Jpn. J. Oral Biol.,40: 497-505, 1998.

ORIGINAL

The blocking effects of tolazoline and on axial movements of incisor teeth and on changes in arterial blood pressure induced by in rats

Hiroko Yamazaki and Shizuyo Yamaguchi

Department of Pharmacology, School of Dental Medicine, Tsurumi University

2-1-3 Tsurumi, Tsurumi-ku, Yokohama 230-8501, Japan

〔Received on June 26, 1998; Accepted on August 3, 1998〕

Key words: adrenaline/ blocker/tooth movement/rat incisor/blood pressure

Abstract: Axial tooth movements and arterial blood pressure were measured following intravenous injec-

tion of adrenaline,1hr before, and 1 and 2hr after the injection of tolazoline (an α-adrenergic blocking

agent) or propranolol (a β-adrenergic blocking agent). The initial increase in blood pressure induced by

adrenaline was significantly suppressed and the successive decrease in blood pressure was markedly

enhanced by pretreatment with tolazoline. In contrast to blood pressure changes, the initial extrusive tooth

movement induced by adrenaline was not suppressed, and successive intrusive tooth movements induced by

adrenaline were not potentiated, but suppressed. The initial increase in blood pressure induced by adrenaline

was enhanced and the successive decrease in blood pressure was suppressed by pretreatment with pro-

pranolol. On the other hand, the initial extrusive tooth movement induced by adrenaline was not significantly

potentiated, but successive intnsive tooth movements induced by adrenaline were markedly suppressed.

Pressure within the socket that may induce axial tooth movements might be regulated by various factors,

such as resistance of the blood vessels, blood flow in the socket, and systemic arterial blood pressure, all of

which are liable to change following an injection of adrenaline under the influence of α-or β-adrenergic

blockers.

抄 録:本 研 究 に お い て は ア ドレ ナ リ ン投 与 に よ る ラ ッ ト全身 血 圧 の変 動 と下 顎 切 歯 の 動 き に対 す る トラ ゾ リ ン (α 遮 断 薬)と プ ロ プ ラ ノ ロー ル(β 遮 断 薬)前 投 与 の 影 響 を調 べ た 。 トラ ゾ リ ン前 投 与 に よ り,ア ドレ ナ リ ン に よ る 初 期 の 血 圧 上 昇 は有 意 に抑 制 さ れ,そ れ に続 く血 圧 下 降 は著 明 に促 進 さ れ た 。 一 方,ア ド レ ナ リ ン に よ る 初 期 の 歯 の 突 出 運 動 は 抑 制 され ず,そ れ に続 く歯 の 引 込 み 運 動 は促 進 さ れ な か っ た 。 プ ロ プ ラ ノ ロ ー ル 前 投 与 に よ り血 圧 上 昇 は促 進 され,血 圧 下 降 は ほ ぼ 完 全 に 抑 制 され た 。 一 方,歯 の 突 出運 動 は 促 進 さ れ ず,引 込 み 運 動 は 著 明 に 抑 制 され た 。以 上 の 結 果 か ら,ア ド レナ リ ン に よ る 全 身 血 圧 の上 昇 は α 遮 断 薬 に よ り抑 制 さ れ β 遮 断 薬 に よ り促 進 さ れ る こ と,血 圧 下 降 は α 遮 断 薬 に よ り促 進 され β 遮 断 薬 に よ り抑 制 さ れ る こ とが 判 明 した 。一 方,歯 の 突 出運 動 お よ び 引 込 み 運 動 は,全 身 血 圧 変 動 と必 ず し も一 致 しな い こ とが 判 明 し た 。 歯 の 動 き を 引 き起 こす と考 え ら れ る顎 骨 内 の 圧 力 変 化 は,全 身 血 圧 の み な らず,血 管 抵 抗 性,血 流 量 な ど さ ま ざ まな 要 因 に よ り調 節 さ れ て いる可能性が示唆された。 498 Jpn. J. Oral Biol.,40: 497-505,1998.

movement and adrenergic receptors. Introduction Materials and Methods Adrenaline induces a dose-dependent rapid extrusivemovement of the rat incisoralmost simulta- 1. Animals neously with an increasein systemic arterialblood Male Wistar rats (n=20), weighing 321 to 357g at pressure,followed by intrusivetooth movement and a 10 to 13 weeks of age, were divided into two equal decrease in blood pressure1).We previouslysuggested groups. They were immobilized by the method de- that extrusivetooth movement is primarilyrelated to scribedpreviously9). In brief,the rats were placed in a the risein arterialblood pressuredue to stimulationof supine positionand anesthetizedvia inhalationof 1.1 vascular α-adrenergic receptors and that stimulation % halothane in air through a trachealtube connected of β-adrenergic receptors in the localized vasculature to an artificialrespirator at 100 strokes/min (3ml/ within the incisor socket causes a reduction in pres- stroke). The lower margin of the jaw bone was surgi- sure and blood volume, followed by marked intrusive cally exposed and secured with a hemostat, which was tooth movement1). affixed to the metal bar of a magnetic stand with

Aars2) and Aars and Linden3) reported that sympa- acrylic resin. Each rat was administered atropine thetic nerve stimulation induces intrusive tooth move- sulfate (25μg) before the operation to prevent tra- ment by altering blood pressure and volume in the cheal secretion. Rectal temperature was maintained periodontal ligament of the rabbit incisor and cat at 35℃ using a heating pad during the experimental canine. They suggested that these responses are period. A polyethylene tube was inserted into the left mediated by α-adrenergic receptors because intrusive hind leg vein; through which, drugs were administer- tooth movement is greatly reduced by injection of the ed to each rat at 1-hr intervals.

α-adrenergic blocking agent, . Adminis- tration of noradrenaline, a potent stimulator of α- 2. Administration of drugs

adrenergic receptors4), also induces intrusive tooth Two experiments were performed as follows. movements in the rabbit incisor5,6) and in the cat Experiment 1. In one group of 10 rats, each animal canine7). was given an intravenous injection of 1mg/kg body

In addition, β-adrenergic antagonists induce a wt of tolazoline, a known α1-and α2-adrenergic recep- marked extrusion of the tooth8). Aars8) suggested that tor blocker (Imidaline, Yamanouchi Seiyaku Co., a reduction in β-adrenergic tone leads to a rise in Tokyo). One hour before (control), and 1 and 2hr pressure and volume in the vessels within the per- after the injection of tolazoline, each animal was iodontal ligament and, therefore, to extrusion of the given intravenous injections of adrenaline (1μg/kg) rabbit incisor. Furthermore, subsequent injection of (Daiichi Seiyaku Co., Tokyo). , a potent stimulator of β-adrenergic recep- Experiment 2. In the other group of 10 rats, each tors, always induces rapid intrusions of the teeth. animal was given an intravenous injection of pro-

Nevertheless, the precise relationship between pranolol (2mg/kg), a known β1-and β2-adrenergic extrusive or intrusive tooth movements and stimula- receptor blocker (Sigma, St. Louis , MO, U.S.A.). As tion or inhibition of vascular α-and β-adrenergic in Experiment 1, 1hr before (control) , and 1 and 2hr receptors in continuously erupting incisors remains after the injection of propranolol, each animal was unclear. given intravenous injections of adrenaline (1μg/kg).

The purposes of the present study were to investi- In both Experiments 1 and 2, the drugs were dissolved gate the effects of adrenaline on axial movements of in physiological saline. The volume of injected solu- the rat mandibular incisor and arterial blood pressure tions was 0.1ml/100g body weight. in rats pretreated with α-or β-adrenergic blocking drugs, and to elucidate the relationship between tooth H. Yamazaki, et al.: Adrenergic blockers and tooth movement 499

3. Axial movements of the incisor intervals during the experimental period. Axial movement of the leftmandibular incisorwas measured by a non-contacting displacement detec- 5. Maximum tooth movement and blood pressure tor; that is, the movement of a thin metal plate change attachedto the toothsurface was recorded9).Data was Tooth positions at the maximum extrusive move- fed into a computer (PC-9801DA; NEC, Tokyo) at ment (peak point), maximum intrusive movement 1-sec intervals.The values recorded by the detector (bottom point), and recovery (recovery point), and were correctedfor the curvatureof the incisorand the arterial blood pressures at the maximum increase radial distance between the tooth surface and the (peak point),maximum decrease (bottom point),and metal plate9). recovery (recovery point) were examined following injectionsof adrenaline before and after an injection 4. Arterial blood pressure of tolazoline or propranolol. Arterialblood pressure was measuredusing a pres- suretransducer (MP-15, Micron Instruments,CA, U. 6. Statisticalanalysis S.A.); thatis, a polyethylenetube was insertedinto Differencesof the mean values were compared by the mid-tailartery; and throughwhich ,the pressure Scheffe'smethod for multiplecomparisons afteranal- was recorded.The arterialblood pressurewas fed ysisof variance (ANOVA). intoa computer (PC-9801DA; NEC, Tokyo) at 1-sec

Fig. 1 Records of tooth displacement (upper column) and arterial blood pres-

sure (lower column) following the injection of adrenaline, 1hr before

(control), and 1 and 2hr after the injection of tolazoline (α-adrenergic

blocking agent). Points (arrow heads) a, b, and c indicate peak, bottom, and recovery of the tooth displacement, respectively; points a',b', and c', indicate peak, bottom, and recovery of the arterial blood pressure, respectively. Arrows indicate the time of drug injection (designated as 0 min). Each curve was obtained from combined values for ten animals . 500 Jpn. J. Oral Biol., 40: 497-505, 1998.

suppressive effect of tolazoline.After the injectionof Results tolazoline,the initialincrease in arterial blood pres- sure by adrenaline was markedly suppressed, but a 1. Effects of tolazoline on tooth displacement successive decrease in blood pressure was markedly and changes in arterialblood pressure induced enhanced both at 1 and 2hr. by adrenaline Figure 1 shows records of tooth displacement and 2. Effects of propranolol on tooth displacement arterial blood pressure following the injection of and changes in arterialblood pressureinduced adrenaline,1hr before (control),and 1 and 2hr after by adrenaline the injection of tolazoline.Before the injection of Figure 2 shows records of tooth displacement and tolazoline, adrenaline induced an initialextrusive arterialblood pressure following the injectionof movement of the incisor and an increase in arterial adrenaline,1hr before (control),and 1 and 2hr after blood pressure. Then, a marked intrusivetooth move- the injectionof propranolol.Effects of adrenalineon ment and a decrease in arterialblood pressure occur- tooth movement, and on arterialblood pressurewere red. One hour after the injection of tolazoline,the similar before the injection of α-and β-adrenergic initial extrusive tooth movement by adrenaline blockers (control). One hour after the injection of appeared to be slightlyenhanced, however, successive propranolol, the initial extrusive tooth movement by intrusive movement was obviously suppressed. At 2 adrenaline appeared to be similar to that of the con- hr, the extrusive tooth movement was similar to that trol but a successive intrusive movement was marked- at 1hr, and the intrusivetooth movement was slightly ly suppressed. At 2hr, the extrusive tooth movement greater than that at 1hr, indicatingrecovery from the was similar to that at 1hr, and the intrusive tooth

Fig. 2 Records of tooth displacement (upper column) and arterial blood pressure

(lower column) following the injection of adrenaline, 1hr before (control),

and 1 and 2hr after the injection of propranolol (β-adrenergic blocking

agent). Peak, bottom, and recovery points were determined as in Fig. 1.

Each curve was obtained from combined values for ten animals. H. Yamazaki, et al.: Adrenergic blockers and tooth movement 501

Fig. 4 Graph showing α-or β-adrenergic blocking effects

on maximum tooth displacements. a and b repre-

sent the maximum values of extrusive and intru-

sive tooth movements, respectively. The intrusive

tooth movements are represented as negative fig- Fig.3 Changes in toothdisplacement (upper column) and ures. Mean±SD is shown in each column. Signifi- cant differences between the control and 1 or 2hr arterialblood pressure(lower column) following the injectionof tolazolineor propranololalone. values, *p<0.01 and **p<0.001. Each curvewas obtainedfrom combinedvalues for ten animals. the tooth returned to the initial level within approxi-

mately 40 min. Arterial blood pressure decreased

immediately (-25 .7mmHg), and returned to the movement was slightlygreater than that at 1hr , initial level within approximately 10 min . Following

indicatingrecovery from the suppressiveeffect of the injection of propranolol, a very slight and tempo-

propranolol.After the injectionof propranolol,an ral intrusive tooth movement (-1 .3μm) was obser- initialincrease in arterialblood pressure by ved, followed by a continuous extrusive tooth move-

adrenaline was obviously enhanced, however, succes- ment. Arterial blood pressure decreased slightly and

sive decrease in blood pressure was markedly suppres- temporarily (-19.8mmHg), and remained almost sed at both 1 and 2hr. constant at a slightly lower level thereafter .

3. Changes in tooth displacement and arterial 4. α-or β-adrenergic blocking effects on maxi-

blood pressure following injection of tol- mum tooth displacement azolineor pmpranolol alone Effects of pretreatment with α-or β-adrenergic Figure 3 shows changes in tooth displacement and blocking agents on maximum tooth displacement in- arterial blood pressure following the injection of tol- duced by adrenaline are shown in Figure 4. Control azoline or propranolol alone; the observation was values were not significantlydifferent between the performed for approximately 40 min. Following the tolazoline-and propranolol-injected groups . Pretreat. injection of tolazoline, a slight extrusive tooth move- ment with either tolazoline or propranolol had no ment (2.1μm; the mean value is shown in parenthe- significanteffect on the initialextrusive movement of ses hereafter) was observed followed by a gentle the incisorat 1 and 2hr afterthe injection.On the intrusive tooth movement (-6.9μm); the position of other hand, the maximum intrusive tooth movement 502 Jpn. J. Oral Biol.,40: 497-505,1998.

with propranolol and the maximum decreases in blood pressure were markedly suppressed at 1 and 2hr (p< 0.001,Scheffe's method).

Discussion

In the present experiment, the doses of tolazoline,

propranolol, and adrenaline were determined accord- ing to previous reports on experimental animals such

as dogs, piglets, rabbits, and rats1,8,10～12) and our pre-

liminary observations (unpublished data). The time

between administratien of a-or β-adrenergic block-

ers and adrenaline was also determined according to

our preliminary observations, when arterial blood

Fig .5 Graph showing α-or β-blocking effects on arterial pressure and tooth movement appeared to have

blood pressure. a' and b' represent the maximum recovered from the single effects of α-or β-adrener- values of the increase and decrease of arterial gic blockers (Fig. 3). Thus, the doses of tolazoline, blood pressure, respectively. The decreases in propranolol, and adrenaline, and the time intervals blood pressure are represented as negative figures. between administration of the blockers and adrenaline Mean±SD is shown in each column. Significant were appropriate in the present study. differences between the control and 1 or 2hr val-

ues, *p<0.01 and **p<0.001. There have been several reports that tolazoline decreases systemic arterial blood pressure11,13,14).

Blockade of α1-adrenergic receptors inhibits vasocon- induced by adrenaline after pretreatment with tol- striction induced by endogenous catecholamines; azoline was significantlyless than the control value vasodilatation may occur in both arteriolar resistance

(p<0.01, Scheffe'smethod) at 1hr but not at 2hr. The vessels and veins resulting in a fall in blood pressure maximum intrusive tooth movements induced by because of decreased peripheral vascular resistance15). adrenaline were markedly suppressed (p<0.001, In the present study, an immediate and temporal

Scheffe's method) at 1 and 2hr after pretreatment decrease in arterial blood pressure was observed after with propranolol. the injection of tolazoline alone (Fig. 3),due perhaps

to the blockade of α-adrenergic receptors and reduc-

5. α-or β-adrenergic blocking effects on arte- tion of the peripheral resistance. Decrease in vascular

rial blood pressure resistance within the socket may reduce internal

Effects of pretreatment with α-or β-adrenergic pressure within the socket, thereby inducing gentle blocking agents on adrenaline-induced changes in intrusive tooth movement (Fig. 3). arterial blood pressure are shown in Figure 5. The Tolazoline effectively blocks the pressor action of maximum increases in arterial blood pressure were adrenaline in experimental animals16,17) and this effect markedly suppressed at 1 and 2hr (p<0.001, Scheffe's is produced by blocking the peripheral vasoconstrict- method) and the maximum decreases in blood pres- ing action of adrenaline18). When α-adrenergic recep- sure were significantly enhanced at 1 and 2hr (p<0. tors are blocked by tolazoline, excess adrenaline acts

001 and p<0.01, Scheffe's method, respectively) after on the β-adrenergic receptors and potentiates the fall pretreatment with tolazoline. On the other hand, the in blood pressure19). In the present study , an initial maximum increases in arterial blood pressure induced adrenaline-induced increase in arterial blood pressure by adrenaline were significantly enhanced at 1 and 2 was effectively suppressed and a successive decrease hr (p<0.001, Scheffe's method) after pretreatment in blood pressure was markedly enhanced by pretreat- H. Yamazaki, et al.: Adrenergic blockers and tooth movement 503 ment with tolazoline, as expected (Figs 1 and 5). transient vasodilatation and then subsequent sus-

In contrast to blood pressure changes, the initial tained vasoconstriction31),it is possiblethat a decrease extrusive tooth movement induced by adrenaline was of cardiac output and initialtransient vasodilatation not suppressed by pretreatment with tolazoline (Figs by the drug causes a temporal decrease of blood 1 and 4). Pretreatment with tolazoline causes a pressure. An almost immediate increase of extrusive decrease in peripheral vascular resistance and an tooth movement, however, was observed following the increase in blood flow14,20～23). In the present experi- injection of propranolol alone (Fig.3). Aars8) has ment, immediately after the injection of adrenaline, reportedthat propranololinduced a marked extrusion we observed a very slight and temporal increase in of the rabbit incisor,probably due to reduced systemic arterial blood pressure (Figs 1 and 5), in- vasodilatortone (or increasedvasoconstrictor tone) dicating an imperfect blockade of vascular α-recep- in periodontal postcapillaryblood vessels.If an tors. It is possible that such a slight increase in increaseof pressurewithin the socket was rapid and arterial blood pressure can cause a marked increase in predominant to a temporal decreaseof blood pressure,

pressure within the socket, particularly when blood an almost immediate extrusivetooth movement in the flow is increased by potentiation of cardiac β1-rece- rat incisorwould occur.

ptors and vascular β2-receptors, resulting in the Propranolol augments the pressor response to extrusive movement of the incisor. adrenaline28,29,32～35). In the present study, the initial

Although blood pressure decreased markedly, the increase in systemic arterial blood pressure induced successive adrenaline-induced intrusive tooth move- by adrenaline was enhanced and the successive

ment was not potentiated but rather suppressed in decrease in blood pressure was suppressed by

rats pretreated with tolazoline (Figs 1 and 4). It is pretreatment with propranolol (Figs 2 and 5). These

possible that the intrusive tooth movement was not results indicate that the pressor action of adrenaline

potentiated by the α-adrenergic blocker due to the due to stimulation of α-adrenergic receptors was

following reasons. Following the injection of potentiated and the depressor action due to stimula-

adrenaline, the pressure in the socket in rats pretreat- tion of β-adrenergic receptors was blocked by pro-

ed with tolazoline did not fall as much as that in the pranolol in our experiments.

control. It is suggested that the low compliant environ- The initial extrusive tooth movement induced by ment in the socket24,25) did not allow further dilatation adrenaline was not significantly potentiated by

of the vasculature, because the blood vessels in the pretreatment with propranolol (Figs 2 and 4). Follow- socket had already been sufficiently relaxed by theα- ing the injection of adrenaline, the pressure in the

adrenergic blocking action of tolazoline. We have no socket in rats pretreated with propranolol did not rise

direct evidence, however, supporting this hypothesis. significantly as compared with control rats, probably

The pressure within the socket could be regulated by because the vascular tone in the socket had been various factors such as the resistance of blood vessels, increased by the β-blocking action of propranolol blood flow in the socket, and systemic arterial blood before the injection of adrenaline. We do not have any pressure, all of which are liable to change following evidence, however, supporting this hypothesis. The the injection of adrenaline under influence of adrener- successive intrusive tooth movement induced by gic blockers. adrenaline was markedly suppressed by pretreatment

After the injection of propranolol alone, a temporal with propranolol. This result supports the view that decrease in blood pressure was observed (Fig. 3), intrusive tooth movement is closely related to the consistent with previous reports26-28). Propranolol stimulation of β-adrenergic receptors, as suggested decreases cardiac output due to blockade of cardiac by previous investigators1,8).

β1-receptors and increases peripheral resistance due to blockade of vascular β2-receptors15,29,30). Because it has been reported that propranolol initially causes a 504 Jpn. J. Oral Biol.,40: 497-505, 1998.

movements of rat mandibular incisorsmeasured Acknowledgements under artificialrespiration with halothane anaesthe- sia.Arch. Oral Biol.40: 269-274, 1995. We express our sinceregratitude to Professor M. 10) Tucker, A., Brown, D.T. and Greenless, K.J.: Chiba, Department of Pharmacology, Tsurumi Uni- Pulmonary and systemic vascular actions of tol- azoline in anesthetizeddogs. Pediatr. Pharmacol. versityfor his continuous guidance and encourage- 2: 231-243, 1982. ment. We also express our appreciationto Professor 11) Clozel,M, Hascoet, J.M., Monin, P. and Vert, P.: K. Seto,First Department of Oral and Maxillofacial Effectsof tolazolineon regionalblood flows in the Surgery, and Professor Y. Amemiya, Department of newborn piglet.Dev. Pharmacol. Ther. 10: 265 Dental Anesthesiology,Tsurumi University. -277, 1987. 12) Wappel, M., Zalewski, A., Savage, M., Hessen, S.,

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