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E L S E V I E R
• BASIC RESEARCH •
Gastroprotection induced by capsaicin in healthy human subjects
Gyula Mózsik, János Szolcsányi, István Rácz
Gyula Mózsik, First Department of Medicine, Medical and Health
Center, University of Pécs, Hungary
Spicy or hot foods are traditionally considered as dietary
János Szolcsányi, Department of Pharmacology and Pharmacotherapy,
Medical and Health Center, University of Pécs, Hungary
factors implicated in the causation of peptic ulcer[1,2]. Early
István Rácz, First Department of Medicine, County Hospital of
and more recent studies[3-6] in human beings with pungent
chilli powders and extracts have come to controversial
Correspondence to: Professor Gyula Mózsik, MD, First Department
conclusions about their injurious influence on gastric mucosa.
of Medicine, Medical and Health Center, University of Pécs,
Capsaicin is a hot topic in studies on gastro-protection[7-16].
In contrast, the effect of this pure ingredient of red peppers
Telephone: +36-72-536-494 Fax: +36-72-536-495
in defined concentrations on the human gastric mucosa
Received: 2004-10-14 Accepted: 2004-12-23
seems not to be interesting for research. Capsaicin activates
the TRPV1/VR1 capsaicin (vanilloid) receptor expressed
by a subgroup of primary afferent nociceptive neurons.
A b s t r a c t
The TRPV1/VR1 receptor has been cloned and turns
out to be a cation channel. It is gated besides capsaicin and
AIM: To evaluate the gastro-protective effect of capsaicin
some vanilloids by low pH, noxious heat and various pain-
against the ethanol- and indomethacin (IND)-induced gastric
producing endogenous and exogenous chemicals. Thus, these
mucosal damage in healthy human subjects.
sensory nerve endings equipped with these ion channels
are prone to be stimulated in gastric mucosa. The aim of
METHODS: The effects of small doses (1-8 µg/mL,
the present study was to analyze the effect of capsaicin on
100 mL) of capsaicin on the gastric acid secretion basal
acid output (BAO) and its electrolyte concentration,
mucosal injury induced by ethanol or the non-selective
gastric transmucosal potential difference (GTPD),
cyclooxygenase inhibitor, indomethacin (IND). Particular
ethanol- (5 mL 300 mL/L i.g.) and IND- (3×25 mg/d)
attention was paid to define whether the action of capsaicin
induced gastric mucosal damage were tested in a
was related to its acute stimulatory effect or to the sensory
randomized, prospective study of 84 healthy human
desensitization, a well known long lasting consequence of
subjects. The possible role of desensitization of
sensory stimulation in animal experiments[22,23].
capsaicin-sensitive afferents was tested by repeated
exposures and during a prolonged treatment.
MATERIALS AND METHODS
RESULTS: Intragastric application of capsaicin decreased
The observations were carried out in 84 healthy human
the BAO and enhanced “non-parietal” component (GTPD)
subjects aged 25-65 years (40±10 years). The physical,
in a dose-dependent manner. The decrease of GTPD
laboratory, and iconographic examinations were normal and
evoked by ethanol was inhibited by the capsaicin application,
which was reproducible. Gastric microbleeding induced
The healthy persons were randomized into different
by IND was inhibited by co-administration with capsaicin,
groups to study the effect of intragastric application of
but was not influenced by two weeks pretreatment with
capsaicin on their gastric mucosa and gastric acid secretion
a daily capsaicin dose of 3×400 µg i.g.
under different conditions.
The observations were carried out according to the good
CONCLUSION: Capsaicin in low concentration range
clinical practice. The studies were carried out from 1997 to
protects against gastric injuries induced by ethanol or
2002, which were permitted by the Regional Ethical
IND, which is attributed to stimulation of the sensory nerve
Committee of Pécs, University of Pécs, Hungary. Written
informed consent was obtained from all participants.
© 2005 The WJG Press and Elsevier Inc. All rights reserved.
Identification of gastric basal acid output (BAO) without and
Key words: Capsaicin; Ethanol; Indomethacin; Gastric
transmucosal potential difference; Gastric microbleeding;
After an overnight fasting, a nasogastric tube was introduced
Gastroprotection; Healthy human subjects
at 8:00 a.m., and the total gastric content was completely
Mózsik G, Szolcsányi J, Rácz I. Gastroprotection induced by
Then the secreted gastric juice was suctioned every 15 min
capsaicin in healthy human subjects. World J Gastroenterol
for 1 h (basal acid output, BAO). The healthy human subjects
2005; 11(33): 5180-5184
received intragastric capsaicin at the doses of 100, 200,
400, and 800 µg in 100 mL volume of saline solution. In
Mózsik G et al. Gastroprotection by capsaicin in human beings
the control group, 100 mL of saline solution was given
whole procedure was repeated thrice before and after the
through the nasogastric tube and the same doses of
administration of IND (without and with application of
capsaicin. Gastric acid secretion was measured by titration
of gastric juice with 0.1 N NaOH to pH 7 (pH titrimeter,
Gastric juice was aspirated. The strength of suction was
Radelkis, Budapest, Hungary). Gastric acid outputs were
adjusted to -50 mmHg.
calculated and expressed in mEq/h after capsaicin
The volume of each recovery sample was measured
administration. The values effective inhibitory dose of
after homogenization for 10 min. Hemoglobin was
capsaicin (ED50) was identified on the gastric BAO.
determined as previously described[36,37]. The quantity of
blood in the aspirated gastric samples was measured. Blue
Chemical composition of gastric juice without and with
color developed (640 nm, pH 3.78, room temperature) and
could be determined. Phenol red was measured spectroph-
The concentrations of Na+, K+, and Ca2+ in gastric juice
otometrically[29,30]. The values of gastric microbleeding were
were measured flamephotometrically. The concentration of
expressed as milliliter per day.
Mg2+ was measured by atom absorption spectrometry, the
chloride concentration by colorimetric method, the protein
Chronic capsaicin (3×400 µg i.g./d) treatment for 2 wk
concentration by the method of biuret reaction.
Ten healthy human subjects were treated with capsaicin
The chloride linked to H+ and sodium was calculated
(3×400 µg orally) for 2 wk. Capsaicin substance (400 µg)
for the determination of “parietal” (chloride linked to H+)
was put into a gelatin capsule containing 0.23 g lactose.
and of “non-parietal” (liked to sodium) components of the
The extent of IND-induced gastric mucosal bleeding
and gastric mucosal preventive effect of capsaicin (200,
400 µg) were tested before and after capsaicin treatment.
Measurement of gastric transmucosal potential difference
Prospective randomized studies were done for three
consecutive days before and after capsaicin treatment.
GTPD was measured during endoscopy. The exploring
mucosal electrode was passed through the biopsy force
channel of gastroscope and the reference electrode was
Capsaicin was from Sigma, Budapest, Hungary. IND was
placed on the volar surface of the left forearm. The electrodes
from Sanofi-Synthelabo, Budapest, Hungary. Capsaicin
were connected to a digital voltmeter (Radelkis, Budapest,
solution was made by dilution with distilled water.
Hungary, OP 211/1). GTPD measurements were done at
the greater curvature of the gastric body and the results
were expressed in -mV (without and with intragastric
The results were calculated as mean±SE. The unpaired or
application of different doses of capsaicin)[24-27]. Capsaicin
paired Student’s t-tests were used for the calculation of the
in 5 mL saline solution was intragastrically applied and only
results between the identical observations. P<0.05 was
saline solution was given to identify the baseline in GTPD.
considered statistically significant.
The GTPD values were expressed in -mV, while -
max was calculated after intragastric application of capsaicin
(n = 10).
The BAO decreased significantly and dose-dependently
Effect of capsaicin on ethanol-induced GTPD changes
(Figure 1). The ED50 value of capsaicin was 400 µg.
The GTPD baseline was identified, and ethanol (5 mL
300 mL/L i.g.) was given intragastrically. The GTPD change
was determined after the ethanol passed through the biopsy
force channel of gastroscope without and with capsaicin
r = 0.97; Y = -0.13*X+1.164; P<0.001; (n = 16)
(given in different doses in the same pathway after 1 min
of ethanol administration) (n = 10).
Gastric microbleeding measurement during 1-d treatment with
indomethacin (IND) and indomethacin plus capsaicin (n = 14)
Fourteen healthy human subjects were studied. They were
randomly divided into different treatment groups.
Examinations were carried out before and after treatment
0 100 200 300 400 500 600 700 800 900
after an overnight fasting. A plastic tube was inserted through
Capsaicin (µg i.g.)
his or her mouth until the intragastric end was 55 cm from
the incisors. There were six openings in the intragastric part
Figure 1 Inhibition of gastric acid output (BAO) by capsaicin in 16 healthy
of the tube.
A test solution containing 100 mL of saline solution and
10 mL solution of concentrated phenol red (40 mg/100 mL),
as a non-absorbable marker, was installed into the stomach
Electrolyte and albumin concentrations in gastric juice
without and with capsaicin (at doses of 200, 400, and 800 µg).
were measured in the healthy human subjects without and
The gastric content was recovered 10 min later[28-30]. The
with capsaicin treatment. H+, K+, Ca2+, and Mg2+ significantly
5182 ISSN 1007-9327 CN 14-1219/ R World J Gastroenterol September 7, 2005 Volume 11 Number 33
The present study provides evidence for the powerful
gastroprotective potency of capsaicin. The threshold
concentration of capsaicin in producing definite hot
sensation is around 1-2 µg/mL and the capsaicinoid level
in chilli sauce varies from 25 µg/mL to 0.5 mg/mL[22,24].
Therefore, the observed defensive responses using capsaicin
have a clear dietary relevance.
Chronic peptic ulcer patients are warned to avoid spicy
foods, although in the era of H2-inhibitors this praxis is far
(n = 10)
less restrictive. Nevertheless contradictory observations
cannot decide whether spicy foods are harmful to or
Figure 2 “Parietal” and “non-parietal” components before (A) and after (B)
beneficial for gastric injury. In healthy subjects mucosal
intragastric application of capsaicin in 10 healthy human subjects.
microbleeding with exfoliation and aggravation of aspirin-
induced gastric bleeding are observed in response to chilli
powder or red pepper “preparations”[3,4]. On the other hand,
decreased (P<0.001), while Na+ and its protein content
ingestion of “highly spiced” meals or chilli by normal
increased (P<0.001) after capsaicin treatment (Table 1).
individuals does not cause endoscopically gastric or duodenal
The “parietal” and “non-parietal” components of BAO
mucosal damage although gastric acid and pepsin secretion
were calculated by taking the H+ output equivalent to Na+
increases[31-33]. In other studies, red pepper sauce induces
and Cl- as gastric H+, Na+, and chloride in gastric juice without
prolongation of gastric emptying and chilli powder evokes
and with capsaicin treatment. The parietal component
18 mmol/L) while the non-parietal component
protective effect against aspirin-induced gastric mucosal
19 mmol/L) in the BAO after capsaicin
injury. Improvement in dyspeptic symptoms of patients
application (Figure 2).
with and without gastro-esophageal reflux disease and irritable
Capsaicin increased the GTPD in a dose-dependent
bowel syndrome after intake of red pepper powder in gelatin
manner. The peak values reached within 3-5 min after
capsules has been reported[8,9]. In the latter case, the
capsaicin application (Figure 3A).
improvement of functional dyspepsia is attributed to
After intragastric application of ethanol (300 mL/L), the
desensitization of gastric nociceptive C-fibers induced by
GTPD dropped from -33.4±2.7 to -10.5±2.4 mV (P<0.001)
capsaicin although this conclusion is not supported by
within 3 min (Figure 3C).
experimental evidence. In our earlier and present studies,
Capsaicin application (at doses of 400 and 800 µg)
pure capsaicin solution was injected into the stomach
significantly prevented the ethanol-induced decrease in
(1-8 µg/mL in 100 mL) of healthy subjects which inhibits
GTPD (Figure 3C).
the H+ output and total secreted volume of gastric juice
The protective effect of capsaicin was reproducible before
for about 1 h in a dose-dependent manner and increases its
(Figure 3B) and after (Figure 3D) ethanol administration.
“non-parietal” component, gastric emptying.
The gastric microbleeding was measured before and after
The important role of capsaicin-sensitive peptidergic
IND (3×25 mg orally) application alone and in combination
sensory fibers in maintaining of gastric mucosal integrity
with 200, 400, and 800 µg capsaicin in 14 healthy human
against injurious interventions has been well established in
volunteers. The gastric microbleeding induced by IND
rats[10-13,15]. Capsaicin-sensitive primary afferent neurons and
increased (8; 25±0.5 mL/d from the basic level of 2.1±0.1;
their nerve endings express the TRPV1/VR1 vanilloid
P<0.001) which was dose-dependently prevented by
receptor[14,21,23]. Stimulation of these chemoreceptive nerve
capsaicin at the dose of 200-800 µg (Y = 0.0071X+7.78;
terminals by H+ or bradykinin, etc. is accompanied with release
r = -0.98; P<0.001, Figure 4A).
of CGRP, tachykinins, somatostatin, and NO from them. The
In order to decide the potential role of desensitizing in the
arterial wall in stomach receives dense supply of these peptidergic
gastric protective effect of capsaicin, a daily dose of 3×400 µg
fibers and capsaicin elicits neurogenic vasodilatation with
capsaicin was applied for 2 wk in 14 healthy human subjects.
enhanced mucosal blood flow. Clear evidence indicates that
Capsaicin protected gastric mucosal against IND-induced
hyperemia is induced by sensory neuropeptides of CGRP
gastric microbleeding. There was no difference between
neurokinin A with NO as well as somatostatin are involved
the pretreated group and the central group (Figure 4B).
in the sensory neuron-mediated gastroprotection[17-20].
Table 1 Chemical composition of gastric juice without (A) and with (B) application of capsaicin in healthy human subjects (mEq/L or in g/L)
B A B
25±1 73±4 89±2 13±1 8±0.6 0.98±0.02 0.88±0.01 0.49±0.01 0.38±0.01 43±3 25±2 126±4 145±4 1.24±0.001 1 630 002
58±2 100±5 122±3 100±8 62±5 100±2
100±2 78±2 100±7 58±5
Mózsik G et al. Gastroprotection by capsaicin in human beings
(n = 10, mean±SE)
(n = 10, mean±SE)
0 1 2 3 4
0 1 2 3 4
(n = 10, mean±SE) d
(n = 10, mean±SE)
- 0 1 2
-1 0 1 2
Figure 3 Dose-dependent gastric mucosal protective effect of capsaicin. A:
dose-response curves for capsaicin-induced gastric mucosal prevention on
Dose-response curve for capsaicin-induced changes in GTPD; B: effect of
ethanol-produced decrease in GTPD; D: effects of repeated capsaicin application
repeated capsaicin application on GTPD applied with 5-min time intervals; C:
on ethanol-induced GTPD changes. aP<0.05, bP<0.01, dP<0.01 vs others.
(n = 14, mean±SE)
r = -0.98; Y = -0.0071*X+7.78; P<0.001; (n = 14)
2 wk caps. treatment (3×400 mg/d)
0 10 20
30 40 50
60 70 80 90
400 mg/d ig
IND+capsaicin (µg ig)
Figure 4 Gastric mucosal protection produced by capsaicin on IND-induced
bP<0.01, dP<0.01 vs others.
gastric mucosal damage before (A) and after (B) capsaicin treatment. aP<0.05,
Opposite effect has been observed in rats desensitized by
injurious effects of ethanol or IND is due to the acute
capsaicin. Functional blockade of gastric sensory nerve
stimulatory effect of the compound. Microbleeding detected
endings elicited by systemic or intragastric capsaicin
after IND administration does not differ from that in the
application results in impaired mucosal protection against
controls. Enhanced GTPD evoked by the first and second
various ulcer-provoking agents[10-14]. Repeated topical or
capsaicin exposure in 1 h shows no sign of decrement.
systemic capsaicin application elicits reproducible effects at
Counteraction of the ethanol-induced drop of gastric
low concentrations and induces decreasing responses
transmucosal potential is identical after the first and second
(desensitization) at high concentrations. In the rat’s eye,
10 µg/mL concentration of capsaicin does not induce any
The enhancement of gastric transmucosal potential is
desensitization. On the human oral mucosa, this
probably related to the mucosal hyperemia[32,34]. This response
concentration of capsaicin induces some diminished
plays a significant role in capsaicin-induced gastroprotection.
sensation of irritation but only for a short time.
Furthermore, the present and earlier findings reveal that
In the present study, the following evidence suggests that
intragastric administration of capsaicin in low concentration
capsaicin-induced gastric mucosal protection against the
inhibits but does not increase[4,5,26] the acid output of stomach
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