for 15

minutes (the

reperfusion stage).

Then animals are

sacrificed for

ulcerative lesions

examination.

Gastric,

Intestinal

Acute

[58], [59]

Mucosectomy induced

ulcers

Rabbits

Guinea pigs

After a median

laparotomy, 0.2 mL

of isotonic saline is

injected into the

submucosal layer of

the upper corpus. A

diameter of 7-10 mm

of the swollen

mucosal layer is

resected with

scissors. After the

procedure, animals

are placed to

individual cages for

recovery.

Gastric,

Acute [60]–[62]

2.2 Chemical methods

Various chemicals are used to induce ulcers because they directly ruptures the gastric mucosa

(Ethanol, Acetic acid) or some other mechanisms are also involved in it.


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2.2.1 NSAID’s induced gastric ulcers

Gastric ulcers are known to be induced by excessive use of several Non-Steroidal Anti-

Inflammatory Drugs (NSAID’s) like aspirin, indomethacin, and ibuprofen.[63]

This is the most

common model used for inducing gastric ulcer. NSAID’s are responsible for the production

of gastric ulcers by inhibiting prostaglandin synthesis via cyclooxygenase (COX)

pathway.[64], [65]

Prostaglandins plays an important and protective role in the production of mucus and

secretion of bicarbonate, which maintains mucosal blood flow and regulates mucosal cell

integrity.[66]

Thus the suppression of production of prostaglandins by NSAIDs leads to the

gastric mucosal damage and gastric ulcers. The mechanism behind NSAIDs -induced gastric

ulceration includes blocking activity of the cyclooxygenase enzymes (COX-1 and COX-2),

by NSAIDs, which further leads to the decreased mucus and bicarbonate secretion, impaired

platelet aggregation, decreased mucosal blood flow, changes in microvascular structures

leading to epithelia damage.[65]

Increased reactive oxygen species (ROS) and lipid

peroxidation (LPO) are also responsible for gastric mucosal damage.[67]

NSAID’s specially

those are having chemically acidic nature, can exert direct cytotoxic effects on epithelial

cells, which disrupt surface active phospholipids on the mucosal surface thus making the

mucosa more susceptible to damage by luminal acid.[68]

Thus this model is commonly used

for the evaluation of antisecretory and cytoprotective agents. Specially, most commonly used

ulcerogen used for the induction of gastric ulcers are aspirin and indomethacin. A correct

route and an appropriate vehicle (e.g. water, 1% carboxymethyl cellulose) is selected for

administration of ulcerogen.

2.2.2 Ethanol induce gastric ulcers

Ethanol has been commonly used as a damaging agent to gastric mucosa for the induction of

gastric ulcers. Administration of absolute ethanol (>99%) has been used as a reproducible

method to induce gastric mucosal damage in experimental animals.[69]

The pathology behind

ethanol-induced gastric ulcer generally involves three main parameters: inflammatory

response, oxidative stress and apoptosis.

In the gastrointestinal tract, the motility of the esophagus, stomach, and gut as well as the

capacity of gut absorption can be severely affected by alcohol exposure. It can cause severe

mucosal damage and even carcinogenesis specially gastric cancer.[70]

Ethanol causes severe

gastric damage by producing several instabilities in the gastric mucosal layer[71]

such as a


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decreased bicarbonate secretion, gastric blood flow and mucus production. Ethanol can

stimulate gastric acid secretion, resulting in microvascular injuries which facilitate vascular

permeability, through release of gastrin and histamine from sensitive nerve terminals present

in the gastric mucosa.[72]

Ethanol ruptures gastric mucosal integrity through exfoliation of

cells, which leads to increase in mucosal permeability and in somehow causes bleeding.[73],

[74] Intra-gastric administration of absolute ethanol results in severe gastric mucosal injury

characterized by disturbances in microcirculation, mast cell secretary products, inhibition of

prostaglandin synthesis, reduction in mucus production and reactive oxygen species.[75]

Neutrophil infiltration in the gastric mucosa is also responsible for the production of lesions

induced by absolute ethanol.[76]

Oxidative stress plays a significant role in alcohol-induced gastric mucosal damage.[77]

Ethanol is also known to increase cellular oxidative stress[78]

and produce changes in gastric

cell calcium levels[79]

which may lead to the pathogenesis of gastric mucosal injury.

However, it is not a suitable animal model to evaluate antisecretory activity and ulceration

dependent on acid secretion, because this model is independent of gastric acid secretion.

Ethanol directly increases the levels of free radicals that can alter the cell structure and

function[75]

and can also gives its direct toxic effects on the gastric mucosa resulting in

reduced bicarbonate secretion and gastric mucus production.[80]

Hence this model is more

preferable for evaluating the gastroprotective potential of test materials which has

cytoprotective as well as antioxidant activities.

2.2.3 HCl/ethanol induced gastric lesions

This model is considered to be an advanced model of an absolute ethanol induced ulcer

model. Instead of ethanol only, a mixture of HCl and ethanol is used to induce ulceration.

Direct necrotizing action of HCl/ethanol is the pathogenesis for gastric lesions on the gastric

mucosa. Hence the combination of ethanol with HCl leads to induction and progression of

gastric injury.[81]

2.2.4 Acetic acid-induced gastric ulcers

Chronicity of the gastric ulcer disease is one of the least understood aspects for researchers.

Takagi et al.,[82]

developed an animal model to induce chronic gastric ulcers by sub-mucosal

injection of acetic acid and he also reported healing process of ulcers for extended time

intervals after the ulcer formation. The experimental gastric ulcers induced by acetic acid are


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considered as chronic ulcers due to its prolonged steadiness in gastric mucosa and

resemblance to human chronic ulcer both physiologically and histologically.

To overcome certain problems like adherence of ulcer to the adjacent organs such as the liver,

method given by Takagi, was modified and the one that is currently most commonly used is

developed by Okabe and Pfeiffer.[83]

This method consists of intraluminal application of

acetic acid solution. Thus acetic acid induced gastric ulcer model is most suitable for

evaluating antisecretory and cytoprotective activity of various test agents against chronic

gastric ulcers.[82], [84]

This model is easy and reliable to produce round and deep ulcers in the

stomach and duodenum of mice, rats, Mongolian gerbils, guinea pigs, cats, dogs, miniature

pigs, and monkeys.[49], [85]

2.2.5 Serotonin-induced gastric ulcers

Serotonin is a vasoconstrictor. It causes disturbance in gastric mucosal microcirculation and

reduces blood flow to gastric mucosa resulting in acute gastric mucosal damage which causes

gastric ulcers.[86]

2.2.6 Reserpine-Induced Peptic Ulcer

Reserpine is also used for induction of gastric ulcers by scientist. Reserpine causes

degranulation of mast cells resulting into release of histamine, mediated by cholinergic

system[87]

and this histamine is responsible for formation of gastric ulcer. Although this

model is dependent on gastric acid secretion, gastric hypermotility also plays an important

role in the induction of gastric mucosal lesions.[53]

2.2.7 Diethyldithiocarbamate induced gastric ulcers

This model is useful to assess the antioxidant activity of test drug which is mediates

gastroprotection by preventing gastric damage[54]

and also to evaluate the cytoprotective

potential of test agents. It is reported that antral lesions are induced by diethyldithiocarbamate

through the mobilization of superoxide and hydroxyl radicals. Superoxide radical and

hydroxyl radicals play a pathogenic role in the induction of this ulcer.[55]

2.2.8 Histamine-induced gastric ulcers

Release of histamine in stomach also causes gastric ulcers and hence histamine can be used

for inducing gastric ulcers in animals. On this basis histamine induced gastric ulcer model is

developed.[57]

Mast cells secretes histamine, which gets bind with receptors which are present


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on the surface of parietal cells, resulting into activation of adenylate cyclase, which is

responsible for the conversion of ATP into c-AMP. This process of conversion of AMP to c-

AMP enhances gastric acid secretion from parietal cells. Histamine produces disturbances in

gastric mucosal layer subsequently cause severe damage in gastric mucosa.[88]

The mechanism by which histamine produces gastric ulcers is its potent acid stimulating and

vasodilatory effect in animals. Vasodilating capability of histamine causes increase in

vascular permeability.[89]

This model is commonly used for evaluation of antisecretory effect

of test drug which acts as H2 receptor antagonists.

2.2.9 Cysteamine-Induced Duodenal Ulcers

Selye and Szabo[32]

depicted the technique for acceptance of duodenal ulcers in rodents by

utilizing cysteamine HCl. Duodenal ulcers incited by cysteamine in rodents has been

generally utilized as a model of duodenal ulcer. Cysteamine prompted ulcer looks like

duodenal ulcer in human as for its area, histopathology and a few parts of pathophysiology

too. The genuine component associated with generation of ulcer by cysteamine has not been

completely known. But it is reported that Cysteamine is responsible for the excessive

secretion of gastric acid and inhibits the alkaline mucus secretion from Brunner’s glands in

the proximal duodenum resulting in the formation of duodenal ulcer. Cysteamine is also

responsible for excessive pepsin secretion in the gastric mucosa[90]

and consequently causes

decrease in the production in defensive factors like bicarbonate and mucus.[91]

From different

studies, it was reported that cysteamine also reduces somatostatin bioavailability and elevates

serum gastrin levels, which is associated with an increase in gastric acid secretion.[92]

Additionally certain transcription factors like early growth response factor-1, hypoxia-

inducible factor-1 and their target genes assumes a vital role in the pathogenesis of

cysteamine-induced duodenal ulcers.[57]

2.3 Surgical methods

By performing a surgical method we can induce gastric ulcers in experimental animals.

2.3.1 Pylorus-ligation induced peptic ulcer

Shay (1945) developed an animal model for the investigation of gastric secretory activity of a

drug by ligating the pylorus end of the stomach which causes accumulation of gastric acid in

the stomach and produces ulcers. This excessive gastric acid is responsible for auto digestion

of gastric mucosal layer which cause breakdown of the gastric mucosa. So obstruction in


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pylorus causes mucosal digestion by an increase in acid pepsin pool. This model is

commonly used for the evaluation of cytoprotective and antisecretory effect of a drug which

increases secretion of mucus and reduce secretion of gastric acid, respectively.[57], [93]

2.3.2 Ischemia-Reperfusion induced gastric ulcer

Gastric mucosa is highly sensitive to ischemia or ischemic shock. Hence reperfusion

followed by ischemia causes formation of free radicals which is responsible for gastric

mucosal injury.[57]

This involves damage to the muscularis mucosac which is developed by

clamping the celiac artery. Intestinal injury is generally induced by 60 min clamping of the

superior mesenteric artery followed by 60 min reperfusion.[59]

2.3.3 Mucosectomy induced gastric ulcer

This is also called as mucosal resection method where gastric mucosa is exposed by median

laparotomy. Normal saline is injected into the submucosal layer of stomach and swollen

mucosal area is resected with scissors.[61]

Endoscopic resections have certain advantages over

conventional methods. They are more economical and less invasive.[62]

3.0 CONCLUSION

Actually it is not possible to understand the actual mechanism of any disease in human. No

one can predict which is the actual factor or mediator responsible for disease progression.

Without knowing this basic information, it is difficult to design treatment strategies for any

disease. In this review, we tried to cover several animal models of gastrointestinal ulcers that

are widely used in clinical research. Here we also reviewed available experimental animal

models of gastrointestinal ulcers for the evaluation new medicinal compounds having

potential antiulcerative as well as gastroprotective activity. In each model. we have discussed

the underlying mechanism behind the production of gastric ulcer. This will definitely help

scientists and investigators to select a suitable animal model of gastric ulcer for the evaluation

of antiulcerative activity of the test compound. Animal models also plays an important role in

pre-clinical research, specially for the identification of drug targets.

4.0 Abbreviations

ROS- Reactive Oxygen Species

NSAIDs- Non-Steroidal Anti Inflammatory Drugs

HCl- Hydrochloric Acid; SMA- Superior Mesenteric Artery

COX- cyclooxygenase


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COX 1- Cyclooxygenase 1

COX 2- Cyclooxygenase 2

ATP- Adenosine triphosphate

c-AMP- Cyclic Adenosine monophosphate.

5.0 Conflict of interest

Authors have no conflict of interest.

6.0 ACKNOWLEDGEMENT

Authors are thankful to Dr. Lokesh kumar Bhatt, HOD Pharmacology department and Dr.

Munira Momin, Principal, SVKM’s Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle,

Mumbai for their kind support.

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