Effect of nifedipine on gingival enlargement and periodontal breakdown in ligature-induced...

AOB-2359; No. of Pages 7

Effect of nifedipine on gingival enlargement and periodontalbreakdown in ligature-induced periodontitis in rats

Marilene Issa Fernandes a, Eduardo Jose Gaio b,*, Cristiano Susin c,Cassiano Kuchenbecker Rosing a, Rui Vicente Oppermann a, Pantelis Varvaki Rados d

a Periodontology, Faculty of Dentistry, Federal University of Rio Grande do SulPorto Alegre, Brazilb Post-Graduate Program in Dentistry, Faculty of Dentistry, Federal University of Rio Grande do Sul, BrazilcDepartments of Periodontics & Oral Biology, Medical College of Georgia School of Dentistry, Augusta, GA, USAdOral Pathology, Faculty of Dentistry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil

a r c h i v e s o f o r a l b i o l o g y x x x ( 2 0 1 0 ) x x x – x x x

a r t i c l e i n f o

Article history:

Accepted 10 May 2010

Keywords:

Alveolar bone loss

Gingival overgrowth

Nifedipine

Periodontitis

Rats

a b s t r a c t

Objective: A recent consensus report could not find specific reports of the effect of nifedipine

on the destruction of the periodontal tissues. The aim of the present study was to evaluate

the effect of nifedipine on gingival enlargement and periodontal breakdown using a liga-

ture-induced periodontitis in rats.

Materials and methods: Fifty, male, 60 days old, Wistar rats, were divided into six groups.

Cotton sutures were placed around the upper second molars. Two groups of 10 rats each did

not receive ligatures and were treated daily with either saline solution or nifedipine 50 mg/

kg/day. Two groups of 10 rats received ligatures and were also treated daily with saline

solution or nifedipine 50 mg/kg/day. Two additional groups (nifedipine 10 and 100 mg/kg/

day) were included to explore a possible dose–response relationship. Animals were eutha-

natised at 30 days. Internal and oral epithelium, total and inflamed connective tissue,

gingival thickness and height, and bone loss were assessed histologically.

Results: Nifedipine alone was not sufficient to promote gingival enlargement or periodontal

destruction in the absence of the ligature. Compared to animals with ligatures only, the

group that received ligatures and nifedipine 50 mg/kg/day showed significant higher esti-

mates for total and inflamed connective tissue, gingival thickness and height. No significant

differences were observed for bone loss between these experimental groups. The other

dosages of nifedipine did not provide additional information.

Conclusion: Nifedipine itself did not lead to gingival enlargement in rats. In the presence of

biofilm accumulation, nifedipine yielded greater gingival enlargement and periodontal

inflammation, but it did not increase periodontal destruction.

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1. Introduction

Drug-influenced gingival enlargements are clinical conditions

characterised by the increase in size of gingival tissues leading

to a modification in gingival contour.1 These clinical condi-

* Corresponding author at: Av. Montenegro, 160/701 – CEP: 90460-160, PE-mail address: [email protected] (E.J. Gaio).

Please cite this article in press as: Fernandes MI, et al. Effect of ni

ligature-induced periodontitis in rats. Archives of Oral Biology (201

0003–9969/$ – see front matter # 2010 Elsevier Ltd. All rights reservedoi:10.1016/j.archoralbio.2010.05.003

tions have been associated with anticonvulsants, immuno-

supressors and calcium channel blockers. Nifedipine is a

calcium channel blocker that has been widely used for

hypertension and angina pectoris.2 Nifedipine-influenced

gingival enlargement is the most common periodontal side

orto Alegre, RS, Brazil. Tel.: +55 51 32330434; fax: +55 51 32330434.

fedipine on gingival enlargement and periodontal breakdown in

0), doi:10.1016/j.archoralbio.2010.05.003

d.

mailto:[email protected]

http://dx.doi.org/10.1016/j.archoralbio.2010.05.003


a r c h i v e s o f o r a l b i o l o g y x x x ( 2 0 1 0 ) x x x – x x x2


effect of this medication affecting approximately 6% of

patients taking the medication.3 Nifedipine-influenced gingi-

val enlargement has been characterised by an increase of

gingival fibroblasts and extracellular matrix of the connective

tissue, with various degrees of chronic inflammatory infil-

trate.4,5 The pathogenesis of this gingival condition remains

largely unknown, but nifedipine-influenced gingival enlarge-

ment has been associated with drug dosage and length of use,

concomitant medications, dental biofilm, periodontal inflam-

mation, demographics and genetic factors.5–7

Gingival enlargement has been clearly associated with

nifedipine use and the presence of biofilm, with plaque control

reducing the severity of the condition.8 In contrast, the role of

nifedipine and dental biofilm on destructive periodontal

disease has been investigated in few studies with conflicting

results. Goncalves et al.9 using a ligature-induced periodontitis

model did not find a significant effect of nifedipine on alveolar

bone loss, whereas Spolidorio et al.10 observed a decreased

alveolar bone density after the use of nifedipine without the

placement of ligatures. Recently, an epidemiological study

found greater periodontal attachment loss/bone loss in

patients using nifedipine.11 The biological plausibility for a

possible relationship between nifedipine use and periodontal

destruction remains unknown, but it might be related to its

effect on bone metabolism and deeper periodontal pockets

favouring pathogenic bacteria.10,11 A consensus report of the

editors of the American Journal of Cardiology and Journal of

Periodontology published in July 2009 stated that ‘‘there are no

specific reports of the effect of calcium channel blockers on

the severity of periodontitis’’.12 Thus, scarce information is

available regarding the role of nifedipine in the destruction of

the periodontal tissues in face of an established microbial

challenge. The experimental hypothesis of the present study

was that nifedipine would cause gingival enlargement and

increase ligature-induced periodontal destruction. The aim of

the present study was to evaluate the effect of nifedipine on

gingival enlargement and periodontal breakdown in ligature-

induced periodontitis in rats.

2. Materials and methods

2.1. Animals

Fifty male, 60 days old, Wistar rats, weighting between 144 and

170 g, were used in the present study. Five rats were housed in

each cage and kept at approximately 20 8C in a 12 h light and

dark cycle. Animals received standard soft diet and water ad

libitum. The study protocol was approved by the Research

Ethics Committee, Faculty of Dentistry, Federal University of

Rio Grande do Sul, Brazil.

2.2. Experimental procedures

Experimental periodontitis was established by the placement

of cotton sutures (Ethicon1, 4-0, Johnson & Johnson1, Sao

Paulo, Brazil) around the upper second molars.13–16 A lingual

knot was used to secure sutures in place. Special care was

taken to avoid injuries to the periodontal tissues during

ligature placement. Ligatures were checked weekly for 30 days



and no ligatures needed replacement. Test groups received

nifedipine (Adalat1, Bayer1, Sao Paulo, Brazil) or saline

solution via gastric gavage (BD1, Sao Paulo, Brazil) for 30

days. Nifedipine was administered daily according to experi-

mental group dose. Nifedipine dosage was adjusted weekly

according to body weight.

2.3. Experimental groups

Animals were randomly assigned to one of six experimental

groups according to presence of ligature and nifedipine use.

Two groups of 10 rats did not receive ligatures (LIG�) and

received either saline solution (NIF0) or nifedipine 50 mg/kg/

day (NIF50). Two groups of 10 rats received ligatures (LIG+) and

were treated with saline solution (SAL) or nifedipine 50 mg/kg/

day (NIF50). These four experimental groups (LIG� NIF0, LIG�NIF50, LIG+ NIF0 and LIG+ NIF50) constituted the main focus of

the present investigation. Two additional groups of 5 rats each

were included to provide some insight in a possible dose–

response relationship between nifedipine dosage and gingival

enlargement and periodontal destruction. These animals

received ligatures at baseline and were treated with nifedipine

at 10 (LIG+ NIF10) or 100 mg/kg/day (LIG+ NIF100) for 30 days.

Thus, the animals were randomly assigned to one of the

following experimental groups:

LIG� NIF0 – no ligature + saline solution (n = 10).

LIG� NIF50 – no ligature + nifedipine 50 mg/kg/day (n = 10).

LIG+ NIF0 – ligature + saline solution (n = 10).

LIG+ NIF10 – ligature + nifedipine 10 mg/kg/day (n = 5).



2.4. Laboratory procedures

Immediately after sacrifice, the maxillae were removed and

fixated in 10% buffered formalin for a period of 48 h. Then,

specimens were decalcified by Anna Morse solution (20%

Sodium Citrate plus 50% Formic Acid) during approximately 40

days. Decalcified specimens were histologically processed. At

the moment of inclusion, the distal surface of the second

molar was placed perpendicular to the cutting plan. Slices

were performed in a microtome (E. Leitz1, Hessen, Germany)

in the buccal-lingual direction with 5 mm thickness until

reaching the region of the teeth. Each block provided three

sections collected every 20 mm. Staining was performed with

standard hematoxylin–eosin technique (Pro-Cito1, Porto

Alegre, Brazil).

2.5. Histological analysis

The histological analysis was performed by two masked

examiners and it was restricted to the buccal aspect of the

upper second molar. Digital images were obtained using a 4

megapixels digital camera (Coolpix1, Nikon1, Ayuthaya,

Thailand) attached to an optical microscope (Zeiss1, Turıngia,

Germany). The focal distance used was 4� and the speed was

set to 1/60. A microscopic calibration scale was photographed

with a known measure using the same lens to convert data

from pixels to micrometers.




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The following inclusion criteria were used to select the

most central histological section for histological analysis:

presence of coronal and radicular portions of the upper second

molar, evident cementoenamel junction (CEJ) and intact

alveolar bone crest. Additionally, periodontal tissues should

not have alterations resulting from the histological proces-

sing.

2.6. Descriptive histological analysis

Characteristics of oral, sulcular and junctional epithelia were

assessed by recording the presence of epithelial crests,

keratin, intercellular spaces and hydropic degeneration. In

the connective tissue, inflammatory infiltrate and the rela-

tionship between the junctional epithelium and CEJ were

evaluated.

2.7. Histometric evaluation

The following linear and area measurements were performed

(a) internal epithelium area: the area of the junctional

epithelium from its most apical portion was added to

the area of the sulcular epithelium until the most marginal

portion of the sulcular epithelium that clearly divided it in

internal and oral epithelia;

Fig. 1 – Representative photomicrographs of the experimental g

saline solution; NIF50 nifedipine 50 mg/kg/day for 30 days. Stai



(b) oral epithelium area: the measurement started at the

transition between oral and internal epithelia and extend-

ed apically to the point corresponding to the junctional

epithelium base;

(c) total connective tissue area: comprised the entire area of

gingival connective tissue until the most apical portion of

the inflammatory infiltrate related to the junctional

epithelium base;

(d) inflamed connective tissue area: corresponded to the area

gingival connective tissue presenting vascular alterations

and inflammatory infiltrate;

(e) alveolar bone loss: the distance from the cementoenamel

junction (CEJ) to the alveolar bone crest;

(f) gingival thickness: the distance from the cementoenamel

junction to the most external portion of the oral epitheli-

um;

(g) gingival height: the distance from the junctional epitheli-

um base to the gingival margin.

2.8. Statistical analysis

Mean and standard deviations were calculated and reported.

Area and linear measurements were compared between

groups by ANOVA. The alpha level was set to 5% and statistical

significance was adjusted for multiple comparisons using the

Bonferroni method.

roups: LIGS no ligatures; LIG+ ligatures for 30 days; NIF0

n: hematoxylin–eosin. Magnification: 100T.






3. Results

One animal was excluded from the study due to an oral

abscess (LIG� NIF0 group) and two animals were lost due to

histological processing of the specimens (LIG�NIF50 and LIG+

NIF0 groups). Representative photomicrographs of the experi-

mental groups are presented in Fig. 1. LIG� NIF50 group

demonstrated a thicker internal epithelium in four of nine rats

that did not allow for an obvious differentiation between

sulcular and junctional epithelia. The junctional epithelium

remained with the base attached to the cementoenamel

junction. All animals that had ligatures placed (LIG+) demon-

strated microscopic attachment and bone loss. The pocket

epithelium showed ret pegs in different points of its extension

and signs of hydropic degeneration. Another detail to be

emphasised was the increase in thickness of the keratin layer

as compared to animals that did not receive ligatures (LIG�).

LIG+ NIF50 group presented an alteration of the gingival

margin to a rectangular structure with the formation of a

tissue plateau as the major morphological characteristic. This

alteration was associated with connective tissue growth. This

tissue presented a chronic inflammatory infiltrate (lympho-

cytes and plasma cells) more concentrated in the pocket

internal side, but extending to the oral epithelium. The

external epithelium presented abundant and deep epithelial

projections.

The results of quantitative histologic analysis are shown in

Tables 1 and 2. No significant differences were observed

between experimental groups that did not receive ligatures

with regards to all parameters analysed. This indicates that

the use of nifedipine alone was not sufficient to promote

Table 1 – Internal and oral epithelium, total and inflamed conligature placement and nifedipine use.

Groupsa Epithelium

InternalMean (SD)

OralMean (SD)

LIG� NIF0 18,479.6 (5231.8)A 31,890.2 (9117.4

LIG� NIF50 16,782.6 (4025.5)A 31,359.2 (8514.9

LIG + NIF0 37,576.4 (11917.4)B 54,098.1 (18286

LIG + NIF50 60,798.5 (12036.7)C 66,014.4 (29780

Means followed by the same capital letters were not statistically differen

significantly different ( p < 0.05).a LIG� no ligatures; LIG+ ligatures for 30 days; NIF0 saline solution; NIF5

Table 2 – Bone loss, gingival thickness and height linear meanifedipine use.

Groupsa Bone lossMean (SD)

LIG� NIF0 222.0 (29.5)A

LIG� NIF50 217.6 (27.0)A

LIG + NIF0 503.6 (122.5)B

LIG + NIF50 562.1 (55.4)B

Means followed by the same capital letters were not statistically differen

significantly different ( p < 0.05).a LIG� no ligatures; LIG+ ligatures for 30 days; NIF0 saline solution; NIF5



gingival enlargement or periodontal destruction in the

absence of the ligature. The group that received only ligatures

(LIG+ NIF0) exhibited significantly higher gingival enlargement

and periodontal destruction than the non-ligated groups

regardless the use of nifedipine (LIG� NIF0 and LIG� NIF50

groups). In this regard, LIG+ NIF0 group had approximately two

to three folds higher area of internal (p < 0.01) and oral

epithelium (p < 0.05), and total (p < 0.01) and inflamed

( p < 0.01) connective tissue than groups without ligature.

Compared to the LIG� NIF0 and LIG� NIF50 groups, the CEJ-

bone crest distance was 2.3 times greater for the LIG+ NIF0

( p < 0.01).

The group that received ligatures and nifedipine 50 mg/kg/

day (LIG+ NIF50) showed significantly higher gingival enlarge-

ment and periodontal destruction than groups that did not

receive ligatures irrespective of the use of nifedipine (Tables 1

and 2). Compared to animals that received ligatures alone

(LIG+ NIF0), the LIG+ NIF50 group showed significant higher

estimates for internal epithelium (p < 0.01), total (p < 0.01)

and inflamed (p < 0.01) connective tissue, gingival thickness

( p < 0.01) and height (p < 0.01). No significant differences were

observed oral epithelium and CEJ-bone crest distance between

these groups. Collectively these findings indicate that nifedi-

pine has an effect on soft tissue and inflammatory reaction

when large amount of plaque is present.

The results of the dose–response analysis between nifedi-

pine dosage and tissue response to ligature-induced peri-

odontitis are shown in Figs. 2 and 3. Overall the results showed

that a dosage of 10 mg/kg/day (LIG+ NIF10) did not elicit

gingival enlargement and periodontal destruction beyond

what was observed with the use of ligatures only (LIG+ NIF0).

nective tissue area measurements, in mm2, according to

Connective tissue

TotalMean (SD)

InflamedMean (SD)

)A 38,178.6 (11596.3)A 8,764.5 (2442.5)A

)A 38,505.6 (10897.0)A 7,888.7 (1766.1)A

.2)B 82,621.5 (29472.4)B 26,645.2 (7223.6)B

.3)B 118,213.0 (16341.3)C 40,510.5 (9632.5)C

t ( p > 0.05), whereas means followed by different capital letters were

0 nifedipine 50 mg/kg/day for 30 days.

surements, in mm, according to ligature placement and

Gingival thicknessMean (SD)

Gingival heightMean (SD)

386.1 (54.4)A 441.3 (59.0)A

387.5 (65.2)A 438.6 (68.0)A

566.4 (96.3)B 503.9 (122.2)B

712.3 (81.4)C 667.9 (91.0)C

t ( p > 0.05), whereas means followed by different capital letters were

0 nifedipine 50 mg/kg/day for 30 days.




Fig. 2 – Internal and oral epithelium, total and inflamed connective tissue area measurements (in mm2) in experimental

groups that received ligatures (LIG+) according to nifedipine dosage (NIF0 – saline solution; NIF10 – nifedipine 10 mg/kg/day;

NIF50 – nifedipine 50 mg/kg/day; NIF100 – nifedipine 100 mg/kg/day).

Fig. 3 – CEJ-bone crest distance, gingival thickness and height measurements (in mm) in experimental groups that received

ligatures (LIG+) according to nifedipine dosage (NIF0 – saline solution; NIF10 – nifedipine 10 mg/kg/day; NIF50 – nifedipine

50 mg/kg/day; NIF100 – nifedipine 100 mg/kg/day).



Similarly the 100 mg/kg/day dose did not yield greater gingival

enlargement or periodontal destruction than the 50 mg/kg/

day dose suggesting a plateau effect.

4. Discussion

The main objective of this study was to evaluate the effect of

nifedipine on gingival enlargement and periodontal break-

down using a ligature-induced periodontitis rat model. The

test group that received nifedipine 50 mg/kg/day in combina-

tion with ligature-induced microbial challenge exhibited

statistically significant greater gingival enlargement than

the control group that received only ligatures. In contrast,

nifedipine did not increase alveolar bone loss further than

what was observed by the sole use of ligatures. The

administration of nifedipine 50 mg/kg/day did not cause

gingival enlargement in ligature-free animals.

Nifedipine clearly induced gingival enlargement in animals

that were subjected to microbial challenge. Compared to LIG+

NIF0, LIG+ NIF50 had significantly greater gingival thickness

and height. Increased gingival dimensions in the LIG+ NIF50

group could be explained by larger internal epithelium, total



and inflamed connective tissue area. Collectively, these

findings indicate that bacterial challenge may modify the

effect of nifedipine on the periodontal tissues. Few studies

have evaluated nifedipine-influenced gingival enlargement

after bacterial challenge using this animal model. In a split-

mouth design study, Fu et al.8 observed that teeth with

ligatures presented a statistically significant increase in the

volume of epithelial and connective tissue, as well as in the

inflammatory infiltrate and in the total gingival tissue area

when compared to contralateral control teeth. Morisaki et al.17

observed that germ-free rats infected with a strain of

Streptococcusmutans had greater nifedipine-influenced gingival

enlargement than germ-free controls. These findings are in

agreement with human studies that observed that accumula-

tion of dental plaque increases the severity of gingival

enlargement.1,18,19

Conflicting results regarding the effect of nifedipine on

periodontal destruction in animal models have been recently

published. Using ligature-induced periodontitis model, Gon-

calves et al.9 did not find a significant effect of nifedipine and/

or cyclosporine A on alveolar bone loss indicating that

nifedipine did not have a detrimental effect on periodontal

status. These findings are in accordance with the present






study that did not observe significant differences in alveolar

bone loss in ligature-induced periodontitis after nifedipine

use. Spolidorio et al.10 observed a decreased alveolar bone

density after the use of nifedipine combined or not with

cyclosporine without the placement of ligatures. In contrast,

the present investigation did not found significant differences

in alveolar bone loss after nifedipine administration in

animals that did not receive ligatures. In recent epidemiologi-

cal study, Li et al.11 also did not find an increased risk for

periodontal destruction in subjects taking nifedipine.

Some study characteristics may explain, at least in part, the

conflicting results observed in the above-mentioned studies.

Whereas the same nifedipine dose of 50 mg/kg/day was used

by our research group as well as by Goncalves et al.9 and

Spolidorio et al.10 different administration methods may have

had unknown impact on the seric levels of the drug.

Additionally, previous studies have shown that nifedipine

effect is time dependent.2,20,21 Nifedipine was administrated,

respectively, for 30 and 45 days in the present and Goncalves

et al.9 study, whereas it was used for 60 days by Spolidorio

et al.10 Age has also been identified as an effect modifier for

nifedipine with younger animals having higher chance of

having gingival enlargement.20,22,23 Sixty days old animals

were presently used and, based on the reported weight of the

animals at the beginning of the study, Goncalves et al.9 also

used older animals. Nevertheless, age did not seem to affect

the relationship between alveolar bone density and nifedipine

use without the placement of ligatures.10 Thus, the present

effect of age on the effect of nifedipine on alveolar bone loss is

unclear.

In the present study, the sole use of nifedipine was not

sufficient to induce gingival enlargement. In contrast, several

studies using a similar animal model observed nifedipine-

influenced gingival enlargement without the use of liga-

tures.2,10,17,21–26 Nifedipine dosage and length of use are

possible explanations for the discrepancy between this and

other studies.20 Studies with shorter experimental periods

used higher nifedipine dosage.2,25 Another factor that may

have influenced the outcome of the study is the inherent

biological reactivity of younger animals.20 Ishida et al.22 and

Spolidorio et al.23 observed an inverse relationship between

gingival enlargement and age with younger animals showing

greater nifedipine-influenced gingival enlargement. This

finding is in accordance with other studies that have also

observed increased gingival enlargement after the sole use of

nifedipine in very young rats.2,21,25–27

In order to get some insight into a possible dose–response

effect of nifedipine on gingival enlargement and periodontal

breakdown, two additional dosages of nifedipine were used in

combination with ligatures in a small group of animals. No

consistent differences were observed between groups indicat-

ing that low doses of nifedipine may have very limited effect

on the periodontal tissues and no additional effect of

nifedipine can be achieved with dosages greater than

50 mg/kg/day. These results are in contrast with Chiu

et al.24 and Fu et al.5 that observed a dose-dependent

relationship between nifedipine dose and gingival enlarge-

ment in the absence of ligatures.

It can be concluded from the present investigation that

nifedipine alone was not sufficient to elicit gingival enlarge-



ment and periodontal destruction in this rat model. However,

nifedipine induced greater gingival enlargement and inflam-

matory response when ligatures were used to accumulate

bacterial plaque. Nifedipine does not seem to be directly

associated with periodontal breakdown.

Acknowledgements

Funding: The present study was partially funded by the

National Council for Scientific and Technological Develop-

ment (CNPq), Ministry of Science and Technology, Brazilia, DF,

Brazil.

Competing interests: The authors declare that they have no

conflict of interest.

Ethical approval: The protocol was approved by the

Research Ethics Committee, Faculty of Dentistry, Federal

University of Rio Grande do Sul, Brazil.

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